Percutaneous coronary intervention with drug-eluting stents versus coronary artery bypass surgery for multivessel coronary artery disease: a meta-analysis of data from the ARTS II, CARDia, ERACI III, and SYNTAX studies and systematic review of observational data.
The aim of this study was to systematically analyse the available data from trials comparing revascularisation by drug-eluting stent (DES) placement versus coronary artery bypass grafting (CABG) in patients with multivessel coronary artery disease (CAD). We searched PubMed, Medline and several internet sources for randomised controlled trials comparing DES placement to CABG in patients with multivessel coronary artery disease. There were no restrictions on journal type or population studied. Prior to data collection we chose to analyse the prospectively performed trials separately from data obtained retrospectively. Four prospective trials were identified which enrolled a total of 3,895 patients: 1,914 in the DES arm and 1,981 patients in the CABG arm. Pooled analysis of data from these four studies showed that in patients treated DES compared to CABG there was a similar risk of the combined endpoints of death, myocardial infarction and stroke (10.2% versus 10.8%, respectively; RR=0.94 [95% CI=0.77-1.116]; p=0.56), but a significantly higher risk of target vessel revascularisation (TVR) (14.6% versus 6.8%, respectively; RR=2.09 [95% CI=1.72-2.55]; <0.001) and, therefore, a significantly higher risk of MACCE (21.2% versus 16.3%, respectively; RR=1.27 [95% CI=1.09-1.48]; p=0.002). Interestingly, when MACCE rates at one year are used for these trials the risk is equivalent between DES and CABG (14.4% versus 12.5%, respectively; RR=1.05 [95% CI=0.70-1.57]; p=0.83). Analysis of observational data revealed similar findings. Overall, PCI with DES placement was safe in patients with multivessel disease compared to CABG, but is associated with a significantly higher risk of TVR.


Severe DCM phenotype of patient harboring RBM20 mutation S635A can be modeled by patient-specific induced pluripotent stem cell-derived cardiomyocytes.
The ability to generate patient-specific induced pluripotent stem cells (iPSCs) provides a unique opportunity for modeling heart disease in vitro. In this study, we generated iPSCs from a patient with dilated cardiomyopathy (DCM) caused by a missense mutation S635A in RNA-binding motif protein 20 (RBM20) and investigated the functionality and cell biology of cardiomyocytes (CMs) derived from patient-specific iPSCs (RBM20-iPSCs). The RBM20-iPSC-CMs showed abnormal distribution of sarcomeric α-actinin and defective calcium handling compared to control-iPSC-CMs, suggesting disorganized myofilament structure and altered calcium machinery in CMs of the RBM20 patient. Engineered heart muscles (EHMs) from RBM20-iPSC-CMs showed that not only active force generation was impaired in RBM20-EHMs but also passive stress of the tissue was decreased, suggesting a higher visco-elasticity of RBM20-EHMs. Furthermore, we observed a reduced titin (TTN) N2B-isoform expression in RBM20-iPSC-CMs by demonstrating a reduction of exon skipping in the PEVK region of TTN and an inhibition of TTN isoform switch. In contrast, in control-iPSC-CMs both TTN isoforms N2B and N2BA were expressed, indicating that the TTN isoform switch occurs already during early cardiogenesis. Using next generation RNA sequencing, we mapped transcriptome and splicing target profiles of RBM20-iPSC-CMs and identified different cardiac gene networks in response to the analyzed RBM20 mutation in cardiac-specific processes. These findings shed the first light on molecular mechanisms of RBM20-dependent pathological cardiac remodeling leading to DCM. Our data demonstrate that iPSC-CMs coupled with EHMs provide a powerful tool for evaluating disease-relevant functional defects and for a deeper mechanistic understanding of alternative splicing-related cardiac diseases.


Acute abdomen: an unusual presentation of disseminated Penicillium marneffei infection.
Varied clinical presentations of Penicillium marneffei, an opportunistic pathogen in HIV disease has been rarely described in literature. We report a patient with advanced AIDS who presented to us with prolonged fever and had features of an acute abdomen. On radiologic imaging he had features of intestinal obstruction and mesenteric lymphadenitis. A diagnosis was made possible by endoscopic biopsies of the small bowel and bone marrow culture which grew P. Marneffei. He was treated with intravenous amphotericin for 2 weeks followed by oral itraconazole. This case is reported for its rarity and unusual presentation and to sensitise clinicians and microbiologists to consider this as an aetiology in patients with advanced HIV/AIDS who present with acute abdomen, more so in patients from a distinct geographic region--South-East Asia.


