Optimized extraction of 2-arachidonyl glycerol and anandamide from aortic tissue and plasma for quantification by LC-MS/MS.
Atherosclerosis is a disease characterized by plaque formation due to an accumulation of fat, cholesterol, and immune cells in the walls of arteries. If a plaque ruptures, an occlusive thrombosis may form that causes either a heart attack or stroke. Macrophages express CB-2 receptors, and are one type of immune cell that plays a role in plaque destabilization and rupture. Endocannabinoids anandamide (AEA) and 2-arachidonyl glycerol (2-AG) have been found to have activity on CB-1 and CB-2 receptors throughout the body and immune system. In this study, we investigated several sample preparation options for the LC-MS quantification of AEA and 2-AG from plasma and aortic tissue. The extractions considered included liquid-liquid (LLE), solid-phase (SPE), and supported liquid (SLE). Some extraction protocols yielded high analyte recovery and prevention of 1-AG/2-AG isomerization. Our results indicate that a liquid-liquid extraction using toluene yields the highest recovery for both analytes, coupled with low ionization suppression in the mass spectrometer. This extraction and corresponding LC-MS/MS assay provides a simple, high throughput mechanism for the quantification of 2-AG and AEA in matrices relevant to the study of endocannabinoids' role in atherosclerosis.


Stress and resilience in a post-Francis world - a qualitative study of executive nurse directors.
The aim of this study was to explore the role stressors experienced by executive nurse directors and strategies employed to maintain resilience. Recent financial pressures on and care quality scandals in the UK NHS impact on the work of executive nurse directors. The short length of tenure and the high number of vacancies for these posts point to the exacting demands of the role and raise questions about the support mechanisms available for the most senior nurses in NHS organizations. A grounded constructivist study. Semi-structured telephone interviews conducted between February-July, 2014. Stressors were both chronic (workload, lack of corporate responsibility for quality, reductions in quality team staffing, tensions between financial solvency and care quality and personal vulnerability) and acute (dealing with complaints and major incidents). Resilience required the support of fellow executives, peers, family and mentors and could be enhanced by self-discipline, good preparation for the post and ongoing coaching. Recent fiscal austerity and scandals relating to quality of care have increased pressure on executive nurse directors. Increasing size of organizations, limited resources devoted to quality combined with poorly defined limits of responsibility are all major stressors and executive nurse directors, both in the United Kingdom and internationally, need clear strategies to maintain resilience. Repetitive demands for data by oversight organizations may detract from more important quality assurance strategies.


A theoretical study of an unusual Y-shaped three-coordinate Pt complex: Pt(0) σ-disilane complex or Pt(II) disilyl complex?
The unusual Y-shaped structure of the recently reported three-coordinate Pt complex Pt[NHC(Dip)(2)](SiMe(2)Ph)(2) (NHC = N-heterocyclic carbene; Dip = 2,6-diisopropylphenyl) was considered a snapshot of the reductive elimination of disilane. A density functional theory study indicates that this structure arises from the strong trans influence of the extremely σ-donating carbene and silyl ligands. Though this complex can be understood to be a Pt(II) disilyl complex bearing a distorted geometry due to the Jahn-Teller effect, its (195)Pt NMR chemical shift is considerably different from those of Pt(II) complexes but close to those of typical Pt(0) complexes. Its Si···Si bonding interaction is ~50% of the usual energy of a Si-Si single bond. The interaction between the Pt center and the (SiMe(2)Ph)(2) moiety can be understood in terms of donation and back-donation interactions of the Si-Si σ-bonding and σ*-antibonding molecular orbitals with the Pt center. Thus, we conclude that this is likely a Pt(0) σ-disilane complex and thus a snapshot after a considerable amount of the charge transfer from disilane to the Pt center has occurred. Phenyl anion (Ph(-)) and [R-Ar](-) [R-Ar = 2,6-(2,6-iPr(2)C(6)H(3))(2)C(6)H(3)] as well as the divalent carbon(0) ligand C(NHC)(2) also provide similar unusual Y-shaped structures. Three-coordinate digermyl, diboryl, and silyl-boryl complexes of Pt and a disilyl complex of Pd are theoretically predicted to have similar unusual Y-shaped structures when a strongly donating ligand coordinates to the metal center. In a trigonal-bipyramidal Ir disilyl complex [Ir{NHC(Dip)(2)}(PH(3))(2)(SiMe(3))(2)](+), the equatorial plane has a similar unusual Y-shaped structure. These results suggest that various snapshots can be shown for the reductive eliminations of the Ge-Ge, B-B, and B-Si σ-bonds.


Do Low Molecular Weight Agents Cause More Severe Asthma than High Molecular Weight Agents?
The aim of this study was to analyse whether patients with occupational asthma (OA) caused by low molecular weight (LMW) agents differed from patients with OA caused by high molecular weight (HMW) with regard to risk factors, asthma presentation and severity, and response to various diagnostic tests. Seventy-eight patients with OA diagnosed by positive specific inhalation challenge (SIC) were included. Anthropometric characteristics, atopic status, occupation, latency periods, asthma severity according to the Global Initiative for Asthma (GINA) control classification, lung function tests and SIC results were analysed. OA was induced by an HMW agent in 23 patients (29%) and by an LMW agent in 55 (71%). A logistic regression analysis confirmed that patients with OA caused by LMW agents had a significantly higher risk of severity according to the GINA classification after adjusting for potential confounders (OR = 3.579, 95% CI 1.136-11.280; p = 0.029). During the SIC, most patients with OA caused by HMW agents presented an early reaction (82%), while in patients with OA caused by LMW agents the response was mainly late (73%) (p = 0.0001). Similarly, patients with OA caused by LMW agents experienced a greater degree of bronchial hyperresponsiveness, measured as the difference in the methacholine dose-response ratio (DRR) before and after SIC (1.77, range 0-16), compared with patients with OA caused by HMW agents (0.87, range 0-72), (p = 0.024). OA caused by LMW agents may be more severe than that caused by HMW agents. The severity of the condition may be determined by the different mechanisms of action of these agents.


Spontaneous healing of acute anterior cruciate ligament (ACL) injuries - conservative treatment using an extension block soft brace without anterior stabilization.
To evaluate the spontaneous healing capability of acute anterior cruciate ligament (ACL) injuries, conservative treatment was applied in a selected group of 31 patients, who had low athletic demands. Each patient demonstrated a continuous ACL on magnetic resonance imaging (MRI), from the original femoral attachment through the tibial attachment, and an area of high intensity was detected in the substance of the ACL. The injured knees were treated using an extension block soft brace without anterior stabilization for 2-3 months. KT-2000 and MRI examinations were carried out regularly during the follow-up. Twenty-three knees (74%) were revealed to be stable in the follow-up examination, with an average of 16.1 months elapsing since the initial injuries. The KT-2000 side-to-side differences of 20 knees were less than 3 mm, and those of the other 3 knees were more than 3 mm but less than 5 mm. MRI confirmed that 21 injured ACL out of 23 knees maintained a femoral to tibial attachment and showed gradual reductions in image intensity. The positions of the other 2 injured ACL femoral attachments were different from the original femoral attachment: one was attached to the posterior cruciate ligament, and the other was located at the lateral femoral condyle anterior to the original femoral attachment. Eight knees (26%) subsequently required ACL reconstructions due to instability. This study indicates that an acutely injured ACL has healing capability. It also suggests that conservative management of the acute ACL injury can yield satisfactory results in a group of individuals who have low athletic demands and continuous ACL on MRI, provided the patients are willing to accept the slight risk of late ACL reconstruction and meniscal injury.


Sex and age as determinants of rat T-cell phenotypic characteristics: influence of peripubertal gonadectomy.
The study examined the influence of age, sex and peripubertal gonadectomy on a set of T-cell phenotypic parameters. Rats of both sexes were gonadectomised at the age of 1 month and peripheral blood and spleen T lymphocytes from non-gonadectomised and gonadectomised 3- and 11-month-old rats were examined for the expression of differentiation/activation (CD90/CD45RC) and immunoregulatory markers. Peripheral blood T lymphocytes from non-gonadectomised rats showed age-dependent sexual dimorphisms in (1) total count (lower in female than male 11-month-old rats); (2) CD4+:CD8 + cell ratio (higher in female than male rats of both ages); (3) the proportion of recent thymic emigrants in CD8 + T cells (lower in female than male 3-month-old rats) and (4) the proportions of mature naïve and memory/activated cells (irrespective of age, the proportion of naïve cells was higher, whereas that of memory/activated cells was lower in females). Gonadectomy influenced magnitudes or direction of these sex differences. Additionally, sex differences in peripheral blood T-lymphocyte parameters did not fully correspond to those observed in T-splenocyte parameters, suggesting the compartment-specific regulation of the major T-cell subpopulations' and their subsets' composition. Furthermore, there was no sexual dimorphism in the proportion of either CD25 + Foxp3 + cells among CD4 + or CD161+ (NKT) cells within CD8 + T lymphocytes. However, there was gonadal hormone-independent age-associated sexual dimorphism in the proportion of CD161 + cells (NKT cells) in CD8 + T splenocytes. Overall, the study revealed age-dependent variations in sexual dimorphisms in T-cell parameters relevant for immune response efficacy and showed that they are T-cell compartment-specific and partly gonadal hormone-related.


