Lack of CpG island methylator phenotype defines a clinical subtype of T-cell acute lymphoblastic leukemia associated with good prognosis.
To examine cancer genes undergoing epigenetic inactivation in a set of T-cell acute lymphoblastic leukemias (T-ALLs) to obtain the CpG island methylator phenotype (CIMP) in the disease and its possible correlation with clinical features and outcome of the patients. Methylation-specific polymerase chain reaction was used to analyze methylation of the ADAMTS-1, ADAMTS-5, APAF-1, ASPP-1, CDH1, CDH13, DAPK, DIABLO, DKK-3, LATS-1, LATS-2, NES-1, p14, p15, p16, p57, p73, PARK-2, PTEN, sFRP1/2/4/5, SHP-1, SYK, TMS-1, and WIF-1 genes in samples from 50 consecutive T-ALL patients (19 children and 31 adults). Results were compared with results obtained in 286 B-cell acute lymphoblastic leukemias (B-ALLs). A total of 88% of the T-ALL samples had at least one gene methylated. According to the number of methylated genes observed in each individual sample, 12 patients (24%) were included in the CIMP- group (zero to two methylated genes), and 38 patients (76%) were included in the CIMP+ group (> two methylated genes). Clinical features and remission rate did not differ significantly among both groups of patients. Estimated disease-free survival (DFS) rate at 12 years and overall survival (OS) rate at 13 years were 100% and 91% for the CIMP- group and 20% and 17% for the CIMP+ group, respectively (P = .0006 and P = .003, respectively). Multivariate analysis demonstrated that methylation profile was an independent prognostic factor in predicting DFS (P = .05) and OS (P = .02). A group of five genes (SYK-1, ASPP-1, sFRP-2, sFRP-5, and WIF-1) showed specificity for T-ALL compared with B-ALL. Our results suggest that the methylation profile may be a potential new biomarker of risk prediction in T-ALL.


Acute exercise and postprandial lipemia in young people.
Exaggerated postprandial triacylglycerol concentrations (TAG) independently predict future cardiovascular events. Acute exercise and diet interventions attenuate postprandial TAG in adults. This paper aims to examine the exercise postprandial lipemia studies published to date in young people. Nine studies satisfied the inclusion criteria adopted for this summary. The majority of studies are in boys (22% girls) and have shown a single ~60-min session of moderate-intensity exercise, performed 12-18 hours before a standardized meal, reduces postprandial TAG. Manipulations of exercise duration and intensity suggest an exercise energy expenditure dose-dependent response is not supported directly in healthy young people. Studies investigating alternative exercise bouts have reported lower postprandial TAG after simulated intermittent games activity, high-intensity interval running and cumulative 10-min blocks over several hours, which may appeal to the spontaneous physical activity habits of young people. Although extension of these initial findings is warranted, exercise may be an effective strategy to promote regular benefits in TAG metabolism in children and adolescents; this may contribute to an improved cardiovascular disease risk profile early in life.


Cerebral blood flow sensitivities to CO2 measured with steady-state and modified rebreathing methods.
It is well established that the ventilatory response to carbon dioxide (CO(2)) measured by modified rebreathing (Sr(VE)) is closer to that measured by the steady-state method (Ss(VE)) than is the response measured by Read's rebreathing method. It is also known that the value estimated by the steady-state method depends upon the combination of data points used to measure it. The aim of this study was to investigate if these observations were also true for cerebral blood flow (CBF), as measured by steady-state (Ss(CBF)) and modified rebreathing (Sr(CBF)) tests. Six subjects undertook two protocols: (a) steady state: PET(CO2) was held at 1.5 mm Hg above normal (isocapnia) for 10 min, then raised to three levels of hypercapnia, (8 min each; 6.5, 11.5 and 16.5 mm Hg above normal, separated by 4 min isocapnia). End-tidal PO2 was held at 300 mm Hg; (b) modified rebreathing: subjects underwent 6 min of voluntary hyperventilation to PET(CO2) approximately 20 mm Hg, and then rebreathed via a 6l bag filled with 6.5% CO(2) in O(2). We confirmed that the value for Ss(VE) depended upon the combination of data points used to calculate it, and also confirmed that Ss(VE) and Sr(VE) were similar. However, this was not the case with CBF. Estimates of Ss(CBF) were the same, regardless of the data points used in calculation, and Ss(CBF) was 89% greater than Sr(CBF) (P<0.05). We interpret these findings as consistent with the notion that the specific CO(2) stimulus differs for CBF and ventilatory control. The data also indicate that prior hypocapnia in the modified rebreathing protocol may have a persistent effect on both cerebral vessels and central ventilatory control.


Transfer-Learning-Based Approach for the Diagnosis of Lung Diseases from Chest X-ray Images.
Using chest X-ray images is one of the least expensive and easiest ways to diagnose patients who suffer from lung diseases such as pneumonia and bronchitis. Inspired by existing work, a deep learning model is proposed to classify chest X-ray images into 14 lung-related pathological conditions. However, small datasets are not sufficient to train the deep learning model. Two methods were used to tackle this: (1) transfer learning based on two pretrained neural networks, DenseNet and ResNet, was employed; (2) data were preprocessed, including checking data leakage, handling class imbalance, and performing data augmentation, before feeding the neural network. The proposed model was evaluated according to the classification accuracy and receiver operating characteristic (ROC) curves, as well as visualized by class activation maps. DenseNet121 and ResNet50 were used in the simulations, and the results showed that the model trained by DenseNet121 had better accuracy than that trained by ResNet50.


Measurement of endotracheal tube cuff leak to predict postextubation stridor and need for reintubation.
The purpose of this study was to determine the predictive value of an endotracheal tube cuff leak for the development of postextubation stridor and the need for reintubation. Consecutive trauma patients who required intubation at a level I trauma center from July 1997 to July 1998 were studied prospectively. Pediatric patients and those who did not meet the standard weaning protocol criteria established by the Division of Trauma and Surgical Critical Care were excluded. Injury Severity Score, endotracheal tube size, reason for intubation, and the number of days intubated before the initial extubation attempt were recorded. At the time of extubation, the difference in exhaled tidal volume from before to after endotracheal tube cuff deflation was calculated. This number was then divided by the exhaled tidal volume before cuff deflation and was recorded as the percent cuff leak. Patients were followed for 24 hours after extubation for the development of stridor or need for reintubation. Statistical analysis to compare subgroups of patients was performed using ANOVA with Scheffé post hoc analysis. Among the 110 patients analyzed, the most common reason for intubation was closed-head injury. Seven patients (6.4%) developed stridor alone and had a mean cuff leak of 5 8 mL (8.4% of tidal volume before cuff deflation). Six patients (5.5%) experienced stridor that required reintubation and had a mean cuff leak of 68 mL (9.2% of tidal volume before cuff deflation). Patients who developed stridor or needed reintubation had been intubated for a significantly greater length of time than those not developing stridor or requiring reintubation (2.6 versus 3.0 days, p < 0.001). There were no differences in Injury Severity Score, endotracheal tube size, or reason for intubation between these groups. A cuff leak of less than 10% of tidal volume before cuff deflation is useful in identifying patients at risk for stridor or reintubation (96% specificity). It appears that the amount of cuff leak decreases after intubation for more than 3 days, increasing the risk of stridor and need for reintubation. This information may be helpful in identifying those patients who need treatment for laryngotracheal edema, ie, use of steroids or anesthesia during extubation, the efficacy of which remains to be determined.


Cardiac computed tomography angiography with automatic tube potential selection: effects on radiation dose and image quality.
Automatic exposure control (AEC) algorithms are widely available in coronary computed tomography angiography (CTA) and have been shown to reduce radiation doses by adjusting tube current to patient size. However, the effects of anthropometry-based automatic potential selection (APS) on image quality and radiation dose are unknown. We sought to investigate the effect of an APS algorithm on coronary CTA radiation dose and image quality. For this retrospective case-control study we selected 38 patients who had undergone coronary CTA for coronary artery assessment in whom tube potential and tube current were selected automatically by a combined automatic tube potential and tube current selection algorithm (APS-AEC) and compared them with 38 controls for whom tube voltage was selected according to standard body mass index (BMI) cutoffs and tube current was selected using automatic exposure control (BMI-AEC). Controls were matched for BMI, heart rate, heart rhythm, sex, acquisition mode, and indication for cardiac CTA. Image quality was assessed as contrast-to-noise ratio and signal-to-noise ratio in the proximal coronary arteries. Subjective reader assessment was also made. Total radiation dose (volume-weighted computed tomography dose index) was measured and compared between the 2 groups. In the study group, comparison was made with conventional BMI-guided prior protocols (site protocols and Society of Cardiovascular Computed Tomography recommendations) through disagreement analysis. The APS-AEC cases received 29.8% lower overall radiation dose compared with controls (P=not significant). APS-AEC resulted in a significantly higher signal-to-noise ratio of the proximal coronary arteries (P<0.01) and contrast-to-noise ratio of the left main (P=0.01). In the study cases, the APS resulted in a change in tube potential versus site protocols and Society of Cardiovascular Computed Tomography recommendations in 45% (n=17) and 50% (n=19) of patients, respectively. Automated tube potential selection software resulted in significantly improved objective image quality versus standard BMI-based methods of tube potential selection, without increased radiation doses.


Endotoxin-induced hypersensitivity to histamine in mice. I. Contrasting effects of bacterial lipopolysaccharides and the classical histamine-sensitizing factor of Bordetella pertussis.
Pieroni, Robert E. (Massachusetts Department of Public Health, Boston), Edward J. Broderick, and Leo Levine. Endotoxin-induced hypersensitivity to histamine in mice. I. Contrasting effects of bacterial lipopolysaccharides and the classical histamine-sensitizing factor of Bordetella pertussis. J. Bacteriol. 91:2169-2174. 1966.-The capacity of typhoid and possibly of pertussis endotoxins to induce histamine-shock susceptibility in some of the mice that survive graded doses of these endotoxins was confirmed. It was demonstrated, however, that pertussis endotoxin cannot be the main source of the typical histamine sensitization of pertussis vaccine. The following points are made. (i) With typhoid and pertussis endotoxins as inducers of histamine shock, no systematic relation between deaths and induction dose could be found, and 100% mortality could not be achieved. In contrast, with pertussis protective fraction as inducer, there was clear dose-response regression, with 100% mortality possible. (ii) The major part of the histamine-sensitizing activity of pertussis vaccine or its extracts was destroyed by trypsinization or by heating for 30 min at 100 C. These processes do not affect the histamine-sensitizing activity of the endotoxins. The implication for purified pertussis vaccine with high histamine-sensitization capacity is that endotoxin need not necessarily be present. The significance and possible mechanisms of action of endotoxin-induced histamine sensitivity are briefly discussed.