Suturable elastomeric tubular grafts with patterned porosity for rapid vascularization of 3D constructs.
Vascularization is considered to be one of the key challenges in engineering functional 3D tissues. Engineering suturable vascular grafts containing pores with diameter of several tens of microns in tissue engineered constructs may provide an instantaneous blood perfusion through the grafts improving cell infiltration and thus, allowing rapid vascularization and vascular branching. The aim of this work was to develop suturable tubular scaffolds to be integrated in biofabricated constructs, enabling the direct connection of the biofabricated construct with the host blood stream, providing an immediate blood flow inside the construct. Here, tubular grafts with customizable shapes (tubes, Y-shape capillaries) and controlled diameter ranging from several hundreds of microns to few mm are fabricated based on poly(glycerol sebacate) (PGS)/poly(vinyl alcohol) (PVA) electrospun scaffolds. Furthermore, a network of pore channels of diameter in the order of 100μm was machined by laser femtosecond ablation in the tube wall. Both non-machined and laser machined tubular scaffolds elongated more than 100% of their original size have shown suture retention, being 5.85 and 3.96 N mm-2respectively. To demonstrate the potential of application, the laser machined porous grafts were embedded in gelatin methacryloyl (GelMA) hydrogels, resulting in elastomeric porous tubular graft/GelMA 3D constructs. These constructs were then co-seeded with osteoblast-like cells (MG-63) at the external side of the graft and human umbilical vein endothelial cells inside, forming a bone osteon model. The laser machined pore network allowed an immediate endothelial cell flow towards the osteoblasts enabling the osteoblasts and endothelial cells to interact and form 3D structures. This rapid vascularization approach could be applied, not only for bone tissue regeneration, but also for a variety of tissues and organs.


Dissection of the molecular defects caused by pathogenic mutations in the DNA repair factor XPC.
XPC is responsible for DNA damage sensing in nucleotide excision repair (NER). Mutations in XPC lead to a defect in NER and to xeroderma pigmentosum (XP-C). Here, we analyzed the biochemical properties behind mutations found within three patients: one amino acid substitution (P334H, XP1MI, and GM02096), one amino acid incorporation in a conserved domain (697insVal, XP8BE, and GM02249), and a stop mutation (R579St, XP67TMA, and GM14867). Using these mutants, we demonstrated that HR23B stabilizes XPC on DNA and protects it from degradation. XPC recruits the transcription/repair factor TFIIH and stimulates its XPB ATPase activity to initiate damaged DNA opening. In an effort to understand the severity of XP-C phenotypes, we also demonstrated that single mutations in XPC perturb other repair processes, such as base excision repair (e.g., the P334H mutation prevents the stimulation of Ogg1 glycosylase because it thwarts the interaction between XPC and Ogg1), thereby leading to a deeper understanding of the molecular repair defect of the XP-C patients.


Changes in resting-state functionally connected parietofrontal networks after videogame practice.
Neuroimaging studies provide evidence for organized intrinsic activity under task-free conditions. This activity serves functionally relevant brain systems supporting cognition. Here, we analyze changes in resting-state functional connectivity after videogame practice applying a test-retest design. Twenty young females were selected from a group of 100 participants tested on four standardized cognitive ability tests. The practice and control groups were carefully matched on their ability scores. The practice group played during two sessions per week across 4 weeks (16 h total) under strict supervision in the laboratory, showing systematic performance improvements in the game. A group independent component analysis (GICA) applying multisession temporal concatenation on test-retest resting-state fMRI, jointly with a dual-regression approach, was computed. Supporting the main hypothesis, the key finding reveals an increased correlated activity during rest in certain predefined resting state networks (albeit using uncorrected statistics) attributable to practice with the cognitively demanding tasks of the videogame. Observed changes were mainly concentrated on parietofrontal networks involved in heterogeneous cognitive functions.