Utility of CYP3A4 and PXR-CAR-CYP3A4/3A7 Transgenic Mouse Models To Assess the Magnitude of CYP3A4 Mediated Drug-Drug Interactions.
Species differences in the expression, activity, regulation, and substrate specificity of metabolizing enzymes preclude the use of animal models to predict clinical drug-drug interactions (DDIs). The objective of this work is to determine if the transgenic (Tg) Cyp3a-/-Tg-3A4Hep/Int and Nr1i2/Nr1i3-/--Cyp3a-/-Tg-PXR-CAR-3A4/3A7Hep/Int (PXR-CAR-CYP3A4/3A7) mouse models could be used to predict in vivo DDI of 10 drugs; alprazolam, bosutinib, crizotinib, dasatinib, gefitinib, ibrutinib, regorafenib, sorafenib, triazolam, and vandetinib (as victims); with varying magnitudes of reported CYP3A4 clinical DDI. As an assessment of the effect of CYP3A4 inhibition, these drugs were coadministered to Cyp3a-/-Tg-3A4Hep/Int mice with the CYP3A inhibitor, itraconazole. For crizotinib, regorafenib, sorafenib, and vandetanib, there was no significant increase of AUC observed; with alprazolam, bosutinib, ibrutinib, dasatinib, and triazolam, pretreatment with itraconazole resulted in a 2-, 4-, 17-, 7-, and 15-fold increase in AUC, respectively. With the exception of gefinitib for which the DDI effect was overpredicted (12-fold in Tg-mice vs 2-fold in the clinic), the magnitude of AUC increase observed in this study was consistent (within 2-fold) with the clinical DDI observed following administration with itraconazole/ketoconazole. As an assessment of CYP3A4 induction, following rifampin pretreatment to PXR-CAR-3A4/3A7Hep/Int mice, an 8% decrease in vandetanib mean AUC was observed; 39-52% reduction in AUC were observed for dasatinib, ibrutinib, regorafenib, and sorafenib compared to vehicle treated mice. The greatest effect of rifampin induction was observed with alprazolam, bosutinib, crizotinib, gefitinib, and triazolam where 72-91% decrease in AUC were observed. With the exception of vandetanib for which rifampin induction was under-predicted, the magnitude of induction observed in this study was consistent (within 2-fold) with clinical observations. These data sets suggest that, with two exceptions, these transgenic mice models were able to exclude or capture the magnitude of CYP3A4 clinical inhibition and induction. Data generated in transgenic mice may be used to gain confidence and complement in vitro and in silico methods for assessing DDI potential/liability.


Rasch analysis of the Rosenberg Self-Esteem Scale with African Americans.
Effectively diagnosing African Americans' self-esteem has posed an unresolved challenge. To address this assessment issue, we conducted exploratory factor analysis and Rasch analysis to assess the psychometric characteristics of the Rosenberg Self-Esteem Scale (RSES, Rosenberg, 1965) for African American college students. The dimensional structure of the RSES was first identified with the first subsample (i.e., calibration subsample) and then held up under cross-validation with a second subsample (i.e., validation subsample). Exploratory factor analysis and Rasch analysis both supported unidimensionality of the measure, with that finding replicated for a random split of the sample. Response scale use was generally appropriate, items were endorsed at a high level reflecting high levels of self-esteem, and person separation and reliability of person separation were adequate, and reflected results similar to those found in prior research. However, as some categories were infrequently used, we also collapsed scale points and found a slight improvement in scale and item indices. No differential item functioning was found by sex or having received professional assistance versus not; there were no mean score differences by age group, marital status, or year in college. Two items were seen as problematic. Implications for theory and research on multicultural mental health are discussed. (PsycINFO Database Record


Organic carbon biostimulates rapid rhizodegradation of perchlorate.
Previous hydroponics and field studies identified phytodegradation and rhizodegradation as the two main mechanisms by which plants metabolize perchlorate. Plant uptake and phytodegradation of perchlorate is a slower and undesired process that poses ecological risks resulting from phytoaccumulation of some fraction of the perchlorate. Meanwhile, rhizodegradation is a more rapid and favored process involving perchlorate-degrading bacteria utilizing dissolved organic carbon (DOC) as a carbon and energy (electron) source to rapidly degrade perchlorate to innocuous chloride. In the present study, rhizodegradation of perchlorate by willow trees (Salix nigra) was biostimulated using electron sources obtained from natural and artificial carbon sources. In bioreactors provided with carbon sources as 500 mg/L DOC, 25 to 40 mg/L of initial perchlorate concentrations were removed to below the ion chromatography method detection limit of 2 microg/L in approximately 9 d. For planted controls provided with no electron donors, the time required for the complete removal of the same doses of perchlorate was up to 70 d. Enhancement of rhizodegradation by organic carbon reduced the phytoaccumulated fraction of perchlorate by an order of magnitude from approximately 430 to 20 mg/kg. The implication of the present study is that the high fraction uptake and phytoaccumulation of perchlorate in agricultural products and the recycling of perchlorate into the ecosystem can be significantly curtailed by supplying electron donors derived from organic carbon sources to the root zone of plants.


Sequencing Reveals Population Structure and Selection Signatures for Reproductive Traits in Yunnan Semi-Fine Wool Sheep (Ovis aries).
Yunnan semi-fine wool sheep are among the most important cultivated sheep breeds in China. However, their population structure, genetic characteristics and traits of interest are poorly studied. In this study, we systematically studied the population characteristics and selection signatures of 40 Yunnan semi-fine wool sheep using SNPs obtained from whole-genome resequencing data. A total of 1393 Gb of clean data were acquired. The mapping rate against the reference genome was 91.23% on average (86.01%-92.26%), and the average sequence depth was 9.51X. After filtering, 28,593,198 SNPs and 4,725,259 indels with high quality were obtained. The heterozygosity rate, inbreeding coefficient and effective population size of the sheep were calculated to preliminarily explore their genetic characteristics. The average heterozygosity rate was 0.264, the average inbreeding coefficient was 0.0099, and the effective population size estimated from the heterozygote excess (HE) was 242.9. Based on the Tajima's D and integrated haplotype score (iHS) approaches, 562 windows and 11,356 core SNPs showed selection signatures in the Yunnan semi-fine wool sheep population. After genome annotation and gene enrichment analysis, we found traces of early domestication in sensory organs, behavioural activity and the nervous system as well as adaptive changes in reproductive and wool traits under selection in this population. Some selected genes related to litter size, including FSHR, BMPR1B and OXT, were identified as being under selection. Specific missense mutations of the FSHR gene that differed from the reference genome were also identified in the population, and we found some SNP variations that may affect litter size. Our findings provide a theoretical basis for the conservation and utilization of Yunnan semi-fine wool sheep. Furthermore, our results reveal some changes common to sheep after domestication and provide a new opportunity to investigate the genetic variation influencing fecundity within a population evolving under artificial selection.


A theory of holistic comfort for nursing.
Although the construct of comfort has been analysed, diagrammed in a two-dimensional content map, and operationalized as a holistic outcome, it has not been conceptualized within the context of a broader theory for the discipline of nursing. The theoretical work presented here utilizes an intra-actional perspective to develop a theory of comfort as a positive outcome of nursing case. A model of human press is the framework within which comfort is related to (a) interventions that enhance the state of comfort and (b) desirable subsequent outcomes of nursing care. The paper concludes with a discussion about the theory of comfort as a significant one for the discipline of nursing.


Long-term Follow-up with AlloDerm in Breast Reconstruction.
Little is known about the long-term fate of acellular dermal matrices in breast implant surgery. A 12-year follow-up case with tissue analysis of AlloDerm in revision breast reconstruction reveals retention of graft volume and integration with an organized collagen structure, minimal capsule formation, and little or no indication of inflammation.


Why has adult hippocampal neurogenesis had so little impact on psychiatry?
Hippocampal neurogenesis continues throughout adult life and potentially plays a crucial role in mood and cognitive disorders. We summarise the preclinical insights and potential translational steps that could be taken to investigate the role and importance of this phenomenon in disease and health in humans. Declaration of interest None.


Downregulation of miRNA-26b inhibits cancer proliferation of laryngeal carcinoma through autophagy by targeting ULK2 and inactivation of the PTEN/AKT pathway.
Laryngeal carcinoma is one of the most common tumors of the head and neck cancers, the pathogenesis of which remains yet unclear. It has been discovered through research that microRNAs (miRNAs) play an important role during the genesis of laryngeal carcinoma. In the present study we investigated the effect of miRNA-26b on the proliferation of laryngeal carcinoma and elucidated the potential underlying mechanisms in order to provide new targets for laryngeal carcinoma. Firstly, we found that miRNA-26b expression was significantly increased in patients with laryngeal carcinoma, compared with normal volunteers. The downregulation of miRNA-26b inhibited cell proliferation and induced apoptosis of Hep-2 cells. Furthermore, downregulation of the expression of miRNA‑26b promoted Bax, LC3 and p62 protein expression, decreased ULK2 mRNA and protein expression, as well as PTEN protein expression and increased phosphorylated‑AKT protein expression in Hep-2 cells as determined using quantification by real-time PCR and western blotting. The concomitant downregulation of ULK2 and miRNA-26b futher enhanced the miRNA‑26b-induced autophagy and apoptosis in addition to the miRNA-26b-inhibited cell proliferation of Hep-2 cells by targeting ULK2 and inactivating the PTEN/AKT pathway as determined by immunocytofluorescence. These findings revealed that miRNA-26b may play a key role in cell growth and death of laryngeal carcinoma through ULK2 and the PTEN/AKT pathway, and thus may be a new target for gene therapy in laryngeal carcinoma.


Reflection on Reflection in Applied Visualization Research.
Reflection is a core method used by visualization researchers to generate knowledge from design practice. There is, however, a lack of standards to inform reflective practice and through which we can judge the quality of the reflection used in visualization research. Reflecting on this gap, we offer priorities for researchers looking to improve the use of reflection in applied visualization research.


Photoexcitation-induced passivation of SnO2 thin film for efficient perovskite solar cells.
A high-quality tin oxide electron transport layer (ETL) is a key common factor to achieve high-performance perovskite solar cells (PSCs). However, the conventional annealing technique to prepare high-quality ETLs by continuous heating under near-equilibrium conditions requires high temperatures and a long fabrication time. Alternatively, we present a non-equilibrium, photoexcitation-induced passivation technique that uses multiple ultrashort laser pulses. The ultrafast photoexcitation and following electron-electron and electron-phonon scattering processes induce ultrafast annealing to efficiently passivate surface and bulk defects, and improve the crystallinity of SnO2, resulting in suppressing the carrier recombination and facilitating the charge transport between the ETL and perovskite interface. By rapidly scanning the laser beam, the annealing time is reduced to several minutes, which is much more efficient compared with conventional thermal annealing. To demonstrate the university and scalability of this technique, typical antisolvent and antisolvent-free processed hybrid organic-inorganic metal halide PSCs have been fabricated and achieved the power conversion efficiency (PCE) of 24.14% and 22.75% respectively, and a 12-square-centimeter module antisolvent-free processed perovskite solar module achieves a PCE of 20.26%, with significantly enhanced performance both in PCE and stability. This study establishes a new approach towards the commercialization of efficient low-temperature manufacturing of PSCs.