Dual nature of magnetic dopants and competing trends in topological insulators.
Topological insulators interacting with magnetic impurities have been reported to host several unconventional effects. These phenomena are described within the framework of gapping Dirac quasiparticles due to broken time-reversal symmetry. However, the overwhelming majority of studies demonstrate the presence of a finite density of states near the Dirac point even once topological insulators become magnetic. Here, we map the response of topological states to magnetic impurities at the atomic scale. We demonstrate that magnetic order and gapless states can coexist. We show how this is the result of the delicate balance between two opposite trends, that is, gap opening and emergence of a Dirac node impurity band, both induced by the magnetic dopants. Our results evidence a more intricate and rich scenario with respect to the once generally assumed, showing how different electronic and magnetic states may be generated and controlled in this fascinating class of materials.


Involvement of ras p21 in neurotrophin-induced response of sensory, but not sympathetic neurons.
Little is known about the signal transduction mechanisms involved in the response to neurotrophins and other neurotrophic factors in neurons, beyond the activation of the tyrosine kinase activity of the neurotrophin receptors belonging to the trk family. We have previously shown that the introduction of the oncogene product ras p21 into the cytoplasm of chick embryonic neurons can reproduce the survival and neurite-outgrowth promoting effects of the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), and of ciliary neurotrophic factor (CNTF). To assess the potential signal-transducing role of endogenous ras p21, we introduced function-blocking anti-ras antibodies or their Fab fragments into cultured chick embryonic neurons. The BDNF-induced neurite outgrowth in E12 nodose ganglion neurons was reduced to below control levels, and the NGF-induced survival of E9 dorsal root ganglion (DRG) neurons was inhibited in a specific and dose-dependent fashion. Both effects could be reversed by saturating the epitope-binding sites with biologically inactive ras p21 before microinjection. Surprisingly, ras p21 did not promote the survival of NGF-dependent E12 chick sympathetic neurons, and the NGF-induced survival in these cells was not inhibited by the Fab-fragments. The survival effect of CNTF on ras-responsive ciliary neurons could not be blocked by anti-ras Fab fragments. These results indicate an involvement of ras p21 in the signal transduction of neurotrophic factors in sensory, but not sympathetic or ciliary neurons, pointing to the existence of different signaling pathways not only in CNTF-responsive, but also in neurotrophin-responsive neuronal populations.


Exploring Participation and Interaction in a Bottom-Up Health Promotion Program for Migrant Women in Norway.
In this article, we examine the participation and interactions of migrant women and experts who attended health parties. Based on data from participation observations and semi-structured interviews from participants of health parties, we examine how health parties may be considered an innovative bottom-up community program that could influence how migrant women focus, learn, and discuss health issues as well as interact with health care. Through a qualitative analysis, the article demonstrates two ways of organizing health parties and different approaches to the health expert role, and how this impacts the social setting and interactions of a health party. In the Norwegian setting, migrant women are considered by health authorities to be the most difficult group to reach due to cultural and language barriers. Health parties may represent an alternative for bridging these barriers and may create a useful context for active participation and learning about health for migrant women.


Cardiac-Gated En Face Doppler Measurement of Retinal Blood Flow Using Swept-Source Optical Coherence Tomography at 100,000 Axial Scans per Second.
To develop and demonstrate a cardiac gating method for repeatable in vivo measurement of total retinal blood flow (TRBF) in humans using en face Doppler optical coherence tomography (OCT) at commercially available imaging speeds. A prototype swept-source OCT system operating at 100-kHz axial scan rate was developed and interfaced with a pulse oximeter. Using the plethysmogram measured from the earlobe, Doppler OCT imaging of a 1.5- × 2-mm area at the optic disc at 1.8 volumes/s was synchronized to cardiac cycle to improve sampling of pulsatile blood flow. Postprocessing algorithms were developed to achieve fully automatic calculation of TRBF. We evaluated the repeatability of en face Doppler OCT measurement of TRBF in 10 healthy young subjects using three methods: measurement at 100 kHz with asynchronous acquisition, measurement at 100 kHz with cardiac-gated acquisition, and a control measurement using a 400-kHz instrument with asynchronous acquisition. The median intrasubject coefficients of variation (COV) of the three methods were 8.0%, 4.9%, and 6.1%, respectively. All three methods correlated well, without a significant bias. Mean TRBF measured at 100 kHz with cardiac-gated acquisition was 40.5 ± 8.2 μL/min, and the range was from 26.6 to 55.8 μL/min. Cardiac-gated en face Doppler OCT can achieve smaller measurement variability than previously reported methods. Although further validation in older subjects and diseased subjects is required, precise measurement of TRBF using cardiac-gated en face Doppler OCT at commercially available imaging speeds should be feasible.


Liquid-filled hollow core microstructured polymer optical fiber.
Guidance in a liquid core is possible with microstructured optical fibers, opening up many possibilities for chemical and biochemical fiber-optic sensing. In this work we demonstrate how the bandgaps of a hollow core microstructured polymer optical fiber scale with the refractive index of liquid introduced into the holes of the microstructure. Such a fiber is then filled with an aqueous solution of (-)-fructose, and the resulting optical rotation measured. Hence, we show that hollow core microstructured polymer optical fibers can be used for sensing, whilst also fabricating a chiral optical fiber based on material chirality, which has many applications in its own right.


The effects of tertiary and quaternary infections on the epidemiology of dengue.
The epidemiology of dengue is characterised by irregular epidemic outbreaks and desynchronised dynamics of its four co-circulating virus serotypes. Whilst infection by one serotype appears to convey life-long protection to homologous infection, it is believed to be a risk factor for severe disease manifestations upon secondary, heterologous infection due to the phenomenon of Antibody-Dependent Enhancement (ADE). Subsequent clinical infections are rarely reported and, since the majority of dengue infections are generally asymptomatic, it is not clear if and to what degree tertiary or quaternary infections contribute to dengue epidemiology. Here we investigate the effect of third and subsequent infections on the transmission dynamics of dengue and show that although the qualitative patterns are largely equivalent, the system more readily exhibits the desynchronised serotype oscillations and multi-annual epidemic outbreaks upon their inclusion. More importantly, permitting third and fourth infections significantly increases the force of infection without resorting to high basic reproductive numbers. Realistic age-prevalent patterns and seroconversion rates are therefore easier reconciled with a low value of dengue's transmission potential if allowing for more than two infections; this should have important consequences for dengue control and intervention measures.


The heat shock-binding protein (HspBP1) protects cells against the cytotoxic action of the Tag7-Hsp70 complex.
Heat shock-binding protein HspBP1 is a member of the Hsp70 co-chaperone family. The interaction between HspBP1 and the ATPase domain of the major heat shock protein Hsp70 up-regulates nucleotide exchange and reduces the affinity between Hsp70 and the peptide in its peptide-binding site. Previously we have shown that Tag7 (also known as peptidoglycan recognition protein PGRP-S), an innate immunity protein, interacts with Hsp70 to form a stable Tag7-Hsp70 complex with cytotoxic activity against some tumor cell lines. This complex can be produced in cytotoxic lymphocytes and released during interaction with tumor cells. Here the effect of HspBP1 on the cytotoxic activity of the Tag7-Hsp70 complex was examined. HspBP1 could bind not only to Hsp70, but also to Tag7. This interaction eliminated the cytotoxic activity of Tag7-Hsp70 complex and decreased the ATP concentration required to dissociate Tag7 from the peptide-binding site of Hsp70. Moreover, HspBP1 inhibited the cytotoxic activity of the Tag7-Hsp70 complex secreted by lymphocytes. HspBP1 was detected in cytotoxic CD8+ lymphocytes. This protein was released simultaneously with Tag7-Hsp70 during interaction of these lymphocytes with tumor cells. The simultaneous secretion of the cytotoxic complex with its inhibitor could be a mechanism protecting normal cells from the cytotoxic effect of this complex.


Maternal mortality in eight European countries with enhanced surveillance systems: descriptive population based study.
To compare maternal mortality in eight countries with enhanced surveillance systems. Descriptive multicountry population based study. Eight countries with permanent surveillance systems using enhanced methods to identify, document, and review maternal deaths. The most recent available aggregated maternal mortality data were collected for three year periods for France, Italy, and the UK and for five year periods for Denmark, Finland, the Netherlands, Norway, and Slovakia. 297 835 live births in Denmark (2013-17), 301 169 in Finland (2008-12), 2 435 583 in France (2013-15), 1 281 986 in Italy (2013-15), 856 572 in the Netherlands (2014-18), 292 315 in Norway (2014-18), 283 930 in Slovakia (2014-18), and 2 261 090 in the UK (2016-18). Maternal mortality ratios from enhanced systems were calculated and compared with those obtained from each country's office of vital statistics. Age specific maternal mortality ratios; maternal mortality ratios according to women's origin, citizenship, or ethnicity; and cause specific maternal mortality ratios were also calculated. Methods for identifying and classifying maternal deaths up to 42 days were very similar across countries (except for the Netherlands). Maternal mortality ratios up to 42 days after end of pregnancy varied by a multiplicative factor of four from 2.7 and 3.4 per 100 000 live births in Norway and Denmark to 9.6 in the UK and 10.9 in Slovakia. Vital statistics offices underestimated maternal mortality by 36% or more everywhere but Denmark. Age specific maternal mortality ratios were higher for the youngest and oldest mothers (pooled relative risk 2.17 (95% confidence interval 1.38 to 3.34) for women aged <20 years, 2.10 (1.54 to 2.86) for those aged 35-39, and 3.95 (3.01 to 5.19) for those aged ≥40, compared with women aged 20-29 years). Except in Norway, maternal mortality ratios were ≥50% higher in women born abroad or of minoritised ethnicity, defined variously in different countries. Cardiovascular diseases and suicides were leading causes of maternal deaths in each country. Some other conditions were also major contributors to maternal mortality in only one or two countries: venous thromboembolism in the UK and the Netherlands, hypertensive disorders in the Netherlands, amniotic fluid embolism in France, haemorrhage in Italy, and stroke in Slovakia. Only two countries, France and the UK, had enhanced methods for studying late maternal deaths, those occurring between 43 and 365 days after the end of pregnancy. Variations in maternal mortality ratios exist between high income European countries with enhanced surveillance systems. In-depth analyses of differences in the quality of care and health system performance at national levels are needed to reduce maternal mortality further by learning from best practices and each other. Cardiovascular diseases and mental health in women during and after pregnancy must be prioritised in all countries.


Plant Invasions Associated with Change in Root-Zone Microbial Community Structure and Diversity.
The importance of plant-microbe associations for the invasion of plant species have not been often tested under field conditions. The research sought to determine patterns of change in microbial communities associated with the establishment of invasive plants with different taxonomic and phenetic traits. Three independent locations in Virginia, USA were selected. One site was invaded by a grass (Microstegium vimineum), another by a shrub (Rhamnus davurica), and the third by a tree (Ailanthus altissima). The native vegetation from these sites was used as reference. 16S rRNA and ITS regions were sequenced to study root-zone bacterial and fungal communities, respectively, in invaded and non-invaded samples and analyzed using Quantitative Insights Into Microbial Ecology (QIIME). Though root-zone microbial community structure initially differed across locations, plant invasion shifted communities in similar ways. Indicator species analysis revealed that Operational Taxonomic Units (OTUs) closely related to Proteobacteria, Acidobacteria, Actinobacteria, and Ascomycota increased in abundance due to plant invasions. The Hyphomonadaceae family in the Rhodobacterales order and ammonia-oxidizing Nitrospirae phylum showed greater relative abundance in the invaded root-zone soils. Hyphomicrobiaceae, another bacterial family within the phyla Proteobacteria increased as a result of plant invasion, but the effect associated most strongly with root-zones of M. vimineum and R. davurica. Functional analysis using Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) showed bacteria responsible for nitrogen cycling in soil increased in relative abundance in association with plant invasion. In agreement with phylogenetic and functional analyses, greater turnover of ammonium and nitrate was associated with plant invasion. Overall, bacterial and fungal communities changed congruently across plant invaders, and support the hypothesis that nitrogen cycling bacteria and functions are important factors in plant invasions. Whether the changes in microbial communities are driven by direct plant microbial interactions or a result of plant-driven changes in soil properties remains to be determined.


The Lac repressor provides a reversible gene expression system in undifferentiated and differentiated embryonic stem cell.
Control of mammalian gene promoters by the bacterial LacI repressor provides reversible regulation and dose-response levels of derepressed expression by the lactose analog isopropyl thiogalactose (IPTG). Here, we show that insertion of LacI-binding sites in the ubiquitous beta-actin promoter confers a strong and dose-dependent IPTG-regulatable expression of transiently transfected reporter genes in mouse embryonic stem (ES) cells expressing LacI. We established ES cell lines stably expressing reporter genes under inducible control and found a five- to tenfold IPTG induction of transgene expression. The kinetics of induction is rapid and stable, and can be rapidly reversed after IPTG removal. Importantly, this regulatable expression was maintained throughout the differentiation process of ES cells, and observed in individual differentiated cardiomyocyte-like cells and neuronal-like cells. This reversible system is the first to function from undifferentiated to individual well-differentiated ES cells, providing a very useful tool to understand molecular mechanisms underlying ES cell self-renewal, commitment and differentiation.


Lessons learned from the Dutch Institute for Clinical Auditing: the Dutch model for quality assurance in lung cancer treatment.
Quality registries play an important role in the professional quality system for cancer treatment in The Netherlands. This article provides insight into the Dutch Lung Cancer Audit (DLCA); its core principles, initiation and development, first results and what lessons can be learned from the Dutch experience. Cornerstones of the DLCA are discussed in detail, including: audit aims; the leading role for clinicians; web-based registration and feedback; data handling; multidisciplinary evaluation of quality indicators; close collaborations with all stakeholders in healthcare and transparency of results. In 2012 the first Dutch lung cancer specific sub-registry, focusing on surgical treatment was started. Since 2016 all major treating specialisms (lung oncologists, radiation-oncologists, general- and cardiothoracic surgeons-represented in the DLCA-L, -R and -S sub-registries respectively) have joined. Over time, the number of participating hospitals and included patients has increased. In 2016, the numbers of included patients with a non-small cell lung cancer (NSCLC) were 3,502 (DLCA-L), 2,427 (DLCA-R) and 1,979 (DLCA-S). Between sub-registries mean age varied from 66 to 70 years, occurrence of Eastern Cooperative Oncology Group (ECOG) performance score 2+ varied from 3.3% to 20.8% and occurrence of clinical stage I-II from 27.6% to 81.3%. Of all patients receiving chemoradiotherapy 64.2% was delivered concurrently. Of the surgical procedures 71.2% was started with a minimally invasive technique, with a conversion rate of 18.7%. In 2016 there were 17 publicly available quality indicators-consisting of structure, process and outcome indicators- calculated from the DLCA. the DLCA is a unique registry to evaluate the quality of multidisciplinary lung cancer care. It is accepted and implemented on a nationwide level, enabling participating healthcare providers to get insight in their performance, and providing other stakeholders with a transparent evaluation of this performance, all aiming for continuous healthcare improvement.


Identification of the Actinomycin D Biosynthetic Pathway from Marine-Derived Streptomyces costaricanus SCSIO ZS0073.
Bioactive secondary metabolites from Streptomycetes are important sources of lead compounds in current drug development. Streptomyces costaricanus SCSIO ZS0073, a mangrove-derived actinomycete, produces actinomycin D, a clinically used therapeutic for Wilm's tumor of the kidney, trophoblastic tumors and rhabdomyosarcoma. In this work, we identified the actinomycin biosynthetic gene cluster (BGC) acn by detailed analyses of the S. costaricanus SCSIO ZS0073 genome. This organism produces actinomycin D with a titer of ~69.8 μg mL-1 along with traces of actinomycin Xoβ. The acn cluster localized to a 39.8 kb length region consisting of 25 open reading frames (ORFs), including a set of four genes that drive the construction of the 4-methyl-3-hydroxy-anthranilic acid (4-MHA) precursor and three non-ribosomal peptide synthetases (NRPSs) that generate the 4-MHA pentapeptide semi-lactone, which, upon dimerization, affords final actinomycin D. Furthermore, the acn cluster contains four positive regulatory genes acnWU4RO, which were identified by in vivo gene inactivation studies. Our data provide insights into the genetic characteristics of this new mangrove-derived actinomycin D bioproducer, enabling future metabolic engineering campaigns to improve both titers and the structural diversities possible for actinomycin D and related analogues.


Gold-catalyzed oxidative hydroacylation reactions of α-iminoalkynes with aldehydes and O2.
Gold-catalyzed aerobic oxidations of α-iminoalkynes with aryl aldehydes led to oxidative 1,3-hydroacyclation reactions, yielding high Z-selectivity. We performed 2H- and 18O-labeling experiments to confirm the role of water as an oxygen donor and O2 as the main oxidant. The Z-selectivity arises from an efficient conjugation between the enone and its aryl substituent. We postulate an initial [4+2]-annulation of α-iminoalkynes with aldehydes to form a six-membered oxonium species that is attacked by water, followed by the O2 oxidation of a key intermediate.


Glutamatergic neurotransmission between the C1 neurons and the parasympathetic preganglionic neurons of the dorsal motor nucleus of the vagus.
The C1 neurons are a nodal point for blood pressure control and other autonomic responses. Here we test whether these rostral ventrolateral medullary catecholaminergic (RVLM-CA) neurons use glutamate as a transmitter in the dorsal motor nucleus of the vagus (DMV). After injecting Cre-dependent adeno-associated virus (AAV2) DIO-Ef1α-channelrhodopsin2(ChR2)-mCherry (AAV2) into the RVLM of dopamine-β-hydroxylase Cre transgenic mice (DβH(Cre/0)), mCherry was detected exclusively in RVLM-CA neurons. Within the DMV >95% mCherry-immunoreactive(ir) axonal varicosities were tyrosine hydroxylase (TH)-ir and the same proportion were vesicular glutamate transporter 2 (VGLUT2)-ir. VGLUT2-mCherry colocalization was virtually absent when AAV2 was injected into the RVLM of DβH(Cre/0);VGLUT2(flox/flox) mice, into the caudal VLM (A1 noradrenergic neuron-rich region) of DβH(Cre/0) mice or into the raphe of ePet(Cre/0) mice. Following injection of AAV2 into RVLM of TH-Cre rats, phenylethanolamine N-methyl transferase and VGLUT2 immunoreactivities were highly colocalized in DMV within EYFP-positive or EYFP-negative axonal varicosities. Ultrastructurally, mCherry terminals from RVLM-CA neurons in DβH(Cre/0) mice made predominantly asymmetric synapses with choline acetyl-transferase-ir DMV neurons. Photostimulation of ChR2-positive axons in DβH(Cre/0) mouse brain slices produced EPSCs in 71% of tested DMV preganglionic neurons (PGNs) but no IPSCs. Photostimulation (20 Hz) activated PGNs up to 8 spikes/s (current-clamp). EPSCs were eliminated by tetrodotoxin, reinstated by 4-aminopyridine, and blocked by ionotropic glutamate receptor blockers. In conclusion, VGLUT2 is expressed by RVLM-CA (C1) neurons in rats and mice regardless of the presence of AAV2, the C1 neurons activate DMV parasympathetic PGNs monosynaptically and this connection uses glutamate as an ionotropic transmitter.


The administration of adjuvant chemo(-immuno) therapy in the post ACOSOG-Z0011 era; a population based study.
The ACOSOG-Z0011-study has resulted in a trend to a more conservative treatment of the axilla for selected sentinel-node-positive patients. However, axillary nodal involvement has always been an important factor for tumor staging and tailoring adjuvant chemotherapy plans. This study evaluates the impact of omitting completion axillary lymph node dissection (cALND) on the administration of adjuvant chemo (-immuno)therapy in Dutch clinical T1-2N0M0 (cT1-2N0M0) sentinel-node-positive breast cancer patients. Data were obtained from the nationwide NABON breast cancer audit. Descriptive analyses were used to demonstrate trends in axillary surgery and adjuvant chemo (-immuno)therapy. Multivariable logistic regression analyses were used to identify factors associated with the prescription of chemo (-immuno)therapy. In this cohort of 4331 patients, the omission of a cALND increased from 34% to 92%, and the administration of chemo (-immuno)therapy decreased from 68% to 55%, between 2011 and 2015 (P < 0.001). Patients treated with cALND had an OR of 2.2 for receiving adjuvant chemo (-immuno)therapy compared with SLNB only patients. Lower age, a hormone receptor (HR) status other than HR-positive, HER2-negative, increasing tumor grade and stage, and a lymph node status ≥ pN2 were independently associated with a higher probability of chemo (-immuno)therapy (P < 0.05). This study showed that Dutch cT1-2N0M0 sentinel node-positive breast cancer patients treated with cALND had a higher independent probability for receiving adjuvant chemo (-immuno)therapy compared with SLNB only patients, even when corrected for lymph node status and HR-status. Probably, the decisions to administer adjuvant chemo (-immuno)therapy were not only based on guidelines and tumor characteristics, but also on the preferences from physicians and patients.