Great toe necrosis predicts an unfavorable limb salvage prognosis.
The initial location of necrosis may affect the limb salvage rate. This study of 130 patients with chronic toe ulcers or gangrene was performed to assess whether the location of initial necrosis in the toes affected limb salvage prognosis. The patients were divided into 2 groups according to whether the initial necrosis was in the great toe or in other toes. Limb salvage prognosis was determined retrospectively. In the great toe group, the rates of total toe loss and major amputation were 50.0% and 24.4%, respectively. When the initial necrosis was in other toes, these rates were 27.3% and 9.3%, respectively. Great toe necrosis is associated with significantly higher rates of total toe loss (odds ratio = 3.10; P = 0.003; 95% confidence interval, 1.43-6.68) and major amputation (odds ratio = 3.66; P = 0.007; 95% confidence interval, 1.37-9.79). The great toe is supplied by 3 source arteries, whereas the lesser toes are fed by 1 or 2 arteries. Therefore, necrosis initiating from the great toe may reflect the presence of severe vascular disorders. The great toe is also anatomically connected to much of the foot via the tendons. Infection is more likely to spread along these tendons, which may reduce limb prognosis. Thus, the initial location of necrosis may be predictive of limb prognosis.


Significant EEG features involved in mathematical reasoning: evidence from wavelet analysis.
Using electroencephalographic (EEG) signals and a novel methodology based on wavelet measures in the time-scale domain, we evaluated cortex reactions during mathematical thinking. Our purpose was to extract more precise information from the cortex reactions during this cognitive task. Initially, the brain areas (lobes) of significant activation during the task are extracted using time-averaged wavelet power spectrum estimation. Then, a refinement step makes use of statistical significance-based criteria for comparing wavelet power spectra between the task and the rest condition. EEG signals are recorded from 15 young normal volunteers using 30 scalp electrodes as participants performed one difficult arithmetic task and the results are compared with a rest situation. The results are in accordance with similar previous studies, showing activations of frontal and central regions. Compared with the alternative spectral-based techniques, the method we propose achieves higher task discrimination on the same dataset and provides additional detail-signal information to evaluate cortical reactivity during local cortical activation.


Monte Carlo analyses of the fusion neutron and gamma signals from the chromium self-powered detector.
To test the applicability of self-powered detectors (SPDs) for radiation monitoring in fusion reactor blankets, several irradiation tests have been undertaken with the ad hoc designed Cr-SPD, which presents the novelty of using chromium as the emitter material. This detector was exposed to an intense 60Co gamma-ray source, and to the 14 MeV neutrons produced by the D-T fusion reaction. Detailed analyses of the measured signals have been done here using a Monte Carlo modeling technique. We describe the simulations of the fusion neutron and gamma tests of the Cr-SPD, and compare their results with the experimental ones. Keeping in view the difficulty in computational reproduction of the sophisticated nuclear-electrical phenomena behind low-level SPD signals, our model is found to perform well, giving correct electrical polarities and orders of magnitude of the signals, as well as valuable insights into their different components. Our experience has highlighted the deficits and the needed improvements for the traditional SPD simulation techniques for prompt signal analyses.


Highly selective tungstate transporter protein TupA from Desulfovibrio alaskensis G20.
Molybdenum and tungsten are taken up by bacteria and archaea as their soluble oxyanions through high affinity transport systems belonging to the ATP-binding cassette (ABC) transporters. The component A (ModA/TupA) of these transporters is the first selection gate from which the cell differentiates between MoO42-, WO42- and other similar oxyanions. We report the biochemical characterization and the crystal structure of the apo-TupA from Desulfovibrio desulfuricans G20, at 1.4 Å resolution. Small Angle X-ray Scattering data suggests that the protein adopts a closed and more stable conformation upon ion binding. The role of the arginine 118 in the selectivity of the oxyanion was also investigated and three mutants were constructed: R118K, R118E and R118Q. Isothermal titration calorimetry clearly shows the relevance of this residue for metal discrimination and oxyanion binding. In this sense, the three variants lost the ability to coordinate molybdate and the R118K mutant keeps an extremely high affinity for tungstate. These results contribute to an understanding of the metal-protein interaction, making it a suitable candidate for a recognition element of a biosensor for tungsten detection.


Invader abundance and contraction of niche breadth during replacement of a native gammarid amphipod.
The introduction of non-native species to new locations is a growing global phenomenon with major negative effects on native species and biodiversity. Such introductions potentially bring competitors into contact leading to partial or total species replacements. This creates an opportunity to study novel species interactions as they occur, with the potential to address the strength of inter- and intraspecific interactions, most notably competition. Such potential has often not been realized, however, due to the difficulties inherent in detecting rapid and spatially expansive species interactions under natural field conditions. The invasive amphipod crustacean Gammarus pulex has replaced a native species, Gammarus duebeni celticus, in river and lake systems across Europe. This replacement process is at least partially driven by differential parasitism, cannibalism, and intraguild predation, but the role of interspecific competition has yet to be resolved. Here, we examine how abundance of an invasive species may affect spatial niche breadth of a native congeneric species. We base our analyses of niche breadth on ordination and factor analysis of biological community and physical parameters, respectively, constituting a summative, multidimensional approach to niche breadth along environmental gradients. Results derived from biological and environmental niche criteria were consistent, although interspecific effects were stronger using the biological niche approach. We show that the niche breadth of the native species is constrained as abundance of the invader increases, but the converse effect does not occur. We conclude that the interaction between invasive G. pulex and native G. d. celticus under natural conditions is consistent with strong interspecific competition whereby a native, weaker competitor is replaced by a superior invasive competitor. This study indicates a strong role of interspecific competition, alongside other known interactions such as differential intraguild predation, in rapid and expansive species replacements following biological invasions.


Biological responses to immobilized microscale and nanoscale surface topographies.
Cellular responses are highly influenced by biochemical and biomechanical interactions with the extracellular matrix (ECM). Due to the impact of ECM architecture on cellular responses, significant research has been dedicated towards developing biomaterials that mimic the physiological environment for design of improved medical devices and tissue engineering scaffolds. Surface topographies with microscale and nanoscale features have demonstrated an effect on numerous cellular responses, including cell adhesion, migration, proliferation, gene expression, protein production, and differentiation; however, relationships between biological responses and surface topographies are difficult to establish due to differences in cell types and biomaterial surface properties. Therefore, it is important to optimize implant surface feature characteristics to elicit desirable biological responses for specific applications. The goal of this work was to review studies investigating the effects of microstructured and nanostructured biomaterials on in vitro biological responses through fabrication of microscale and nanoscale surface topographies, physico-chemical characterization of material surface properties, investigation of protein adsorption dynamics, and evaluation of cellular responses in specific biomedical applications.


Which interval is most crucial to presentation and survival in gastroesophageal cancer: A systematic review.
The aim of this study was to identify the most crucial interval to encourage earlier diagnosis in with gastroesophageal cancer and to identify potential factors effecting this interval. Gastroesophageal malignancy is the eighth most commonly presenting cancer with one of the worst survival rates. Identifying the most crucial period for intervention to inform earlier diagnosis is an important step towards improving survival. Mixed methods literature review. CINAHL, MEDLINE and Academic search primer online databases were searched using keywords and inclusion/exclusion criteria. Empirical evidence published between 2000-2016 with a focus on gastroesophageal cancer presentation and survival was reviewed to inform this study. Twelve studies were extracted for further review. Selected studies were appraised and presented through Olensen's "delay interval" framework to inform the most crucial interval to survival in gastroesophageal cancer. The findings identify the patient interval as the most critical period for encouraging earlier presentation and reducing advanced stage presentation in gastroesophageal cancer. The article also highlighted some methodological limitations to cancer research, such as a lack of consensus in definitions which prevent statistical meta-analysis of cancer data, survivor bias in gastroesophageal cancer studies and a significant lack of qualitative evidence to reveal patient experience in presenting with this cancer. Further research into the patient interval is required to elicit information on how and why patients present with their cancer symptoms.


[Surveillance of HIV seroprevalence in Mauritania].
The results of our study in four years, blood donors and tuberculosis patients HIV seroprevalence using ELISA for detection HIV1/HIV2 antibodies and Western-blot for confirmation, indicate that seroprevalence in blood donors is 0.28% without a significant increase tendency. Our data show that 88 HIV seropositive confirmed, 70% were HIV1, 25% HIV2 and 5% double reactivity HIV1/HIV2.


Serum leptin concentration in cord blood: relationship to birth weight and gender.
To investigate the effect of leptin on fetal growth, serum leptin concentrations in venous cord blood were measured in 82 newborns (male = 43, female = 39, gestational age 36-42 weeks, birth weight 2,306-4,128 g). Serum leptin concentrations in cord blood ranged from 2.0 to 84.5 ng/mL (mean 19.9 +/- 17.4 ng/mL). Serum leptin concentrations in males (mean 15.3 +/- 15.6 ng/mL, range 2.0 to 79.3 ng/mL) were significantly (P = 0.011) lower than those in females (mean 25.0 +/- 18.0 ng/mL, range 2.1 to 84.5 ng/mL). Serum leptin concentrations in cord blood were positively correlated with birth weight (r = 0.555, P <0.0001), birth weight SD (r = 0.540, P <0.0001), Kaup index (r = 0.505, P <0.0001) and body weight/body height (r = 0.560, P <0.0001). The serum concentrations of estradiol and testosterone did not differ between males and females and did not correlate with the leptin concentration. It is unlikely that the gender difference in fetal leptin levels is due either to body fat content or distribution or to reproductive hormone status, but may be attributed to genetic differences between males and females.


Anomalous suppression of the orthorhombic lattice distortion in superconducting Ba(Fe1-xCox)2As2 single crystals.
High-resolution x-ray diffraction measurements reveal an unusually strong response of the lattice to superconductivity in Ba(Fe1-xCox)2As2. The orthorhombic distortion of the lattice is suppressed and, for Co doping near x=0.063, the orthorhombic structure evolves smoothly back to a tetragonal structure. We propose that the coupling between orthorhombicity and superconductivity is indirect and arises due to the magnetoelastic coupling, in the form of emergent nematic order, and the strong competition between magnetism and superconductivity.


3D printability and biochemical analysis of revalorized orange peel waste.
Orange peels are often discarded as food waste despite being a nutritious source of vitamins and antioxidants. These orange peel wastes (OPW) are produced in millions of tons globally every year; discarding them results in detrimental environmental and economical impacts. This paper discusses the application of 3D printing technology to effectively upcycle the OPW into edible, healthy snacks for consumption. We aimed to develop a method to enable OPW to formulate 3D-printable inks for direct ink writing (DIW). Using DIW 3D printing, we successfully created edible constructs of rheologically modified inks containing OPW. The formulated ink possessed an initial viscosity of 22.5 kPa.s, a yield stress of 377 Pa, and a storage modulus of 44.24 kPa. To validate the method, we conducted a biochemical analysis of the OPW at each stage of the fabrication process. This study suggested that our ink formulation and 3D printing process did not affect the content of bioflavonoids and antioxidants of the OPW. The cell viability test using human dermal microvascular endothelium (HMEC-1) suggested that the OPW did not exhibit cytotoxicity throughout the entire process of the ink manipulation. Overall, this study has highlighted a potential scenario to revalorize food waste into the food value chain using 3D printing toward more sustainable and circular food manufacturing and consumption.


Clinical effectiveness of garlic (Allium sativum).
The objective of this review is to update and assess the clinical evidence based on rigorous trials of the effectiveness of garlic (A. sativum). Systematic searches were carried out in Medline, Embase, Amed, the Cochrane Database of Systematic Reviews, Natural Standard, and the Natural Medicines Comprehensive Database (search date December 2006). Our own files, the bibliographies of relevant papers and the contents pages of all issues of the review journal FACT were searched for further studies. No language restrictions were imposed. To be included, trials were required to state that they were randomized and double blind. Systematic reviews and meta-analyses of garlic were included if based on the results of randomized, double-blind trials. The literature searches identified six relevant systematic reviews and meta-analysis and double-blind randomized trials (RCT) that were published subsequently. These relate to cancer, common cold, hypercholesterolemia, hypertension, peripheral arterial disease and pre-eclampsia. The evidence based on rigorous clinical trials of garlic is not convincing. For hypercholesterolemia, the reported effects are small and may therefore not be of clinical relevance. For reducing blood pressure, few studies are available and the reported effects are too small to be clinically meaningful. For all other conditions not enough data are available for clinical recommendations.


Identification of mistakes and their correction by a small group discussion as a revision exercise at the end of a teaching module in biochemistry.
Graduate medical students often get less opportunity for clarifying their doubts and to reinforce their concepts after lecture classes. The Medical Council of India (MCI) encourages group discussions among students. We evaluated the effect of identifying mistakes in a given set of wrong statements and their correction by a small group discussion by graduate medical students as a revision exercise. At the end of a module, a pre-test consisting of multiple-choice questions (MCQs) was conducted. Later, a set of incorrect statements related to the topic was given to the students and they were asked to identify the mistakes and correct them in a small group discussion. The effects on low, medium and high achievers were evaluated by a post-test and delayed post-tests with the same set of MCQs. The mean post-test marks were significantly higher among all the three groups compared to the pre-test marks. The gain from the small group discussion was equal among low, medium and high achievers. The gain from the exercise was retained among low, medium and high achievers after 15 days. Identification of mistakes in statements and their correction by a small group discussion is an effective, but unconventional revision exercise in biochemistry.


Ligation of membrane immunoglobulin leads to inactivation of the signal-transducing ability of membrane immunoglobulin, CD19, CD21, and B-cell gp95.
We have examined the ability of membrane immunoglobulin-binding ligands to desensitize several human B-cell surface molecules that normally transduce signals leading to Ca2+ mobilization. Ligation of membrane IgM or IgD leads to heterologous desensitization of the reciprocal receptor in Epstein-Barr virus-transformed B-cell lines and peripheral blood B cells, as evidenced by a failure of cells to mobilize in response to receptor ligation. Under these conditions CD19, CD21, and B-cell gp95 ligation also did not lead to normal Ca2+ mobilization, indicating that these transducers are also desensitized. The desensitization does not reflect receptor modulation from the cell surface or reduced accessibility to ligand and is long lived, lasting greater than 16 hr. Finally, data that indicate that desensitized cells remain responsive to the G protein activating agent AIF4-, as measured by Ca2+ mobilization, suggest that desensitization reflects uncoupling of these receptors from G proteins that are intermediaries in their transduction of signals. We hypothesize that the molecular target of desensitization may be a recently described membrane immunoglobulin-associated and inducibly tyrosine-phosphorylated protein complex that may function as a master transducer in B cells, analogous to CD3 in T cells.


Studies on Solubility Enhancement of Poorly Soluble NSAID Using Dual Approach of Micro-environmental pH Modulation and Melt Granulation.
The present work describes the role of melt granulation and microenviron-mental pH modulation technique in solubility enhancement of a poorly water soluble NSAID, Aceclofenac (ACL). ACL is a BCS Class II drug showing dissolution rate limited absorption and pH dependent solubility, with higher solubility at alkaline pH. The limited solubility of ACL affects drug absorption and hence, therapeutic effect as the drug is indicated in conditions of pain where rapid onset of action is desired. Solubility enhancement of ACL was carried out by melt granulation technique using Gelucire 50/13 as molten carrier. The solubility of ACL was improved further by incorporating sodium hydrogen carbonate as pH modifier. The granules of ACL thus developed, were compressed into tablets using adsorbing carriers and other tableting excipients. This dual approach not only enhanced ACL solubility but also aided in achieving a pH independent release. The developed tablets exhibited pH independent release as well as enhanced rate of dissolution which is indicated by in vitro dissolution studies and ex-vivo intestinal permeation studies. The pH independent release would ensure absorption of drug throughout the gastrointestinal tract. The solubility enhancement of ACL was further confirmed by characterization studies such as DSC and XRD. Thus, the dual approach of melt granulation and micro-environmental pH modulation can be simple and scalable method for solubility enhancement of poorly soluble drugs showing pH dependent dissolution rate limited absorption.


Therapeutic options in atrial flutter and fibrillation.
Newer antiarrhythmic agents can control atrial flutter and fibrillation in many patients, although individual episodes may require cardioversion. Catheter ablation is often curative for refractory flutter. Ablation of atrial fibrillation is more difficult, because of its different mechanism. Surgical and catheter-based ablation procedures have been pioneered for fibrillation but remain experimental.


How PEO-PPO-PEO triblock polymer micelles control the synthesis of gold nanoparticles: temperature and hydrophobic effects.
Aqueous micellar solutions of F68 (PEO(78)-PPO(30)-PEO(78)) and P103 (PEO(17)-PPO(60)-PEO(17)) triblock polymers were used to synthesize gold (Au) nanoparticles (NPs) at different temperatures. All reactions were monitored with respect to reaction time and temperature by using UV-visible studies to understand the growth kinetics of NPs and the influence of different micellar states on the synthesis of NPs. The shape, size, and locations of NPs in the micellar assemblies were determined with the help of TEM, SEM, and EDS analyses. The results explained that all reactions were carried out with the PEO-PPO-PEO micellar surface cavities present at the micelle-solution interface and were precisely controlled by the micellar assemblies. Marked differences were detected when predominantly hydrophilic F68 and hydrophobic P103 micelles were employed to conduct the reactions. The UV-visible results demonstrated that the reduction of gold ions into nucleating centers was channeled through the ligand-metal charge-transfer complex (LMCT) and carried out by the surface cavities. Excessive hydration of the surface cavities in the case of F68 micelles produced a few small NPs, but their yield and size increased as the micelles were dehydrated under the effect of increasing temperature. The results concluded that the presence of well-defined predominantly hydrophobic micelles with a compact micelle-solution interfacial arrangement of surface cavities ultimately controlled the reaction.


Effect of Aristolochia petersiana on the efficacy of fansidar.
This study sought to determine the effect of the traditional antimalarial plant, Aristolochia petersiana (Malundu) extract on the efficacy of fansidar, a pharmaceutical antimalarial drug. A. petersiana is used by traditional healers for the treatment of malaria and sore throat, as well as snakebite antivenom. It grows wild in the south eastern areas of Zimbabwe (Chimanimani and Chipinge) and in the north and north western regions (Binga and Lupane). The effect of the methanolic extract of the roots of A. petersiana, fansidar, and the extract fansidar mixture were compared on malaria parasites, revealing that the inhibition of growth of the malaria parasite was greater for the mixture than for either A. pertesiana extract or fansidar individually. Fansidar is a known inhibiter of protozoal growth, hence it was used as a positive control and the culture in which no drug was applied was used as a negative control. The results were suggestive of a synergistic relationship between A. petersiana and fansidar in their inhibition of the malaria parasite growth. The study could be extended to the establishment of formulations for use in the treatment of malaria.


Acceleration of cholesterol phase transitions in analog bile by chlorpromazine, pentobarbital and ethinyl estradiol.
The effects of incorporation of chlorpromazine, pentobarbital and ethinyl estradiol on the maintenance of cholesterol supersaturation was studied in bile analogs. Bile solutions were initially supersaturated and microscopically clear. Chlorpromazine and pentobarbital were almost totally solubilized; ethinyl estradiol was poorly solubilized. Chlorpromazine and pentobarbital in concentrations of 5 and 10 mg/ml rapidly (less than 3-5 h) diminished cholesterol in bile filtrates compared to controls; ethinyl estradiol did so at a concentration of 1 mg/ml but less rapidly (24 h). Bile acid and lecithin concentrations, over time, did not differ significantly between groups. The results indicate that drug interactions with bile constituents, without causing their precipitation, can alter the maintenance of cholesterol supersaturation and phase transitions in bile.


Advanced microinjection protocol for gene manipulation using the model newt Pleurodeles waltl.
Urodele amphibian newts have an outstanding history as experimental animals in various research fields such as developmental biology and regeneration biology. We have reported a model experimental system using the Spanish newt, Pleurodeles waltl, and it enables reverse/molecular genetics through gene manipulation. Microinjection is one of the core techniques in gene manipulation in newts. In the present study, we examined the conditions of the microinjection method, such as egg preparation, de-jelly solution, and formulation of injection medium. We have successfully optimized the injection protocol for P. waltl newts, and our improved protocol is more efficient and lower in cost than previous methods. This protocol can be used for the microinjection of plasmid DNA with I-SceI or mRNA, as well as genome editing using the CRISPR-Cas9 system. This protocol will facilitate research through gene manipulation in newts.