Anticancer effects of the MHY218 novel hydroxamic acid-derived histone deacetylase inhibitor in human ovarian cancer cells.
To investigate the anticancer effects of the novel hydroxamic acid-derived histone deacetylase (HDAC) inhibitor MHY218, its efficacy was compared to that of suberoylanilide hydroxamic acid (SAHA) in human ovarian cancer cells. The anticancer effects of MHY218 on cell viability, cell cycle regulation and apoptosis were investigated. In addition, MHY218 or SAHA was administered for 28 days in a tumor carcinomatosis model with SKOV-3 cells. MHY218 significantly reduced the expression of HDAC4 and HDAC7 in SKOV-3 cells. Similarly, MHY218 also inhibited total HDAC, HDAC1, HDAC4 and HDAC7 enzyme activity in a concentration-dependent manner. The anticancer effect of MHY218 (IC50, 3.2 microM) was more potent than SAHA (IC50, 3.9 microM) in suppressing the SKOV-3 cell viability. Moreover, MHY218 markedly increased expression of p21WAF1/CIP1, which acts as a cell cycle inhibitor. Cell cycle analysis showed that the high dose (5 microM) of MHY218 significantly increased the proportion of cells in the G2/M phase. In particular, MHY218 and SAHA significantly increased the sub-G1 population and the number of TUNEL-positive apoptotic cells compared with those in the untreated control. These results were confirmed by analysis of poly-ADP ribose polymerase (PARP), where MHY218 and SAHA increased the level of an 85-kDa fragment resulting from PARP cleavage as well as caspase-3 activity. Likewise, MHY218-induced apoptosis through caspase-3 activation was confirmed by the increase in the release of cytochrome c and Bax/Bcl-2 ratio. In an in vivo tumor carcinomatosis model, the growth of transplanted SKOV-3 cells was inhibited by 71% after treatment with MHY218 (10 mg/kg), whereas SAHA (25 mg/kg) suppressed growth by 48%. These results indicate that MHY218 is a potent HDAC inhibitor that targets regulating multiple aspects of cancer cell death and might have preclinical value in ovarian cancer chemotherapy, warranting further investigation.


The relationship between blood viscosity and blood pressure in a random sample of the population aged 55 to 74 years.
Blood viscosity is elevated in hypertensive subjects, but the association of viscosity with arterial blood pressure in the general population, and the influence of social, lifestyle and disease characteristics on this association, are not established. In the Edinburgh Artery Study, 1592 men and women aged 55-74 years selected randomly from the general population attended a university clinic. A fasting blood sample was taken for the measurement of blood viscosity and its major determinants (haematocrit, plasma viscosity and fibrinogen). Systolic pressure was related univariately to blood viscosity (P < 0.001), plasma viscosity (P < 0.001) and plasma fibrinogen (P < 0.01), but the association with fibrinogen did not persist after adjusting for body mass index. Diastolic pressure was related univariately to blood viscosity (P < 0.001) and plasma viscosity (P < 0.001) and haematocrit (P < 0.001) but not to fibrinogen. The only difference between the sexes was that the association between blood viscosity and systolic pressure was confined to males. Blood viscosity was associated equally with systolic and diastolic pressures in males, and remained independently related on multivariate analysis adjusting for age, sex, body mass index, social class, smoking, alcohol intake, exercise, angina, HDL and non-HDL cholesterol, diabetes mellitus, plasma viscosity, fibrinogen, and haematocrit.


[Diabetes as primary or associated cause of death in the state of São Paulo, Brazil, 1992].
Analysis of mortality data are usually performed with reference to the underlying cause of death. The importance of diabetes as a cause of death is always underestimated, because diabetics generally die from chronic complications of the disease, these being considered as the underlying cause of the death. To attenuate this problem, mortality data should be analyzed on the basis of all the causes listed on the death certificate. Frequency of references to diabetes on death certificates and the principal associated causes were evaluated as a contribution to the solution of this problem. Specific death rates and proportional mortality by diabetes, as underlying or associated cause, were calculated on the basis of information derived from death certificates by the ACME program (Automated Classification of Medical Entities), for the State of S. Paulo, in 1992. Of a total of 202,141 deaths, diabetes was mentioned in 13,786 (6.8%) and as being the underlying cause in 5,305(2.6%). The proportion was higher for women than men (10.1 vs. 4.6% as mentioned, and 6.1 vs 2.9% as underlying cause). Among deaths with a mention of diabetes on the certificate, the main underlying causes were: diabetes (38.5%), cardiovascular (37.2%) and respiratory (8.5%) diseases, and neoplasias (4.8%). When diabetes was the underlying cause, the main associated causes were: cardiovascular (42.2%), respiratory (10.7%) and genitourinary (10.1%) diseases. When diabetes was an associated cause, the main underlying causes were: cardiovascular (60.5%) and respiratory (13.8%) diseases, and neoplasias (7.9%). In spite of the limitation of the data from death certificates, it is possible to observe the importance of diabetes as cause of death, reflecting its magnitude as a health problem. Also, the analysis by multiple causes of deaths gives an idea of the morbidity profile associated with diabetes at the time of death, showing the importance of the group of cardiovascular diseases.


Intramolecular binding mode of the C-terminus of Escherichia coli single-stranded DNA binding protein determined by nuclear magnetic resonance spectroscopy.
Single-stranded DNA (ssDNA) binding protein (SSB) is an essential protein to protect ssDNA and recruit specific ssDNA-processing proteins. Escherichia coli SSB forms a tetramer at neutral pH, comprising a structurally well-defined ssDNA binding domain (OB-domain) and a disordered C-terminal domain (C-domain) of ∼ 64 amino acid residues. The C-terminal eight-residue segment of SSB (C-peptide) has been shown to interact with the OB-domain, but crystal structures failed to reveal any electron density of the C-peptide. Here we show that SSB forms a monomer at pH 3.4, which is suitable for studies by high-resolution nuclear magnetic resonance (NMR) spectroscopy. The OB-domain retains its 3D structure in the monomer, and the C-peptide is shown by nuclear Overhauser effects and lanthanide-induced pseudocontact shifts to bind to the OB-domain at a site that harbors ssDNA in the crystal structure of the SSB-ssDNA complex. (15)N relaxation data demonstrate high flexibility of the polypeptide segment linking the C-peptide to the OB-domain and somewhat increased flexibility of the C-peptide compared with the OB-domain, suggesting that the C-peptide either retains high mobility in the bound state or is in a fast equilibrium with an unbound state.


Single molecular force across single integrins dictates cell spreading.
Cells' ability to sense and interpret mechanical signals from the extracellular milieu modulates the degree of cell spreading. Yet how cells detect such signals and activate downstream signaling at the molecular level remain elusive. Herein, we utilize tension gauge tether (TGT) platform to investigate the underlying molecular mechanism of cell spreading. Our data from both differentiated cells of cancerous and non-cancerous origin show that for the same stiff underlying glass substrates and for same ligand density it is the molecular forces across single integrins that ultimately determine cell spreading responses. Furthermore, by decoupling molecular stiffness and molecular tension we demonstrate that molecular stiffness has little influence on cell spreading. Our data provide strong evidence that links molecular forces at the cell-substrate interface to the degree of cell spreading.


Estrogen metabolites increase nociceptor hyperactivity in a mouse model of uterine pain.
Pain emanating from the female reproductive tract is notoriously difficult to treat, and the prevalence of transient pelvic pain has been placed as high as 70%-80% in women surveyed. Although sex hormones, especially estrogen, are thought to underlie enhanced pain perception in females, the underlying molecular and cellular mechanisms are not completely understood. Here, we showed that the pain-initiating TRPA1 channel was required for pain-related behaviors in a mouse model of estrogen-induced uterine pain in ovariectomized female mice. Surprisingly, 2- and 4-hydroxylated estrogen metabolites (2- and 4-HEMs) in the estrogen hydroxylation pathway, but not estrone, estradiol, or 16-HEMs, directly increased nociceptor hyperactivity through TRPA1 and TRPV1 channels, and picomolar concentrations of 2- and 4-hydroxylation estrone (2- or 4-OHE1) could sensitize TRPA1 channel function. Moreover, both TRPA1 and TRPV1 were expressed in uterine-innervating primary nociceptors, and their expression was increased in the estrogen-induced uterine pain model. Importantly, pretreatment with 2- or 4-OHE1 recapitulated estrogen-induced uterine pain-like behaviors, and intraplantar injections of 2- and 4-OHE1 directly produced a TRPA1-dependent mechanical hypersensitivity. Our findings demonstrated that TRPA1 is critically involved in estrogen-induced uterine pain-like behaviors, which may provide a potential drug target for treating female reproductive tract pain.


Spike detection using the continuous wavelet transform.
This paper combines wavelet transforms with basic detection theory to develop a new unsupervised method for robustly detecting and localizing spikes in noisy neural recordings. The method does not require the construction of templates, or the supervised setting of thresholds. We present extensive Monte Carlo simulations, based on actual extracellular recordings, to show that this technique surpasses other commonly used methods in a wide variety of recording conditions. We further demonstrate that falsely detected spikes corresponding to our method resemble actual spikes more than the false positives of other techniques such as amplitude thresholding. Moreover, the simplicity of the method allows for nearly real-time execution.


Incident myocardial infarction associated with major types of arthritis in the general population: a systematic review and meta-analysis.
To synthesise, quantify and compare risks for incident myocardial infarction (MI) across five major types of arthritis in population-based studies. A systematic search was performed in MEDLINE, EMBASE and CINAHL databases with additional manual/hand searches for population-based cohort or case-control studies published in English of French between January 1980 and January 2015 with a measure of effect and variance for associations between incident MI and five major types of arthritis: rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), gout or osteoarthritis (OA), adjusted for at least age and sex. All search screening, data abstraction quality appraisals were performed independently by two reviewers. Where appropriate, random-effects meta-analysis was used to pool results from studies with a minimum of 10 events. We identified a total of 4, 285 articles; 27 met review criteria and 25 criteria for meta-analyses. In studies adjusting for age and sex, MI risk was significantly increased in RA (pooled relative risk (RR): 1.69, 95% CI 1.50 to 1.90), gout (pooled RR: 1.47, 95% CI 1.24 to 1.73), PsA (pooled RR: 1.41, 95% CI 1.17 to 1.69), OA (pooled RR: 1.31, 95% CI 1.01 to 1.71) and tended towards increased risk in AS (pooled RR: 1.24, 95% CI 0.93 to 1.65). Traditional risk factors were more prevalent in all types of arthritis. MI risk was attenuated for each type of arthritis in studies adjusting for traditional risk factors and remained significantly increased in RA, PsA and gout. MI risk was consistently increased in multiple types of arthritis in population-based studies, and was partially explained by a higher prevalence of traditional risk factors in all types of arthritis. Findings support more integrated cardiovascular (CV) prevention strategies for arthritis populations that target both reducing inflammation and enhancing management of traditional CV risk factors.