ERK-Induced Activation of TCF Family of SRF Cofactors Initiates a Chromatin Modification Cascade Associated with Transcription.
We investigated the relationship among ERK signaling, histone modifications, and transcription factor activity, focusing on the ERK-regulated ternary complex factor family of SRF partner proteins. In MEFs, activation of ERK by TPA stimulation induced a common pattern of H3K9acS10ph, H4K16ac, H3K27ac, H3K9acK14ac, and H3K4me3 at hundreds of transcription start site (TSS) regions and remote regulatory sites. The magnitude of the increase in histone modification correlated well with changes in transcription. H3K9acS10ph preceded the other modifications. Most induced changes were TCF dependent, but TCF-independent TSSs exhibited the same hierarchy, indicating that it reflects gene activation per se. Studies with TCF Elk-1 mutants showed that TCF-dependent ERK-induced histone modifications required Elk-1 to be phosphorylated and competent to activate transcription. Analysis of direct TCF-SRF target genes and chromatin modifiers confirmed this and showed that H3S10ph required only Elk-1 phosphorylation. Induction of histone modifications following ERK stimulation is thus directed by transcription factor activation and transcription.


MuSIC report III: tumour microcirculation patterns and development of metastasis in long-term follow-up of melanocytic uveal tumours.
To statistically determine differences in microcirculation patterns between nevi and uveal melanomas and the influence of these patterns on metastatic potential in the long-term follow-up of 112 patients with melanocytic uveal tumours. In vivo markers indicating malignancy and metastatic potential have implications for treatment decision. Primary diagnosis and work-up included clinical examination, fundus photography, standardized A and B scan echography as well as evaluation of tumour microcirculation patterns via confocal fluorescein and indocyanine green angiography (ICGA). Patient data were collected from the patient files, the tumour registry or personal contact. Statistical analysis was performed with spss 22.0 using chi-square, Fisher's exact test and Kaplan-Meier survival analysis. Forty-three uveal melanocytic lesions remained untreated and were retrospectively classified as benign nevi, whereas 69 lesions were malignant melanomas (T1: 32, T2: 28, T3: 6 and T4: 3). 'Silent' and 'arcs without branching' were found significantly more often in nevi (p = 0.001 and p = 0.010), whereas 'parallel with cross-linking' and 'networks' were significantly more frequent in melanomas (p = 0.022 and p = 0.029). The microcirculation pattern 'parallel with cross-linking' proved significantly more frequent in patients who developed metastases (p = 0.001). Certain microcirculation patterns may guide us in differentiating uveal nevi from malignant melanomas. A non-invasive prognostic marker can be of great value for borderline lesions in which cytology is less likely taken. 'Parallel with cross-linking' did not only indicate malignancy, but it was also associated with later tumour metastasis.


Daytime Sleepiness in Children With Asthma: Examining Respiratory and Non-respiratory Factors.
Objective Daytime sleepiness is common in youth with asthma (YWA). Treatments designed to mitigate daytime sleepiness in YWA require an understanding of the primary causes of this problem. We examined respiratory- and non-respiratory-related factors associated with daytime sleepiness in YWA. Methods One hundred YWA (eight to 17 years old) were included in a cross-sectional study. Daytime sleepiness, quality of life, anxiety, bedtime cellphone use, and respiratory symptoms were self-reported. Asthma severity, lung function, and the number of prescribed medications were obtained from electronic medical records. Multivariable regression models identifying variables associated with daytime sleepiness were generated. Results Participants were 54% male and 45% Black, with a mean age of 12.1 years. The multivariable regression model showed decreased quality of life (b = -0.328, p = 0.004) and increased bedtime cellphone use (b = 0.300, p = 0.004)were significantly related to daytime sleepiness, while anxiety (b = 0.213, p = 0.05), prescribed asthma medications (b = 0.173, p = 0.05), and worse lung function (b = -0.173, p = 0.05)were marginally related to daytime sleepiness. Conclusions In addition to optimizing asthma control, strategies targeting anxiety, quality of life, and nocturnal cellphone use are important to mitigate daytime sleepiness in YWA.


Differential osteoclast activation in endochondral and intramembranous bone.
Osteoclast activation within the temporal bone leads to hearing loss in a variety of pathologic conditions, including otosclerosis, osteogenesis imperfecta, Paget's disease of bone, and chronic otitis media. Although endochondral (EC) bone is remodeled in these diseases, it is relatively more resistant to remodeling when compared to intramembranous (IM) bone. In this study, localized bone resorption and remodeling were induced on the inner surface of the middle ear by pressurization with air to 10 mm Hg above atmospheric. Osteoclast surface increased in IM bone, but not in EC bone. This study supports the concept that there may be fundamental differences between EC and IM bone and that EC is more resistant to pressure-induced localized resorption than IM bone.


The psychology of cosmetic surgery: old problems in patient selection seen in a new way--Part II.
Numerous patient referrals and discussions with the plastic surgeons of the Zurich University Hospital, and the lack of "hard" data in the literature motivated me to delve more into the problems of patient selection in cosmetic surgery. The first section of this article consists of a discussion of the selection criteria in the literature. Although they may be important in single cases, none of the criteria proves to be statistically significant in regard to the outcome of cosmetic surgery. After a short outline of the development of research in cosmetic surgery, a systemic-interactional model of thinking is introduced and applied to the patient selection process. The sections on coping, the patient/surgeon/psychiatrist triangle, and management of the patient in the screening interview illustrate that the systemic hypothesis can enhance the understanding of patient attitudes and behaviors. Practical implications are discussed.


Adaptive synchronization of coupled chaotic oscillators.
We experimentally demonstrate and numerically simulate an adaptive method to maintain synchronization between coupled nonlinear chaotic oscillators, when the coupling between the systems is unknown and time-varying (e.g., due to environmental parameter drift). The technique is applied to optoelectronic feedback loops exhibiting high-dimensional chaotic dynamics. In addition to keeping the two systems isochronally synchronized in the presence of a priori unknown time-varying coupling strength, the technique provides an estimate of the time-varying coupling.


Two-Way Chemical Communication between Artificial and Natural Cells.
Artificial cells capable of both sensing and sending chemical messages to bacteria have yet to be built. Here we show that artificial cells that are able to sense and synthesize quorum signaling molecules can chemically communicate with V. fischeri, V. harveyi, E. coli, and P. aeruginosa. Activity was assessed by fluorescence, luminescence, RT-qPCR, and RNA-seq. Two potential applications for this technology were demonstrated. First, the extent to which artificial cells could imitate natural cells was quantified by a type of cellular Turing test. Artificial cells capable of sensing and in response synthesizing and releasing N-3-(oxohexanoyl)homoserine lactone showed a high degree of likeness to natural V. fischeri under specific test conditions. Second, artificial cells that sensed V. fischeri and in response degraded a quorum signaling molecule of P. aeruginosa (N-(3-oxododecanoyl)homoserine lactone) were constructed, laying the foundation for future technologies that control complex networks of natural cells.


Increased fetal nuchal translucency at 11-14 weeks.
Nuchal translucency (NT) is the sonographic appearance of a subcutaneous collection of fluid behind the fetal neck. The measurement of fetal NT thickness at the 11-14-week scan has been combined with maternal age to provide an effective method of screening for trisomy 21; for an invasive testing rate of 5%, about 75% of trisomic pregnancies can be identified. When maternal serum free-beta human chorionic gonadotrophin (beta-hCG) and pregnancy-associated plasma protein-A (PAPP-A) at 11-14 weeks are also taken into account, the detection rate of chromosomal defects is about 90%. Increased NT can also identify a high proportion of other chromosomal abnormalities and is associated with major defects of the heart and great arteries, and a wide range of skeletal dysplasias and genetic syndromes. In monochorionic twins, discordancy for increased NT is an early marker of twin-to-twin transfusion syndrome (TTTS). As with the introduction of any new technology into routine clinical practice, it is essential that those undertaking the 11-14-week scan are adequately trained and their results are subjected to rigorous audit.


[Dental fluorosis prevalence in eight cohorts of Mexicans born during the implementation of the Fluoridated Domestic Salt National Program].
to determine the effect of birth cohort on dental fluorosis in Mexican schoolchildren during the implementation of the national program to fluoridate domestic salt. in a cross-sectional study we examined 1,644 schoolchildren 6-13 years old born between 1985-1992 in Campeche, México; a community where there is negligible naturally available fluoride in water supplies. Dental fluorosis was assessed with the Dean's index in the permanent dentition. Questionnaires were used to identify diverse socio-demographic and socio-economic variables. In the statistical analysis logistic regression was used. the prevalence of fluorosis was 15.5%. In the multivariate model,we observed fluorosis was associated with larger family sizes (OR: 0.91; 95% CI: 0.84-0.99) and female sex (OR: 0.74; 95%CI: 0.57-0.98). Furthermore, using the cohort of 1985 as a comparison group, no significant dental fluorosis differences were found with those born between 1986-1987; in contrast, in the cohorts born between 1989-1992 the risk of dental fluorosis increased by almost four times (p < 0.05). the prevalence of fluorosis was low compared to other studies in Mexico. In this community with negligible fluoride in water supplies the likelihood of dental fluorosis increased as the windows of susceptibility in birth cohorts were closer to the chronologic beginning of the national domestic salt fluoridation program in 1991. This trend was more apparent after 1991.


NIPSNAP1 and NIPSNAP2 act as "eat me" signals to allow sustained recruitment of autophagy receptors during mitophagy.
Removal of damaged mitochondria is vital for cellular homeostasis especially in non-dividing cells, like neurons. Damaged mitochondria that cannot be repaired by the ubiquitin-proteasomal system are cleared by a form of selective autophagy known as mitophagy. Following damage, mitochondria become labelled with 'eat-me' signals that selectively determine their degradation. Recently, we identified the mitochondrial matrix proteins, NIPSNAP1 (nipsnap homolog 1) and NIPSNAP2 as 'eat-me' signals for damaged mitochondria. NIPSNAP1 and NIPSNAP2 accumulate on the mitochondrial outer membrane following mitochondrial depolarization, recruiting autophagy receptors and adaptors, as well as human Atg8 (autophagy-related 8)-family proteins to facilitate mitophagy. The NIPSNAPs allow a sustained recruitment of SQSTM1-like receptors (SLRs) to ensure efficient mitophagy. Zebrafish lacking Nipsnap1 show decreased mitophagy in the brain coupled with increased ROS production, loss of dopaminergic neurons and strongly reduced locomotion.


Protein crystallization in stirred systems--scale-up via the maximum local energy dissipation.
Macromolecular bioproducts like therapeutic proteins have usually been crystallized with µL-scale vapor diffusion experiments for structure determination by X-ray diffraction. Little systematic know-how exists for technical-scale protein crystallization in stirred vessels. In this study, the Fab-fragment of the therapeutic antibody Canakinumab was successfully crystallized in a stirred-tank reactor on a 6 mL-scale. A four times faster onset of crystallization of the Fab-fragment was observed compared to the non-agitated 10 µL-scale. Further studies on a liter-scale with lysozyme confirmed this effect. A 10 times faster onset of crystallization was observed in this case at an optimum stirrer speed. Commonly suggested scale-up criteria (i.e., minimum stirrer speed to keep the protein crystals in suspension or constant impeller tip speed) were shown not to be successful. Therefore, the criterion of constant maximum local energy dissipation was applied for scale-up of the stirred crystallization process for the first time. The maximum local energy dissipation was estimated by measuring the drop size distribution of an oil/surfactant/water emulsion in stirred-tank reactors on a 6 mL-, 100 mL-, and 1 L-scale. A comparable crystallization behavior was achieved in all stirred-tank reactors when the maximum local energy dissipation was kept constant for scale-up. A maximum local energy dissipation of 2.2 W kg(-1) was identified to be the optimum for lysozyme crystallization at all scales under study.


[Use of a tumor prosthesis in the management of complications from a Guepar-type knee prosthesis].
In the operative treatment of the knee diseases Guepar prosthesis was used formerly more frequently, presently however only rarely. The frequence of complications and their treatment are many times serious problems. Authors describe one case in which the postoperative supracondylaer fracture necessitated the insertion of a special knee prosthesis.


Transient myeloproliferative disorder with trisomy 12.
The authors report the first case of transient myeloproliferative disorder (TMD) in a neonate with trisomy 12. The clinical course consisted of respiratory distress since birth with probability of transient tachypnea of newborn, but routine investigation revealed total leukocyte count of 56000/microL with 91% blasts, which returned to normal spontaneously during the subsequent 3 weeks. GTG-banded karyotype from peripheral blood was done to detect any mutation, specifically trisomy 21, but the proband revealed trisomy 12 and denaturing polyacrylamide gel electrophoresis (PAGE) detected mutation in exon 2 of GATA1. The condition has been described in association with Down syndrome (trisomy 21) but never with trisomy 12. This case demonstrates the importance of knowing this entity so that it is not erroneously diagnosed as a leukemic process. This is extremely important because most cases of TMD resolve spontaneously within a few weeks to months and do not require treatment other than supportive measures. A search of the literature did not reveal any similar case.


Characteristics and outcomes of patients with multifocal/multicentric and unifocal breast cancer.
The clinical behavior and outcome of multifocal (MF) and multicentric (MC) breast tumors are not well characterized. The purpose of this study was to compare the prognosis of MF/MC tumors with unifocal (UF)tumors and its correlation with other pathological characteristics and patient outcomes. Eighty-three patients with MC/MF breast cancer and 501 with UF breast cancer treated at the Surgical Clinic Nis were studied. We compared MC/MF and UF breast cancer patients with respect to demographics, tumor characteristics- adjuvant systemic therapy, local recurrence-free survival (LRFS) and overall survival (OS). There was no significant statistical difference between the two groups with respect to mean age at diagnosis, tumor grade, nodal status, estrogen receptor status, lymphovascular invasion (LVI) and adjuvant systemic therapy. The MC/MF group had more patients with modified radical mastectomy and the UF group had more patients with breast-conserving surgery. Cox multivariate regression analysis showed that the regional lymph node metastases and LVI were the most important predictors of 5-year OS rate. During this period, locoregional recurrence was registered in 29 (5.78%) patients in the UF group and in 5 (6.02%) patients in the MF/MC group (p=0.48). No statistically significant differences in the 5-year LRFS and OS between the two groups were noticed. The prognostic value of MF/MC disease is still not well known, although some studies have suggested that it is associated with a worse prognosis. This study showed no statistically significant difference in the 5-year LRFS and OS between UF and MF/MC groups.


Phase stability and elastic properties of chromium borides with various stoichiometries.
Phase stability is important to the application of materials. By first-principles calculations, we establish the phase stability of chromium borides with various stoichiometries. Moreover, the phases of CrB3 and CrB4 have been predicted by using a newly developed particle swarm optimization (PSO) algorithm. Formation enthalpy-pressure diagrams reveal that the MoB-type structure is more energetically favorable than the TiI-type structure for CrB. For CrB2, the WB2-type structure is preferred at zero pressure. The predicted new phase of CrB3 belongs to the hexagonal P-6m2 space group and it transforms into an orthorhombic phase as the pressure exceeds 93 GPa. The predicted CrB4 (space group: Pnnm) phase is more energetically favorable than the previously proposed Immm structure. The mechanical and thermodynamic stabilities of predicted CrB3 and CrB4 are verified by the calculated elastic constants and formation enthalpies. The full phonon dispersion calculations confirm the dynamic stability of WB2 -type CrB2 and predicted CrB3. The large shear moduli, large Young's moduli, low Poisson ratios, and low bulk and shear modulus ratios of CrB4-PSC and CrB4-PSD indicate that they are potential hard materials. Analyses of Debye temperature, electronic localization function, and electronic structure provide further understanding of the chemical and physical properties of these borides.


A new device for administration of nasal continuous positive airway pressure in the newborn: an experimental study.
During treatment with continuous positive airway pressure (CPAP), optimal re-expansion of lung units with minimal work of breathing is best accomplished when the airway pressure (Paw) is kept constant at the desired CPAP level throughout the entire breathing cycle. To achieve this, a new device was constructed in which CPAP was generated by a jet of fresh gas close to the nasal airway. The performance of the new device was investigated experimentally using a lung model which simulated the breathing pattern of a newborn. Paw, flow, and external work of breathing were measured at three CPAP levels, with and without controlled airway leakage. The new device was compared with a traditional continuous-flow CPAP system with standard nasal prongs. Despite a virtually constant pressure within the traditional system, Paw variations and external workload were considerably less with the new device, which was also less sensitive to airway leakage.


Differential corticostriatal plasticity during fast and slow motor skill learning in mice.
Motor skill learning usually comprises "fast" improvement in performance within the initial training session and "slow" improvement that develops across sessions. Previous studies have revealed changes in activity and connectivity in motor cortex and striatum during motor skill learning. However, the nature and dynamics of the plastic changes in each of these brain structures during the different phases of motor learning remain unclear. By using multielectrode arrays, we recorded the simultaneous activity of neuronal ensembles in motor cortex and dorsal striatum of mice during the different phases of skill learning on an accelerating rotarod. Mice exhibited fast improvement in the task during the initial session and also slow improvement across days. Throughout training, a high percentage of striatal (57%) and motor cortex (55%) neurons were task related; i.e., changed their firing rate while mice were running on the rotarod. Improvement in performance was accompanied by substantial plastic changes in both striatum and motor cortex. We observed parallel recruitment of task-related neurons in both structures specifically during the first session. Conversely, during slow learning across sessions we observed differential refinement of the firing patterns in each structure. At the neuronal ensemble level, we observed considerable changes in activity within the first session that became less evident during subsequent sessions. These data indicate that cortical and striatal circuits exhibit remarkable but dissociable plasticity during fast and slow motor skill learning and suggest that distinct neural processes mediate the different phases of motor skill learning.


Referral and ascertainment bias in patients with synchronous and metachronous endometrial malignancy.
The purpose of this study was to evaluate the frequency in patients with endometrial cancer of other malignancies and the influence of referral and ascertainment biases on these associations. Analysis of 1,028 local and referred patients who had a hysterectomy for endometrial cancer was based on residence at the time of diagnosis. Altogether, 208 patients had a history of another malignancy, most frequently breast, colon, and ovary. At the time of surgery for endometrial cancer, the prevalence of lymphoma and breast and ovarian cancers was greater than expected although the higher prevalence of lymphoma was limited to referred patients. During follow-up after hysterectomy, the incidence of lung cancer was lower than expected, whereas the incidence of lymphoma was higher. Breast, colorectal, and bladder cancers were more common than expected although this finding was limited to local patients. We concluded that results of epidemiologic studies from tertiary care centers may be misleading if they do not account for referral and ascertainment biases.


Mechanical inserts for the treatment of faecal incontinence: A systematic review.
Objective: To perform a systematic review of the literature to examine original research on the role of mechanical inserts, both vaginal and anal, for the treatment of faecal incontinence (FI). Materials and methods: We searched the PubMed, Cochrane Library, and ClinicalTrials.gov databases for any peer-reviewed original research in English on the role of mechanical inserts for the treatment of FI. Results: We identified 35 unique citations. After title review and exclusion of articles not reporting original research, eight publications were included in the final review: two focused on vaginal inserts and six focused on anal inserts. Limited evidence indicates that both vaginal and anal inserts can be an effective and safe therapeutic option for patients with FI. Conclusions: Data regarding vaginal and anal mechanical inserts for the treatment of FI, albeit limited, suggest that inserts can be included in a discussion of therapeutic options for a patient with FI. Further studies are needed to elucidate long-term usability, efficacy, and safety. Abbreviations: FI: faecal incontinence; (m)ITT: (modified) intention-to-treat.


Low-Profile Dual-Band Reflector Antenna for High-Frequency Applications.
A high-gain low-profile reflector antenna with dual-band radiation ability is presented in this paper. The antenna achieves a relative 2 dB gain bandwidth of 10% around fl, and a relative 2 dB gain bandwidth of 20%, around fh, where fl and fh are the center operating frequencies of the frequency bands of 29.4~32.4 GHz and 142~174 GHz, respectively. To achieve the dual-band radiation ability, a composite dual-band feed with an fh/fl ratio of around 5 is proposed as the feed for the reflector antenna, which includes a higher-band circular waveguide and a lower-band coaxial horn. The metallic elliptical surface serves as the subreflector (SR) in the higher band, while the SR is the planar reflectarray in the lower band. Due to the design of the dual reflector, the dual-band reflector antenna features a low focal-to-diameter (F/D) ratio of approximately 0.2. According to the simulated results, the proposed reflector antenna achieves efficiencies of 59.0% and 42.9% at fl and fh, respectively. For verification purposes, a Ku/E-band scaled prototype is manufactured. The measured VSWRs, radiation patterns, and gains are in reasonable agreement with the simulated ones, proving the correctness of the proposed design method.