Major drawbacks and additional benefits of agonist trigger--not ovarian hyperstimulation syndrome related.
The GnRH agonist trigger alters traditional IVF paradigms when compared with hCG-only triggers. The agonist trigger induces rapid luteolysis and therefore separates the oocyte maturation aspect of LH from the luteal support previously afforded by lingering hCG. This might allow customized and more optimal luteal support. The agonist trigger option also allows continued stimulation and subsequent trigger of high responders with reasonable safety, potentially leading to retrievals of larger cohorts of mature oocytes. It may also reduce the number of retrievals needed to achieve a large family. The agonist trigger might alter other paradigms as well, such as making oocyte donation more efficient per stimulation by virtually eliminating follicular-phase cycle cancellation, coasting, and premature triggering. There are both corresponding potential benefits and drawbacks of using the agonist trigger and the shifting paradigms it allows.


Rapid evaluation for health and social care innovations: challenges for "quick wins" using interrupted time series.
Rapid evaluation was at the heart of National Health Service England's evaluation strategy of the new models of care vanguard programme. This was to facilitate the scale and spread of successful models of care throughout the health & social care system. The aim of this paper is to compare the findings of the two evaluations of the Enhanced health in Care Homes (EHCH) vanguard in Gateshead, one using a smaller data set for rapidity and one using a larger longitudinal data set and to investigate the implications of the use of rapid evaluations using interrupted time series (ITS) methods. A quasi-experimental design study in the form of an ITS was used to evaluate the impact of the vanguard on secondary care use. Two different models are presented differing by timeframes only. The short-term model consisted of data for 11 months data pre and 20 months post vanguard. The long-term model consisted of data for 23 months pre and 34 months post vanguard. The cost consequences, including the cost of running the EHCH vanguard, were estimated using both a single tariff non-elective admissions methodology and a tariff per bed day methodology. The short-term model estimated a monthly cost increase of £73,408 using a single tariff methodology. When using a tariff per bed day, there was an estimated monthly cost increase of £14,315. The long-term model had, using a single tariff for non-elective admissions, an overall cost increase of £7576 per month. However, when using a tariff per bed-days, there was an estimated monthly cost reduction of £57,168. Although it is acknowledged that there is often a need for rapid evaluations in order to identify "quick wins" and to expedite learning within health and social care systems, we conclude that this may not be appropriate for quasi-experimental designs estimating effect using ITS for complex interventions. Our analyses suggests that care must be taken when conducting and interpreting the results of short-term evaluations using ITS methods, as they may produce misleading results and may lead to a misallocation of resources.


Arginase: A Multifaceted Enzyme Important in Health and Disease.
The arginase enzyme developed in early life forms and was maintained during evolution. As the last step in the urea cycle, arginase cleaves l-arginine to form urea and l-ornithine. The urea cycle provides protection against excess ammonia, while l-ornithine is needed for cell proliferation, collagen formation, and other physiological functions. In mammals, increases in arginase activity have been linked to dysfunction and pathologies of the cardiovascular system, kidney, and central nervous system and also to dysfunction of the immune system and cancer. Two important aspects of the excessive activity of arginase may be involved in diseases. First, overly active arginase can reduce the supply of l-arginine needed for the production of nitric oxide (NO) by NO synthase. Second, too much l-ornithine can lead to structural problems in the vasculature, neuronal toxicity, and abnormal growth of tumor cells. Seminal studies have demonstrated that increased formation of reactive oxygen species and key inflammatory mediators promote this pathological elevation of arginase activity. Here, we review the involvement of arginase in diseases affecting the cardiovascular, renal, and central nervous system and cancer and discuss the value of therapies targeting the elevated activity of arginase.


Peripheral intravenous catheter duration and failure in paediatric acute care: A prospective cohort study.
Children admitted to hospital commonly require peripheral intravenous catheters (PIVCs) for treatment. This study sought to address a gap in the literature about current practice in the securement and dressing of PIVCs in paediatric acute care, and to ascertain the duration and failure of these devices. A prospective cohort study conducted at the Royal Children's Hospital in Queensland, Australia. All patients aged 0-15 years, who presented to the ED between 16 July and 16 October 2012, and had a PIVC inserted prior to emergent admission to the hospital were included. Of 458 participants, median device duration was 29 h (IQR 13-58 h), and ranged from less than 1 h to 16 days. One quarter (113/456, 24.8%) of PIVCs were removed due to device failure, presenting as: infiltration (65/456, 14.3%); accidental dislodgement (23/456, 5.0%); blockage (12/456, 2.6%); phlebitis (7/456, 1.5%); or 'other' (6/456, 1.3%). PIVC securement and dressings were predominantly bordered polyurethane dressings and splints (n = 457/458, 99.8%). PIVC placement in the antecubital fossa, in comparison to the hand, was significantly associated with an increased risk for failure (P = 0.03). No other patient and device characteristics had a significant association with device failure (P > 0.05). The median dwell time of PIVCs that failed was significantly longer than the PIVCs that did not fail (44.0 vs 25.5 h; P = 0.002). Less than half (53/113, 46.9%) of failed catheters were replaced with a new PIVC. Observed failure rates were high for a clinically essential device; however, there is no established rate of acceptability against which the results can be benchmarked against to facilitate effectiveness of practice. Many PIVCs appeared to remain in place longer than needed. Dressing and securement practice was homogenous. PIVC placement in the antecubital fossa should be minimised to reduce the risk of paediatric PIVC failure.


Weight change in middle adulthood and risk of cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.
Obesity is a risk factor for several major cancers. Associations of weight change in middle adulthood with cancer risk, however, are less clear. We examined the association of change in weight and body mass index (BMI) category during middle adulthood with 42 cancers, using multivariable Cox proportional hazards models in the European Prospective Investigation into Cancer and Nutrition cohort. Of 241 323 participants (31% men), 20% lost and 32% gained weight (>0.4 to 5.0 kg/year) during 6.9 years (average). During 8.0 years of follow-up after the second weight assessment, 20 960 incident cancers were ascertained. Independent of baseline BMI, weight gain (per one kg/year increment) was positively associated with cancer of the corpus uteri (hazard ratio [HR] = 1.14; 95% confidence interval: 1.05-1.23). Compared to stable weight (±0.4 kg/year), weight gain (>0.4 to 5.0 kg/year) was positively associated with cancers of the gallbladder and bile ducts (HR = 1.41; 1.01-1.96), postmenopausal breast (HR = 1.08; 1.00-1.16) and thyroid (HR = 1.40; 1.04-1.90). Compared to maintaining normal weight, maintaining overweight or obese BMI (World Health Organisation categories) was positively associated with most obesity-related cancers. Compared to maintaining the baseline BMI category, weight gain to a higher BMI category was positively associated with cancers of the postmenopausal breast (HR = 1.19; 1.06-1.33), ovary (HR = 1.40; 1.04-1.91), corpus uteri (HR = 1.42; 1.06-1.91), kidney (HR = 1.80; 1.20-2.68) and pancreas in men (HR = 1.81; 1.11-2.95). Losing weight to a lower BMI category, however, was inversely associated with cancers of the corpus uteri (HR = 0.40; 0.23-0.69) and colon (HR = 0.69; 0.52-0.92). Our findings support avoiding weight gain and encouraging weight loss in middle adulthood.


Low-load high volume resistance exercise stimulates muscle protein synthesis more than high-load low volume resistance exercise in young men.
We aimed to determine the effect of resistance exercise intensity (%1 repetition maximum-1RM) and volume on muscle protein synthesis, anabolic signaling, and myogenic gene expression. Fifteen men (21+/-1 years; BMI=24.1+/-0.8 kg/m2) performed 4 sets of unilateral leg extension exercise at different exercise loads and/or volumes: 90% of repetition maximum (1RM) until volitional failure (90FAIL), 30% 1RM work-matched to 90%FAIL (30WM), or 30% 1RM performed until volitional failure (30FAIL). Infusion of [ring-13C6] phenylalanine with biopsies was used to measure rates of mixed (MIX), myofibrillar (MYO), and sarcoplasmic (SARC) protein synthesis at rest, and 4 h and 24 h after exercise. Exercise at 30WM induced a significant increase above rest in MIX (121%) and MYO (87%) protein synthesis at 4 h post-exercise and but at 24 h in the MIX only. The increase in the rate of protein synthesis in MIX and MYO at 4 h post-exercise with 90FAIL and 30FAIL was greater than 30WM, with no difference between these conditions; however, MYO remained elevated (199%) above rest at 24 h only in 30FAIL. There was a significant increase in AktSer473 at 24h in all conditions (P=0.023) and mTORSer2448 phosphorylation at 4 h post-exercise (P=0.025). Phosporylation of Erk1/2Tyr202/204, p70S6KThr389, and 4E-BP1Thr37/46 increased significantly (P<0.05) only in the 30FAIL condition at 4 h post-exercise, whereas, 4E-BP1Thr37/46 phosphorylation was greater 24 h after exercise than at rest in both 90FAIL (237%) and 30FAIL (312%) conditions. Pax7 mRNA expression increased at 24 h post-exercise (P=0.02) regardless of condition. The mRNA expression of MyoD and myogenin were consistently elevated in the 30FAIL condition. These results suggest that low-load high volume resistance exercise is more effective in inducing acute muscle anabolism than high-load low volume or work matched resistance exercise modes.


Neurolinguistic measures of typological effects in multilingual transfer: introducing an ERP methodology.
This article has two main objectives. First, we offer an introduction to the subfield of generative third language (L3) acquisition. Concerned primarily with modeling initial stages transfer of morphosyntax, one goal of this program is to show how initial stages L3 data make significant contributions toward a better understanding of how the mind represents language and how (cognitive) economy constrains acquisition processes more generally. Our second objective is to argue for and demonstrate how this subfield will benefit from a neuro/psycholinguistic methodological approach, such as event-related potential experiments, to complement the claims currently made on the basis of exclusively behavioral experiments.


Binaural unmasking with multiple adjacent masking electrodes in bilateral cochlear implant users.
Bilateral cochlear implant (BiCI) users gain an advantage in noisy situations from a second implant, but their bilateral performance falls short of normal hearing listeners. Channel interactions due to overlapping electrical fields between electrodes can impair speech perception, but its role in limiting binaural hearing performance has not been well characterized. To address the issue, binaural masking level differences (BMLD) for a 125 Hz tone in narrowband noise were measured using a pair of pitch-matched electrodes while simultaneously presenting the same masking noise to adjacent electrodes, representing a more realistic stimulation condition compared to prior studies that used only a single electrode pair. For five subjects, BMLDs averaged 8.9 ± 1.0 dB (mean ± s.e.) in single electrode pairs but dropped to 2.1 ± 0.4 dB when presenting noise on adjacent masking electrodes, demonstrating a negative impact of the additional maskers. Removing the masking noise from only the pitch-matched electrode pair not only lowered thresholds but also resulted in smaller BMLDs. The degree of channel interaction estimated from auditory nerve evoked potentials in three subjects was significantly and negatively correlated with BMLD. The data suggest that if the amount of channel interactions can be reduced, BiCI users may experience some performance improvements related to binaural hearing.


The effect of sesamol on rats with ischemic stroke.
[Purpose] Although previous studies have demonstrated several effects of sesamol on neurological diseases, its effects on ischemic stroke are unclear. We evaluated the direct effects of sesamol on infarcts and efficacy in terms of functional improvement in rats with transient middle cerebral artery occlusion (MCAO). [Subjects and Methods] Male Sprague Dawley rats (n = 30) were randomly divided into two groups: an MCAO with sesamol group and an MCAO group. MCAO was induced for 2 h, and sesamol was administered in the treatment group just after reperfusion. Infarct size was calculated 5 days after MCAO. Efficacy in function was assessed using a modified sticky-tape test (MST) and percent weight borne on the paretic leg during 5 days. [Results] Infarct volumes did not differ significantly between the two MCAO groups. The values of MST did not differ between the two MCAO groups. Based on the values of percent weight borne on the paretic leg, function of the hindlimb in the MCAO with sesamol group was significantly better than in the MCAO group throughout the experimental period. [Conclusion] These results demonstrate that sesamol induced functional improvements during 5 days after MCAO, and could be a useful addition to the therapeutic regimen for the treatment of ischemic stroke.


Physical therapy in critically ill adult patients: recommendations from the Brazilian Association of Intensive Care Medicine Department of Physical Therapy.
Complications from immobility in intensive care unit patients contribute to functional decline, increased healthcare costs, reduced quality of life and higher post-discharge mortality. Physical therapy focuses on promoting recovery and preserving function, and it may minimize the impact of these complications. A group of Brazilian Association of Intensive Care Medicine physical therapy experts developed this document that contains minimal physical therapy recommendations appropriate to the Brazilian real-world clinical situation. Prevention and treatment of atelectasis, procedures related to the removal of secretions and treatment of conditions related to physical deconditioning and functional decline are discussed. Equally important is the consideration that prescribing and executing activities, mobilizations and exercises are roles of the physical therapist, whose diagnosis should precede any intervention.


The Drosophila cell shape regulator c-Jun N-terminal kinase also functions as a stress-activated protein kinase.
Mammalian c-Jun N-terminal kinases (JNKs) are members of a group of stress-activated intracellular signalling molecules within the MAP kinase family. Molecular genetic analysis of a highly evolutionarily conserved Drosophila JNK homologue, DJNK, has demonstrated that this molecule plays an essential developmental role in cell shape regulation. However, it remains to be determined whether DJNK also responds to the broad range of cellular stresses and other stimuli that affect its mammalian counterpart. Here we demonstrate that c-Jun, a substrate for mammalian JNKs, is a specific substrate for DJNK and that an antiserum that cross-reacts with activated mammalian JNK at the conserved threonyl-prolyl-tyrosyl (TPY) motif within the activation loop also specifically recognises the activated form of DJNK. Using these two assays, we show that DJNK activity is stimulated in cultured cells by several treatments that activate mammalian JNKs, including addition of arsenite, vanadate and ceramide derivatives. It is therefore concluded that in addition to its essential developmental functions, DJNK plays an important role in stress responses that mirrors its mammalian counterpart.


Supported cognitive-behavioural self-help versus treatment-as-usual for depressed informal carers of stroke survivors (CEDArS): study protocol for a feasibility randomized controlled trial.
Increased life expectancy has resulted in a greater provision of informal care within the community for patients with chronic physical health conditions. Informal carers are at greater risk of poor mental health, with one in three informal carers of stroke survivors experiencing depression. However, currently no psychological treatments tailored to the unique needs of depressed informal carers of stroke survivors exist. Furthermore, informal carers of stroke survivors experience a number of barriers to attending traditional face-to-face psychological services, such as lack of time and the demands of the caring role. The increased flexibility associated with supported cognitive behavioral therapy self-help (CBTsh), such as the ability for support to be provided by telephone, email, or face-to-face, alongside shorter support sessions, may help overcome such barriers to access. CBTsh, tailored to depressed informal carers of stroke survivors may represent an effective and acceptable solution. This study is a Phase II (feasibility) randomized controlled trial (RCT) following guidance in the MRC Complex Interventions Research Methods Framework. We will randomize a sample of depressed informal carers of stroke survivors to receive CBT self-help supported by mental health paraprofessionals, or treatment-as-usual. Consistent with the objectives of assessing the feasibility of trial design and procedures for a potential larger scale trial we will measure the following outcomes: a) feasibility of patient recruitment (recruitment and refusal rates); (b) feasibility and acceptability of data collection procedures; (c) levels of attrition; (d) likely intervention effect size; (e) variability in number, length and frequency of support sessions estimated to bring about recovery; and (f) acceptability of the intervention. Additionally, we will collect data on the diagnosis of depression, symptoms of depression and anxiety, functional impairment, carer burden, quality of life, and stroke survivor mobility skill, self-care and functional ability, measured at four and six months post-randomization. This study will provide important information for the feasibility and design of a Phase III (effectiveness) trial in the future. If the intervention is identified to be feasible, effective, and acceptable, a written CBTsh intervention for informal carers of stroke survivors, supported by mental health paraprofessionals, could represent a cost-effective model of care. Current Controlled Trials ISRCTN63590486.


Genome-Wide Association Mapping of Grain Micronutrients Concentration in Aegilops tauschii.
Bread wheat is an important and the most consumed cereal worldwide. However, people with predominantly cereal-based diets are increasingly affected by micronutrient deficiencies, suggesting the need for biofortified wheat varieties. The limited genetic diversity in hexaploid wheat warrants exploring the wider variation present in wheat wild relatives, among these Aegilops tauschii, the wild progenitor of the bread wheat D genome. In this study, a panel of 167 Ae. tauschii accessions was phenotyped for grain Fe, Zn, Cu, and Mn concentrations for 3 years and was found to have wide variation for these micronutrients. Comparisons between the two genetic subpopulations of Ae. tauschii revealed that lineage 2 had higher mean values for Fe and Cu concentration than lineage 1. To identify potentially new genetic sources for improving grain micronutrient concentration, we performed a genome-wide association study (GWAS) on 114 non-redundant Ae. tauschii accessions using 5,249 genotyping-by-sequencing (GBS) markers. Best linear unbiased predictor (BLUP) values were calculated for all traits across the three growing seasons. A total of 19 SNP marker trait associations (MTAs) were detected for all traits after applying Bonferroni corrected threshold of -log10(P-value) ≥ 4.68. These MTAs were found on all seven chromosomes. For grain Fe, Zn, Cu, and Mn concentrations, five, four, three, and seven significant associations were detected, respectively. The associations were linked to the genes encoding transcription factor regulators, transporters, and phytosiderophore synthesis. The results demonstrate the utility of GWAS for understanding the genetic architecture of micronutrient accumulation in Ae. tauschii, and further efforts to validate these loci will aid in using them to diversify the D-genome of hexaploid wheat.


Efficacy of primaquine regimens for primaquine-resistant Plasmodium vivax malaria in Thailand.
To define the current efficacy of Fansidar (F. Hoffmann-La Roche Ltd., Basel Switzerland) (pyrimethamine and sulfadoxine), primaquine in a high dose, and artesunate for treating acute Plasmodium vivax malaria, we conducted a comparative clinical trial of these 3 drugs in an open-label study. Patients (15-65 years old) were assigned to 1 of 4 treatments regimens in a serial order. Ninety percent of the patients were infected at Thailand-Myanmar border. Patients in group I (n = 23) received Fansidar (3 tablets, 75 mg of pyrimethamine and 1,500 mg of sulfadoxine, a single dose on the first day), group II (n = 23) received Fansidar (3 tablets, 75 mg of pyrimethamine and 1,500 mg of sulfadoxine, a single dose on the first day) and then received primaquine (30 mg a day for 14 days), group III (n = 23) received primaquine (30 mg a day for 14 days), and group IV (n = 23) received artesunate (200 mg once a day for 3 days) and then primaquine (30 mg a day for 14 days). Cure rates on day 28 of follow-up were 40%, 100%, 100%, and 100% in groups I, II, II, and IV, respectively. There were 4 and 5 patients in group I showing post-treatment reappearance of parasitemia at < or = 16 days and between 17 and 28 days, respectively. Patients in the other 3 groups showed negative parasitemias within 7 days after treatment. Artesunate plus primaquine (group IV) cleared parasitemia faster than the other 3 regimens. There is a high proportion of ineffectiveness of Fansidar for treatment of P. vivax malaria and it should be no longer used for treatment of P. vivax malaria acquired at the Thailand-Myanmar border. A high dose of primaquine is safe and effective in the treatment of P. vivax malaria during the 28-day follow-up period.


Induction of MMP-9 release from human dermal fibroblasts by thrombin: involvement of JAK/STAT3 signaling pathway in MMP-9 release.
It has been recognized that dermal fibroblasts and matrix metalloproteases (MMP) play crucial roles in wound healing process in skin. Thrombin was found to stimulate IL-8 release from human dermal fibroblasts (HDFs). However, little is known of the effect of thrombin on secretion of MMPs from dermal fibroblasts. In the present study, the influence of thrombin on proMMP-2 and proMMP-9 activity release from primary cultured HDFs, and its potential signaling pathways were investigated. The results showed that thrombin induced proMMP-9, but not proMMP-2 release from HDFs in a dose dependent manner at 6 h following incubation. Thrombin also upregulated expression of proMMP-9 mRNA in HDFs. Hirudin completely abolished the action of thrombin on HDFs. An agonist peptide of protease-activated receptor-1, SFLLR-NH2 stimulated an enhanced release of proMMP-9 from HDFs. AG490, an inhibitor of STAT3 inhibited basal and thrombin-provoked proMMP-9 release and phosphorylation of STAT3. PD98059, an inhibitor of MAPK and LY294002, an inhibitor PI3K failed to significantly inhibit thrombin induced proMMP-9 release. Thrombin is a potent stimulus of proMMP-9 release from HDFs. Thrombin induced proMMP-9 release is most likely through activation of PAR-1. JAK/STAT3 signaling pathway is involved in proMMP-9 release from HDFs.