[Health services research and guidelines--from the Association of the Scientific Medical Societies' (AWMF) perspective].
The Association of the Scientific Medical Societies (AWMF, Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften) is an umbrella organization. It currently represents 151 scientific societies and thus the majority of medical researchers in Germany. Through the coordination and support of the scientific medical societies, the AWMF significantly contributes to health services research by establishing guidelines that ensure a high quality of healthcare. To this purpose, AWMF founded a guideline committee in 1995, whose objective is to assist AWMF member societies in the establishment of guidelines, the organization of training sessions for AWMF guideline representatives, the hosting of regular guideline conferences and the close cooperation with the German Medical Association (Bundesärztekammer, BAK) and the National Association of Statutory Health Insurance Physicians (Kassenärztliche Bundesvereinigung, KBV) in the development of national disease management guidelines (Nationale Versorgungs Leitlinien, NVL). Together with the Agency for Quality in Medicine [AQuMed; Arztliches Zentrum für Qualität in der Medizin (AZQ)], AWMF published a 'German Instrument for Methodological Guideline Appraisal' ('Deutsches Instrument zur methodischen Leitlinien-Bewertung', DELBI) in order to assure the quality of the guideline development process. A close cooperation has also developed between AWMF and the German Medical Association within the scope of their program for promoting health services research and with the Board of the German Network for Health Services Research (Deutsches Netzwerk for Versorgungsforschung, DNVF). Furthermore, AMWF has acknowledged a special need for improving the financial and conceptual promotion of a systematic evaluation of guideline development and the implementation and application of guidelines in everyday clinical practice.


Characterization of glucoamylase from Aspergillus terreus 4.
A strain of Aspergillus terreus 4 was found to show extracellular amylolytic activity and the amylase was identified as glucoamylase enzyme. The optimum temperature for the enzyme activity was 60% and it was stable at this temperature for 1 h. The enzyme was optimally active at pH 5.0 and stable between pH 3.0-8.0. Km values of glucoamylase for soluble starch, amylose and amylopectin were 5.9 mg/ml, 4.8 mg/ml and 2.6 mg/ml respectively.


Pharmacologic Management of Delirium in the ICU: A Review of the Literature.
Conflicting data exists on the pharmacologic management of intensive care unit (ICU) delirium. This review appraises the current evidence of pharmacologic management of ICU delirium. A systematic literature search of MEDLINE and Embase was conducted to answer the population, intervention, comparison, and outcome (PICO) question of: "Does the use of a pharmacologic agent compared to standard of care or placebo improve ICU delirium in a critically ill patient population?" After application of the PICO question and the inclusion and exclusion criteria, 13 articles were included. Of these articles, 7 were prospective randomized controlled trials, 1 was a prospective nonrandomized controlled trial, and 5 were retrospective investigations. The included articles differed in the agents evaluated, primary outcome, and method of identifying delirium. The variability of outcomes illustrates the need for a large-scale investigation to further evaluate the role of pharmacologic management of ICU delirium.


NMDA receptor encephalitis--expanding the clinical spectrum.
A young woman presented with memory problems of subacute onset. Imaging was normal. She was admitted with severe complex partial status epilepticus requiring intensive care support and ventilation. Fits proved difficult to control requiring high dose anticonvulsants. She developed a profound amnesic syndrome. A clinical diagnosis of autoimmune encephalitis was considered and she was treated with intravenous steroids with an excellent cognitive outcome. She continues to have occasional seizures.


Carotenoid 3',4'-desaturase is involved in carotenoid biosynthesis in the radioresistant bacterium Deinococcus radiodurans.
Deinococcus radiodurans strain R1 synthesizes deinoxanthin, a unique carotenoid product, which contributes to cell resistance following various stresses. The biosynthetic pathway of deinoxanthin is unclear, although several enzymes are presumed to be involved. The gene (dr2250) predicted by gene homologue analysis to encode carotenoid 3',4'-desaturase (CrtD) was deleted to investigate its function. A mutant deficient in the gene homologue of crtLm (dr0801) was also constructed to verify the catalytic function of the gene product in the native host. Carotenoid analysis of the resultant mutants verified that DR2250 encodes carotenoid 3',4'-desaturase, which catalyses the C-3',4'-desaturation of the monocyclic precursor of deinoxanthin but not acyclic carotenoids. Mutation of the gene homologue of crtLm (dr0801) resulted in accumulation of lycopene, confirming that it encodes the lycopene cyclase in the native host. The lack of CrtD decreased the antioxidant capacity of the mutant deficient in dr2250 compared with the wild-type, indicating that the C-3',4'-desaturation step contributes to the antioxidant capacity of deinoxanthin in D. radiodurans.


Seroepidemiology of Helicobacter pylori and hepatitis A virus and the mode of transmission of infection: a 9-year cohort study in rural Japan.
We compared the seroepidemiologic patterns of Helicobacter pylori and hepatitis A virus (HAV) infections among participants in 2 independent cross-sectional studies conducted in Japan in 1986 and 1994. Subgroups were monitored with successive blood sampling. H. pylori and HAV infection status was defined by results of enzyme-linked immunosorbent assay. In 1986, the prevalence of H. pylori infection and HAV infection, respectively, were 80% and 70% among adults and 31% and 5% among children. The prevalence of both infections increased with age. Concordant infections were found in 74.5% of adults (kappa=0.2) versus 2% of children (kappa=0.05). During the 9-year study period, the incidence of H. pylori infection was 1.1% among adults and 2% among children. The seroprevalence of HAV remained constant. The disparity between the increase in prevalence of H. pylori and HAV infection with age is likely associated with improvements in hygienic practices. The discordance between the presence of the infections among younger persons is evidence against a common source and/or vehicle for transmission.


Toxicity of Mitoxantrone-loaded Superparamagnetic Iron Oxide Nanoparticles in a HT-29 Tumour Spheroid Model.
Cancer research is commonly carried out in two-dimensional (2D) cell cultures, which poorly reflect in vivo settings where the growing tumours are exposed to mechanical forces and biochemical gradients. In this study we established a HF-29 colon carcinoma tumor spheroid model to investigate the effect of free mitoxantrone (MTO) and its nanoparticle-bound form (SPION(MTO)) under 3D cell culture conditions. Tumour spheroids were generated by seeding HT-29 colon carcinoma cells on agarose-coated cell culture wells. Growth of the spheroids was monitored daily by transmission microscopy upon treatment with free MTO, SPION(MTO) or unloaded SPION. Unloaded SPION did not affect the spheroid size compared to untreated controls, while both free MTO and SPION(MTO) inhibited growth of the spheroids in a dose- and time-dependent manner. In comparison to free MTO, the effect of SPION(MTO) on spheroid growth was slightly delayed. Further analyses are necessary to investigate if MTO infiltrates spheroids in its nanoparticle-bound form or whether it is released from SPION before infiltration.


Insulin- and quercetin-loaded liquid crystalline nanoparticles: implications on oral bioavailability, antidiabetic and antioxidant efficacy.
The present study reports insulin (INS)- and quercetin (QT)-lyotropic liquid crystalline nanoparticles (LCNPs) with improved bioavailability, antidiabetic and antioxidant efficacy following oral administration. The developed INS-QT-LCNPs were evaluated for simulated gastric fluid stability. In vitro Caco-2 uptake studies were also performed. Furthermore, in vivo pharmacokinetics and pharmacodynamics of INS-QT-LCNPs were evaluated. INS entrapped within LCNPs demonstrated excellent stability in simulated gastric fluid. Higher uptake of fluorescein isothiocyanate-INS-LCNPs were observed in Caco-2 cells. INS-LCNPs demonstrated approximately 20% relative bioavailability compared with subcutaneously administered INS. Significant decrease in oxidative stress was confirmed by reduction in malondialdehyde level. Overall, combination strategy not only overcomes poor oral bioavailability of INS and QT, but also prevents the generation of reactive oxygen species, responsible for diabetes-mediated complications.


The role of Vitamin E in hip implant-related corrosion and toxicity: Initial outcome.
In orthopedic healthcare, Total Hip Replacement (THR) is a common and effective solution to hip-related bone and joint diseases/fracture; however, corrosion of the hip implant and the release of degradation metal ions/particles can lead to early implant failure and pose potential toxicity risk for the surrounding tissues. The main objective of this work was to investigate the potential role of Vitamin E to minimize corrosion-related concerns from CoCrMo hip implants. The study focused on two questions (i) Can Vitamin E inhibit CoCrMo corrosion? and (ii) Does Vitamin E moderate the toxicity associated with the CoCrMo implant particles? In the study (i) the electrochemical experiments (ASTM G61) with different concentrations of Vitamin E (1, 2, 3 mg/ml against the control) were performed using normal saline and simulated synovial fluid (Bovine calf serum-BCS, 30 g/L protein, pH 7.4) as electrolytes. The polished CoCrMo disc (Ra 50 nm) was the working electrode. The findings suggested that both Vitamin E-Saline (45 ± 0.9%) and Vitamin E-BCS (91 ± 3%) solutions protected against implant corrosion at a Vitamin E concentration of 3 mg/ml, but Vitamin E-BCS showed protection at all Vitamin E (1-3 mg/ml) concentration levels. These results suggested that the Vitamin E and the protein present in the BCS imparted additive effects towards the electrochemical inhibition. In the study (ii) the role of Vitamin E in cytotoxicity inhibition was studied using a mouse neuroblastoma cell line (N2a) for CoCrMo particles and Cr ions separately. The CoCrMo particles were generated from a custom-built hip simulator. The alamarBlue assay results suggested that Vitamin E provides significant protection (85% and 75% proliferation) to N2a cells against CoCrMo particles and Cr ions, respectively at 1 μg/ml concentration, as compared to the control group. However, the results obtained from ROS expression and DNA fiber staining suggest that Vitamin E is only effective against CoCrMo degradation particles and not against Cr ions. In summary, the findings show that Vitamin E can minimize the corrosion processes and play a role in minimizing the potential toxicity associated with implants.