The effects of health education on health science teachers' intention to recommend adolescent HPV vaccine for female students in Japan.
The Japanese government suspended proactive recommendation of human papillomavirus (HPV) vaccination due to several reports of adverse events related to it in 2013. After that, the immunization rate of HPV vaccine quickly declined in Japan. Health science teachers (HSTs) are qualified and licensed teachers in charge of health care and health education for students in Japanese schools. HSTs have not recommended HPV vaccination to female students, since active governmental recommendation for HPV vaccination was halted for 5 y. We conducted a primary survey targeting HSTs (N = 39) and university students taking the HST training course (N = 123). In each group, awareness regarding HPV vaccine and disease burden was evaluated and factors related to and barriers to HPV vaccine recommendation were identified. The primary survey found that many HSTs and university students recognized their insufficient knowledge regarding the HPV vaccine. Based on the primary survey's results, infectious disease specialists, collaborating with Japanese HSTs, developed educational slide sets on HPV vaccine. A secondary survey was conducted before and after the lecture with HSTs (N = 162), where we evaluated their intelligibility and intention to recommend HPV vaccination for female students. In the post-lecture, secondary survey, the number of HSTs who recommended the HPV vaccine to their students had statistically increased from 76 before the lecture, to 103 (p < .05). An educational lecture using appropriate materials improved HSTs' vaccine confidence and intention to recommend the HPV vaccine to their students, verifying the study's hypothesis.


First Report of Rice yellow mottle virus on Rice in the Democratic Republic of Congo.
Rice yellow mottle virus (RYMV), genus Sobemovirus, is a widespread rice pathogen reported in nearly all rice-growing countries of Africa. Although the virus was detected in Cameroon, Chad, Tanzania, Rwanda, Burundi, and Uganda (2,3), RYMV has never been described in the Democratic Republic of Congo (DRC). In July 2012, plants with leaf yellowing and mottling symptoms were observed in large irrigated rice production schemes 30 km south of Bukavu, in eastern DRC, and in lowland subsistence fields in the surroundings of Bukavu. Several dozen hectares affected by the disease were abandoned by the farmers. Symptomatic leaf samples were collected in different farmer fields. Back-inoculations to susceptible rice variety IR64 resulted in the same yellowing and mottling symptoms 7 to 9 days post-inoculation. Infected leaves gave positive results using double antibody sandwich (DAS)-ELISA tests with polyclonal antisera (as described in [1]), indicating for the first time the presence of RYMV in DRC. Triple antibody sandwich (TAS)-ELISA tests with discriminant monoclonal antibodies (1) revealed that they all belong to serotype 4 found in the neighboring region in Rwanda. Total RNA of three samples from South Kivu was extracted with the RNeasy Plant Mini kit (Qiagen, Germany). The 720 nucleotide coat protein (CP) gene was amplified by reverse transcription (RT)-PCR with primers 5'CTCCCCCACCCATCCCGAGAATT3' and 5'CAAAGATGGCCAGGAA3' (1). The sequences were deposited in GenBank (Accessions KC788208, KC788209, and KC788210). A set of CP sequences of 45 isolates representative of the RYMV diversity in Africa, including the sequences of the DRC samples, were used for phylogenetic reconstruction by maximum-likelihood method. The isolates from South Kivu belonged to strain S4-lv, mainly found around Lake Victoria. Specifically, within the S4-lv strain, the South Kivu isolates clustered with isolates from eastern and southern provinces of Rwanda and Burundi, respectively (2), suggesting a recent spread from these countries. Recently, efforts have been directed to shift from the traditional upland system to lowland and irrigated systems in which water availability allows sequential planting and maintenance of higher crop intensity. This agricultural change may increase insect vectors and alternate host plant populations which may result in higher RYMV incidence in DRC (3). Similar yellowing and mottling symptoms have been observed in Bas-Congo and Equateur provinces of the country, which would justify further surveys and characterisation of RYMV in the DRC. References: (1) D. Fargette et al. Arch. Virol. 147:583, 2002. (2) I. Ndikumana et al. Plant Dis. 96:1230, 2012. (3) O. Traoré et al. Mol. Ecol. 14:2097, 2005.


Introducing an integrated climate change perspective in POPs modelling, monitoring and regulation.
This paper presents a review on the implications of climate change on the monitoring, modelling and regulation of persistent organic pollutants (POPs). Current research gaps are also identified and discussed. Long-term data sets are essential to identify relationships between climate fluctuations and changes in chemical species distribution. Reconstructing the influence of climatic changes on POPs environmental behaviour is very challenging in some local studies, and some insights can be obtained by the few available dated sediment cores or by studying POPs response to inter-annual climate fluctuations. Knowledge gaps and future projections can be studied by developing and applying various modelling tools, identifying compounds susceptibility to climate change, local and global effects, orienting international policies. Long-term monitoring strategies and modelling exercises taking into account climate change should be considered when devising new regulatory plans in chemicals management.


Hypotensive constituents from the pods of Moringa oleifera.
Hypotensive activity of the ethanolic and aqueous extracts of Moringa oleifera whole pods and their parts, namely, coat, pulp, and seed was investigated. The activity of the ethanolic extract of both the pods and the seeds was equivalent at the dose of 30 mg/kg. The ethyl acetate phase of the ethanolic extract of pods was found to be the most potent fraction at the same dose. Its bioassay-directed fractionation led to the isolation of thiocarbamate and isothiocyanate glycosides which were also the hypotensive principles of the pods as observed in case of Moringa leaves. Two new compounds, O-[2'-hydroxy-3'-(2"-heptenyloxy)]-propyl undecanoate (1) and O-ethyl-4-[(alpha-L-rhamnosyloxy)-benzyl] carbamate (2) along with the known substances methyl p-hydroxybenzoate (3) and beta-sitosterol have also been isolated in the present studies. The latter two compounds and p-hydroxybenzaldehyde showed promising hypotensive activity. Structures of all these compounds have been deduced by spectroscopy and chemical reactions.


Highly efficient Yb:YAG channel waveguide laser written with a femtosecond-laser.
Using a femtosecond Ti:Sapphire laser, micro-tracks of material damage were written into Yb:YAG crystals. Waveguiding was achieved in a channel between pairs of tracks with guiding losses of 1.3 dB/cm at a wavelength of 1063 nm, due to a stress induced change of the refractive index. Pumped at a wavelength of 941 nm, highly efficient laser oscillation in a Yb:YAG channel waveguide at a wavelength of 1030 nm was demonstrated. An output power of 0.8 W at 1.2 W of launched pump power was achieved, resulting in a record slope efficiency of 75%.


Extended and standard duration weight-loss programme referrals for adults in primary care (WRAP): a randomised controlled trial.
Evidence exist that primary care referral to an open-group behavioural programme is an effective strategy for management of obesity, but little evidence on optimal intervention duration is available. We aimed to establish whether 52-week referral to an open-group weight-management programme would achieve greater weight loss and improvements in a range of health outcomes and be more cost-effective than the current practice of 12-week referrals. In this non-blinded, parallel-group, randomised controlled trial, we recruited participants who were aged 18 years or older and had body-mass index (BMI) of 28 kg/m2 or higher from 23 primary care practices in England. Participants were randomly assigned (2:5:5) to brief advice and self-help materials, a weight-management programme (Weight Watchers) for 12 weeks, or the same weight-management programme for 52 weeks. We followed-up participants over 2 years. The primary outcome was weight at 1 year of follow-up, analysed with mixed-effects models according to intention-to-treat principles and adjusted for centre and baseline weight. In a hierarchical closed-testing procedure, we compared combined behavioural programme arms with brief intervention, then compared the 12-week programme and 52-week programme. We did a within-trial cost-effectiveness analysis using person-level data and modelled outcomes over a 25-year time horizon using microsimulation. This study is registered with Current Controlled Trials, number ISRCTN82857232. Between Oct 18, 2012, and Feb 10, 2014, we enrolled 1269 participants. 1267 eligible participants were randomly assigned to the brief intervention (n=211), the 12-week programme (n=528), and the 52-week programme (n=528). Two participants in the 12-week programme had been found to be ineligible shortly after randomisation and were excluded from the analysis. 823 (65%) of 1267 participants completed an assessment at 1 year and 856 (68%) participants at 2 years. All eligible participants were included in the analyses. At 1 year, mean weight changes in the groups were -3·26 kg (brief intervention), -4·75 kg (12-week programme), and -6·76 kg (52-week programme). Participants in the behavioural programme lost more weight than those in the brief intervention (adjusted difference -2·71 kg, 95% CI -3·86 to -1·55; p<0·0001). The 52-week programme was more effective than the 12-week programme (-2·14 kg, -3·05 to -1·22; p<0·0001). Differences between groups were still significant at 2 years. No adverse events related to the intervention were reported. Over 2 years, the incremental cost-effectiveness ratio (ICER; compared with brief intervention) was £159 per kg lost for the 52-week programme and £91 per kg for the 12-week programme. Modelled over 25 years after baseline, the ICER for the 12-week programme was dominant compared with the brief intervention. The ICER for the 52-week programme was cost-effective compared with the brief intervention (£2394 per quality-adjusted life-year [QALY]) and the 12-week programme (£3804 per QALY). For adults with overweight or obesity, referral to this open-group behavioural weight-loss programme for at least 12 weeks is more effective than brief advice and self-help materials. A 52-week programme produces greater weight loss and other clinical benefits than a 12-week programme and, although it costs more, modelling suggests that the 52-week programme is cost-effective in the longer term. National Prevention Research Initiative, Weight Watchers International (as part of an UK Medical Research Council Industrial Collaboration Award).


Maternal and littermate deprivation disrupts maternal behavior and social-learning of food preference in adulthood: tactile stimulation, nest odor, and social rearing prevent these effects.
Maternal and littermate (social) separation, through artificial rearing (AR), disrupts the development of subsequent maternal behavior and social learning in rats. The addition of maternal-licking-like stimulation during AR, partially reverses some of these effects. However, little is know about the role of social stimuli from littermates and nest odors during the preweaning period, in the development of the adult maternal behavior and social learning. The purpose of this study was to examine the effects of peer- and peer-and-odor rearing on the development of maternal behavior and social learning in rats. Female pups were reared with mothers (mother reared-MR) or without mothers (AR) from postnatal day (PND) 3. AR rats received three different treatments: (1) AR-CONTROL group received minimal tactile stimulation, (2) AR-ODOR females received exposure to maternal nest material inside the AR-isolation-cup environment, (3) AR-SOCIAL group was reared in the cup with maternal nest material and a conspecific of the same-age and same-sex and received additional tactile stimulation. MR females were reared by their mothers in the nest and with conspecifics. In adulthood, rats were tested for maternal behavior towards their own pups and in a social learning task. Results confirm our previous report that AR impairs performance of maternal behavior and the development of a social food preference. Furthermore, social cues from a littermate, in combination with tactile stimulation and the nest odor, reversed the negative effects of complete isolation (AR-CONTROL) on some of the above behaviors. Exposure to the odor alone also had effects on some of these olfactory-mediated behaviors. These studies indicate that social stimulation from littermates during the preweaning period, in combination with odor from the nest and tactile stimulation, contributes to the development of affiliative behaviors.


Validation of the AFP model as a predictor of HCC recurrence in patients with viral hepatitis-related cirrhosis who had received a liver transplant for HCC.
The AFP model was shown to be superior to the Milan criteria for predicting hepatocellular carcinoma (HCC) recurrence after liver transplantation in a French population. Our aim was to test the AFP model in a non-French, post-hepatitic cirrhosis-based population of HCC candidates. 574 patients transplanted for HCC in four Italian centers were studied. AFP score was assessed at the last evaluation before liver transplantation (LT). Probabilities of recurrence and survival were estimated by the log-rank test or competing risk analysis and compared according to the AFP model. 24.7% patients were beyond Milan criteria. HCC complicated hepatitis C virus (HCV) and hepatitis B virus (HBV) cirrhosis in 58.7% and 24% of the cases, respectively. Five-year probabilities of recurrence differed according to AFP score ⩽2 vs. >2 in the whole population (13.2±1.8% vs. 49.8±8.7%, p<0.001, HR=4.98), in patients within Milan criteria (12.8±2.0% vs. 32.4±12.1%, p=0.009, HR=3.51), beyond Milan criteria (14.9±4.2% vs. 58.9±11.5%, p<0.001, HR=4.26), HCV patients (14.9±2.5% vs. 67.6±14.7%, p<0.001, HR=6.56) and HBV patients (11.6±3.4% vs. 34.3±12.5%, p=0.012, HR=3.49). By net reclassification improvement analysis AFP score significantly improved prediction of non-recurrence compared to Milan criteria. Overall five-year survival rates according to AFP score ⩽2 or >2 were 71.7±2.2% vs. 42.2±8.3% (p<0.001, HR=2.14). The AFP model identifies HCC candidates at low risk of recurrence, otherwise excluded by Milan criteria in a population with a predominance of post-hepatitic-related HCC. The AFP score can be proposed for selection of HCC candidates in programs with a high proportion of viral/HCV-related cirrhosis. Selection criteria for liver transplantation of patients affected with hepatocellular carcinoma (HCC) are based on the Milan criteria, which have been shown to be too restrictive, precluding access to liver transplantation for some patients who might be cured by this operation. Recently, a French group of researchers developed a new selection model called the AFP model, or AFP score, allowing some patients with HCC not meeting Milan criteria to be transplanted with excellent results. In the present work, the AFP score was tested in a population of non-French patients transplanted for HCC occurring mainly on post-hepatitic (HCV or HBV) cirrhosis. The results confirm that in this specific population, as in the original French population of patients, the AFP model better selects patients with HCC eligible for transplantation, compared to Milan criteria. We conclude that the AFP score, which has been officially adopted by the French organization for Organ Sharing for HCC patients, can also be implemented in countries with an important burden of HCC occurring on post-hepatitic cirrhosis.


Dataset of search queries to map scientific publications to the UN sustainable development goals.
The dataset includes search queries that can be used to identify scientific publications related to the United Nations Sustainable Development Goals (SDGs). We propose a new approach to mitigate the polysemy of terms as much as possible by targeting the most relevant subject areas for each SDG. In addition, we also used a text-mining tool to identify as many relevant phrases as possible. Publications identified through this process cannot be considered as evidence of the commitment of authors and their institutions to actions towards the targets established by the UN. However, they can be an accurate indicator of which research is relevant to the issues addressed by the SDGs, whether or not it is a direct contribution.


In vivo Microwave-induced Thermoacoustic Endoscopy for Colorectal Tumor Detection in Deep Tissue.
Optical endoscopy, as one of the common clinical diagnostic modalities, provides irreplaceable advantages in the diagnosis and treatment of internal organs. However, the approach is limited to the characterization of superficial tissues due to the strong optical scattering properties of tissue. In this work, a microwave-induced thermoacoustic (TA) endoscope (MTAE) was developed and evaluated. The MTAE system integrated a homemade monopole sleeve antenna (diameter = 7 mm) for providing homogenized pulsed microwave irradiation to induce a TA signal in the colorectal cavity and a side-viewing focus ultrasonic transducer (diameter = 3 mm) for detecting the TA signal in the ultrasonic spectrum to construct the image. Our MTAE, system combined microwave excitation and acoustic detection; produced images with dielectric contrast and high spatial resolution at several centimeters deep in soft tissues, overcome the current limitations of the imaging depth of optical endoscopy and mechanical wave-based imaging contrast of ultrasound endoscopy, and had the ability to extract complete features for deep location tumors that could be infiltrating and invading adjacent structures. The practical feasibility of the MTAE system was evaluated in vivo with rabbits having colorectal tumors. The results demonstrated that colorectal tumor progression could be visualized from the changes in electromagnetic parameters of the tissue via MTAE, showing its potential clinical application.


Urinary neutrophil gelatinase-associated lipocalin as a predictor of cardiovascular events in patients with chronic kidney disease.
Chronic kidney disease (CKD) is associated with an increased risk of cardiovascular (CV) events. Recently, elevated neutrophil gelatinase-associated lipocalin (NGAL) levels have been reported in patients with heart failure, coronary heart disease, or stroke. Our aim was to assess urinary NGAL as a predictor of CV events in patients with CKD. This was a prospective observational cohort study of 404 patients with predialysis CKD. CV events were defined as CV death, acute coronary syndrome, hospitalization for worsening heart failure, stroke and dissection of aorta. During a mean follow-up period of 33 months, 77 CV events (19.1 %) occurred. After adjustment for gender, age, diabetes, previous cardiovascular disease, urinary albumin/creatinine ratio (UACR), estimated glomerular filtration rate, hemoglobin, and high-sensitivity C-reactive protein, patients with the other quartiles of urinary NGAL had significantly higher risk of CV events compared with patients with the lowest quartile (hazard ratio (HR) 2.81, 95 % confidence interval (CI) 1.01-7.81, P = 0.047 for Q2, HR 3.31, 95 % CI 1.22-9.00, P = 0.019 for Q3, and HR 3.27, 95 % CI 1.15-9.29, P = 0.026 for Q4). Regarding the combination of urinary NGAL with UACR, we also stratified patients into four groups according to whether the level of each marker was above or below the median (61.8 μg per gram creatinine (gCr) for NGAL and 351.1 mg/gCr for UACR). Four-year CV event-free survival rates were 89.2, 79.6, 71.8, and 51.5 % in order for the four respective groups (P < 0.0001). Elevated urinary NGAL was able to predict future CV events in CKD patients, and had incremental predictive value with elevated UACR.


The role of sports clubs in helping older people to stay active and prevent frailty: a longitudinal mediation analysis.
Frailty is a common syndrome in older adults characterised by increased vulnerability to adverse health outcomes as a result of decline in functional and physiological measures. Frailty predicts a range of poor health and social outcomes and is associated with increased risk of hospital admission. The health benefits of sport and physical activity and the health risks of inactivity are well known. However, less is known about the role of sports clubs and physical activity in preventing and managing frailty in older adults. The objective of this study is to examine the role of membership of sports clubs in promoting physical activity and reducing levels of frailty in older adults. We used data from waves 1 to 7 of the English Longitudinal Study of Ageing (ELSA). Survey items on physical activity were combined to produce a measure of moderate or vigorous physical activity for each wave. Frailty was measured using an index of accumulated deficits. A total of sixty deficits, including symptoms, disabilities and diseases were recorded through self-report and tests. Direct and indirect relationships between sports club membership, levels of physical activity and frailty were examined using a cross-lagged panel model. We found evidence for an indirect relationship between sports club membership and frailty, mediated by physical activity. This finding was observed when examining time-specific indirect pathways and the total of all indirect pathways across seven waves of survey data (Est = -0.097 [95% CI = -0.124,-0.070], p = <0.001). These analyses provide evidence to suggest that sports clubs may be useful in preventing and managing frailty in older adults, both directly and indirectly through increased physical activity levels. Sports clubs accessible to older people may improve health in this demographic by increasing activity levels and reducing frailty and associated comorbidities. There is a need for investment in these organisations to provide opportunities for older people to achieve the levels of physical activity necessary to prevent health problems associated with inactivity.


Activation of dura-sensitive trigeminal neurons and increased c-Fos protein induced by morphine withdrawal in the rostral ventromedial medulla.
Aims Overuse of medications used to treat migraine headache can increase the frequency of headaches. Sudden abstinence from migraine medication can also lead to a period of withdrawal-induced headaches. The aim of this study was to examine the effect of morphine withdrawal localized to the rostral ventromedial medulla (RVM) on the activity of dura-sensitive spinal trigeminal nucleus caudalis (Vc) neurons. Methods Rats were implanted with either morphine or placebo pellets for six to seven days before the microinjection of naloxone methiodide or phosphate-buffered saline into the RVM in urethane-anesthetized animals. Dura-sensitive neurons were recorded in the Vc and the production of c-Fos-like immunoreactivity was quantified. Results In chronic morphine-treated animals, naloxone methiodide microinjections produced a significant increase both in ongoing and facial heat-evoked activity and an increase in Fos-positive neurons in the Vc and in the nucleus reticularis dorsalis, a brainstem region involved in diffuse noxious inhibitory controls. Conclusions These results indicate that activation of pronociceptive neurons in the RVM under conditions of morphine withdrawal can increase the activity of neurons that transmit headache pain. Modulation of the subnucleus reticularis dorsalis by the RVM may explain the attenuation of conditioned pain modulation in patients with chronic headache.


Activation of the calcium-sensing receptor before renal ischemia/reperfusion exacerbates kidney injury.
Activation of the calcium-sensing receptor (CaSR) by ischemia/reperfusion (I/R) favours apoptosis in cardiomyocytes, hepatocytes and neurons. Its role in renal I/R is unknown. We investigated the impact of pharmacological preactivation of the CaSR on kidney structure and function in a murine model of bilateral renal 30-min ischemia and 48-hour reperfusion, and in a 6-year cohort of kidney transplant recipients (KTR). C57BL/6J mice were administered daily with CaSR agonist, R-568, or with vehicle for 48 hours. Evaluation of serum urea and creatinine levels, renal histology and urine metabolome by nuclear magnetic resonance showed that R-568 was not nephrotoxic per se. Following I/R, serum urea and creatinine levels increased higher in R-568-treated animals than in controls. Jablonski's score was significantly greater in R-568-treated kidneys, which showed a higher rate of cell proliferation and apoptosis in comparison to controls. Next, we retrospectively identified 36 patients (10.7% of our cohort) who were treated by CaSR agonist, cinacalcet, at the time of kidney transplantation (KTx). After matching these to 61 KTR upon type of donor, cold ischemic time, residual diuresis, and donor age, we observed that delayed graft function, i.e. need for dialysis in the first week after KTx, occurred in 42 and 23% of cinacalcet-treated and control groups, respectively (p≤0.05). These data suggest that pharmacological preactivation of the CaSR before renal I/R exacerbates kidney injury.