Correction and verification of x-ray imaging crystal spectrometer analysis on Wendelstein 7-X through x-ray ray tracing.
X-ray ray tracing is used to develop ion-temperature corrections for the analysis of the X-ray Imaging Crystal Spectrometer (XICS) used at Wendelstein 7-X (W7-X) and perform verification on the analysis methods. The XICS is a powerful diagnostic able to measure ion-temperature, electron-temperature, plasma flow, and impurity charge state densities. While these systems are relatively simple in design, accurate characterization of the instrumental response and validation of analysis techniques are difficult to perform experimentally due to the requirement of extended x-ray sources. For this reason, a ray tracing model has been developed that allows characterization of the spectrometer and verification of the analysis methods while fully considering the real geometry of the XICS system and W7-X plasma. Through the use of ray tracing, several important corrections have been found that must be accounted for in order to accurately reconstruct the ion-temperature profiles. The sources of these corrections are described along with their effect on the analyzed profiles. The implemented corrections stem from three effects: (1) effect of sub-pixel intensity distribution during de-curving and spatial binning, (2) effect of sub-pixel intensity distribution during forward model evaluation and generation of residuals, and (3) effect of defocus and spherical aberrations on the instrumental response. Possible improvements to the forward model and analysis procedures are explored, along with a discussion of trade-offs in terms of computational complexity. Finally, the accuracy of the tomographic inversion technique in stellarator geometry is investigated, providing for the first time a verification exercise for inversion accuracy in stellarator geometry and a complete XICS analysis tool-chain.


An improved model for the hTERT promoter quadruplex.
Mutations occur at four specific sites in the hTERT promoter in >75% of glioblastomas and melanomas, but the mechanism by which the mutations affect gene expression remains unexplained. We report biophysical computational studies that show that the hTERT promoter sequence forms a novel G-quadruplex structure consisting of three contiguous, stacked parallel quadruplexes. The reported hTERT mutations map to the central quadruplex within this structure, and lead to an alteration of its hydrodynamic properties and stability.


[Promoting the establishment of group standards in public health areas for China].
To better practice the Deepening Standardization Reform Plan, announced by the State Council, to promote the leadership of standard in healthy development of preventive medicine and public health, the Chinese Preventive Medicine Association (CPMA) established the Standardization Committee of Chinese Preventive Medicine Association (SC-CPMA). The SC-CPMA was responsible for the work of standardization developments of CPMA, including review of project's qualification and proposal, pre-qualification and qualification review of standard, publicity and training of standard, evaluation of standard implementation, review of standard, and public response monitoring of the standard. At December 13, 2018, CPMA published two group standards, the Technical specification of data processing for large population-based cohort study (T/CPMA 001-2018) and Technical specification of data security for large population-based cohort study (T/CPMA 002-2018). This was the first time that a group standard was published by CPMA and produced for large cohort study's establishment and research. These two standards were the milestones for public health areas and the academic achievement of team, leading by Dr. Li Liming, after decade of research and practice. The two standards were developed based on the China Kadoorie Biobank Study and aimed to formulate professional standards and standardized operation procedures that met the nationals conditions, with strong operability and generality of population cohort establishments. The group standards were also aimed to guide the establishments for other population-based cohort studies to maximum support the decision making and practice for disease control and prevention. The increasing disease burden of non-communicable disease (NCD) became severe public health problem and the etiology for NCD is complex. Large cohort studies, which became more popular recently, played an important role in observation and explanation of NCD etiology and risk factors. Under the current situation with growing number of large cohort studies, it is necessary to have a standard, which could be shared and used to guide other professional as critical scientific protocols. CPMA was committed to promoting the development of group standards in the field of public health, and supporting the implementation of the Healthy China Strategy.


A Neonatal Murine Model of Coxsackievirus A6 Infection for Evaluation of Antiviral and Vaccine Efficacy.
Hand, foot, and mouth disease (HFMD) is a global health concern. Family Picornaviridae members, particularly enterovirus A71 (EVA71) and coxsackievirus A16 (CVA16), are the primary etiological agents of HFMD; however, a third enterovirus A species, CVA6, has been recently associated with epidemic outbreaks. Study of the pathogenesis of CVA6 infection and development of antivirals and vaccines are hindered by a lack of appropriate animal models. We have developed and characterized a murine model of CVA6 infection that was employed to evaluate the antiviral activities of different drugs and the protective efficacies of CVA6-inactivated vaccines. Neonatal mice were susceptible to CVA6 infection via intramuscular inoculation, and the susceptibility of mice to CVA6 infection was age and dose dependent. Five-day-old mice infected with 105.5 50% tissue culture infective doses of the CVA6 WF057R strain consistently exhibited clinical signs, including reduced mobility, lower weight gain, and quadriplegia with significant pathology in the brain, hind limb skeletal muscles, and lungs of the infected mice in the moribund state. Immunohistochemical analysis and quantitative reverse transcription-PCR (qRT-PCR) analyses showed high viral loads (11 log10/mg) in skeletal muscle, and elevated levels of interleukin-6 (IL-6; >2,000 pg/ml) were associated with severe viral pneumonia and encephalitis. Ribavirin and gamma interferon administered prophylactically diminished CVA6-associated pathology in vivo, and treatment with IL-6 accelerated the death of neonatal mice. Both specific anti-CVA6 serum and maternal antibody play important roles in controlling CVA6 infection and viral replication. Collectively, these findings indicate that this neonatal murine model will be invaluable in future studies to develop CVA6-specific antivirals and vaccines.IMPORTANCE Although coxsackievirus A6 (CVA6) infections are commonly mild and self-limiting, a small proportion of children may have serious complications, such as encephalitis, acute flaccid paralysis, and neurorespiratory syndrome, leading to fatalities. We have established a mouse model of CVA6 infection by inoculation of neonatal mice with a CVA6 clinical isolate that produced consistent pathological outcomes. Here, using this model of CVA6 infection, we found that high levels of IL-6 were associated with severe viral pneumonia and encephalitis, as in an evaluation of antiviral efficacy in vivo, IL-6 had no protective effect and instead accelerated death in neonatal mice. We demonstrated that, as antiviral drugs, both gamma interferon and ribavirin played important protective roles in the early stages of infection, with increased survival in treated neonatal mice challenged with CVA6. Moreover, active and passive immunization with the inactivated vaccines and anti-CVA6 serum also protected mice against homologous challenge infections.


Immunovirologic characteristics of human immunodeficiency virus-infected patients consisting mainly of injecting drug users on highly active antiretroviral treatment with prolonged virologic failure.
Immunovirologic parameters of 24 heavily antiretroviral drug-pretreated patients with prolonged virologic treatment failure under highly active antiretroviral therapy, and who harbored highly resistant human immunodeficiency virus (HIV) isolates, were studied in this retrospective cross-sectional study. Most of the patients were injecting drug users (71%) and male (88%). All patients were studied for CD4(+) cell count, HIV viral load, resistance mutations, and viral phenotype. The patients showed a high accumulation of resistance-associated mutations, their CD4(+) cell count and viral load directly correlated with their respective values at initiation of therapy, and the presence of K103N was inversely associated with lower viral load. On the other hand, patients with K103N had the same level of CD4(+) cell count compared with patients without this mutation. Among the patients, a majority with a specific viral phenotype was not present. Rather, a dual-tropic virus was found most frequently, suggesting a preferential suppression of X4-specific strains and less cytopathogenicity during antiretroviral therapy and a greater proportion of R5X4 viruses due to an adaptation to that pressure.


Capnocytophaga felis sp. nov. isolated from the feline oral cavity.
Four strains, KC07070T, KC07105, 11 025B-8C and 11 026B-8-C, were isolated from the oral cavity of cats in 2007 or 2011 in Japan. These strains were Gram-stain-negative rods, exhibited gliding motility, grew in air with 5 % CO2 and showed catalase and oxidase activity. The sequences of 16S rRNA genes of the four strains were 100 % identical. Additionally, the sequences of 16S rRNA genes of KC07070T had identity to those of the type strains of Capnocytophaga canimorsus (97.7 %), Capnocytophaga cynodegmi (97.8 %) and Capnocytophaga canis (97.4 %) and 91.2-93.8% identity to those of other species of the genus Capnocytophaga. The major cellular fatty acids of KC07070T were iso-C15 : 0 (56.2 %) and summed feature 11 (14.9 %). The G+C content of the DNA from KC07070T was 35.6 mol%, and the genome size was 2.88 Mbp. KC07070T had digital DNA-DNA hybridization (dDDH) values of 26.2-27.6% and average nucleotide identity (ANI) values of 75.4-83.3 % to the type strains of the closest relatives, C. canimorsus, C. cynodegmi and C. canis. These results of phylogenetic analysis of 16S rRNA gene sequence, cellular fatty acids compositions and dDDH and ANI values indicate that strain KC07070T represents a novel species, for which we propose the name Capnocytophaga felis sp. nov., with type strain KC07070T (=JCM 32681T=DSM 107251T).


Effects of epidermal growth factor on ornithine decarboxylase activity and DNA synthesis in rats during the perinatal period.
The effects of epidermal growth factor (EGF) on ornithine decarboxylase (ODC) activity and DNA synthesis were studied during the perinatal period in rats. EGF administration to neonatal rats increased ODC activity and DNA synthesis in neonatal rat liver, but not in brain. EGF administration to maternal rats increased ODC activity in maternal rat liver, but not in rat placenta and fetal rat liver. These data suggest that EGF has mitogenic effects on neonatal and maternal rat liver and play some important roles in fetal and neonatal growth.


Regional variation in shea butter lipid and triterpene composition in four African countries.
The triacylglycerol, fatty acid, and polycyclic triterpene compositions of shea butter were determined for 150 samples from the sub-Saharan countries of Mali, Burkina Faso, Nigeria, and Uganda. The compositional profiles showed high variability in all three classes of compounds. Shea butter is made up mainly of four triglycerides (TAG) differing in carbon number (CN) by two, starting from CN 50 to CN 56. The greatest source of variation was in the CN 54 TAG. Shea butter is characterized by 16 saturated and unsaturated fatty acids in greatly varying proportion, the major ones being the even homologues in the range of C(16)-C(20). Oleic acid is dominant in Ugandan provenances, whereas stearic acid is dominant in West African shea butter. Acetyl and cinnamyl polycyclic triterpene means for countries ranged from 3.69 to 12.57%, with the highest values found in Nigerian provenances. Statistical comparisons of fat composition show that the geographic distance between shea populations is reflected in the degree of separation of their chemical profiles.