Doxorubicin resistance in breast cancer is driven by light at night-induced disruption of the circadian melatonin signal.
Chemotherapeutic resistance, particularly to doxorubicin (Dox), represents a major impediment to successfully treating breast cancer and is linked to elevated tumor metabolism and tumor over-expression and/or activation of various families of receptor- and non-receptor-associated tyrosine kinases. Disruption of circadian time structure and suppression of nocturnal melatonin production by dim light exposure at night (dLEN), as occurs with shift work, and/or disturbed sleep-wake cycles, is associated with a significantly increased risk of an array of diseases, including breast cancer. Melatonin inhibits human breast cancer growth via mechanisms that include the suppression of tumor metabolism and inhibition of expression or phospho-activation of the receptor kinases AKT and ERK1/2 and various other kinases and transcription factors. We demonstrate in tissue-isolated estrogen receptor alpha-positive (ERα+) MCF-7 human breast cancer xenografts, grown in nude rats maintained on a light/dark cycle of LD 12:12 in which dLEN is present during the dark phase (suppressed endogenous nocturnal melatonin), a significant shortening of tumor latency-to-onset, increased tumor metabolism and growth, and complete intrinsic resistance to Dox therapy. Conversely, a LD 12:12 dLEN environment incorporating nocturnal melatonin replacement resulted in significantly lengthened tumor latency-to-onset, tumor regression, suppression of nighttime tumor metabolism, and kinase and transcription factor phosphorylation, while Dox sensitivity was completely restored. Melatonin acts as both a tumor metabolic inhibitor and circadian-regulated kinase inhibitor to reestablish the sensitivity of breast tumors to Dox and drive tumor regression, indicating that dLEN-induced circadian disruption of nocturnal melatonin production contributes to a complete loss of tumor sensitivity to Dox chemotherapy.


A core outcome set for bronchiectasis in children and adolescents for use in clinical research: an international consensus study.
Improving the treatment of non-cystic fibrosis bronchiectasis in children and adolescents requires high-quality research with outcomes that meet study objectives and are meaningful for patients and their parents and caregivers. In the absence of systematic reviews or agreement on the health outcomes that should be measured in paediatric bronchiectasis, we established an international, multidisciplinary panel of experts to develop a core outcome set (COS) that incorporates patient and parent perspectives. We undertook a systematic review from which a list of 21 outcomes was constructed; these outcomes were used to inform the development of separate surveys for ranking by parents and patients and by health-care professionals. 562 participants (201 parents and patients from 17 countries, 361 health-care professionals from 58 countries) completed the surveys. Following two consensus meetings, agreement was reached on a ten-item COS with five outcomes that were deemed to be essential: quality of life, symptoms, exacerbation frequency, non-scheduled health-care visits, and hospitalisations. Use of this international consensus-based COS will ensure that studies have consistent, patient-focused outcomes, facilitating research worldwide and, in turn, the development of evidence-based guidelines for improved clinical care and outcomes. Further research is needed to develop validated, accessible measurement instruments for several of the outcomes in this COS.


Characterization of the Novel Leaderless Bacteriocin, Bawcin, from Bacillus wiedmannii.
The rise of drug-resistant bacteria is a major threat to public health, highlighting the urgent need for new antimicrobial compounds and treatments. Bacteriocins, which are ribosomally synthesized antimicrobial peptides produced by bacteria, hold promise as alternatives to conventional antibiotics. In this study, we identified and characterized a novel leaderless bacteriocin, bawcin, the first bacteriocin to be characterized from a Bacillus wiedmannii species. Chemically synthesized and purified bawcin was shown to be active against a broad range of Gram-positive bacteria, including foodborne pathogens Staphylococcus aureus, Bacillus cereus, and Listeria monocytogenes. Stability screening revealed that bawcin is stable over a wide range of pH (2.0-10.0), temperature conditions (25-100 °C), and against the proteases, papain and pepsin. Lastly, three-dimensional structure homology modeling suggests that bawcin contains a saposin-fold with amphipathic helices and a highly cationic surface that may be critical for membrane interaction and the subsequent cell death of its targets. This study provides the foundational understanding of the activity and properties of bawcin, offering valuable insights into its applications across different antimicrobial uses, including as a natural preservative in food and livestock industries.


Evaluation and selection of indicators for land degradation and desertification monitoring: types of degradation, causes, and implications for management.
Indicator-based approaches are often used to monitor land degradation and desertification from the global to the very local scale. However, there is still little agreement on which indicators may best reflect both status and trends of these phenomena. In this study, various processes of land degradation and desertification have been analyzed in 17 study sites around the world using a wide set of biophysical and socioeconomic indicators. The database described earlier in this issue by Kosmas and others (Environ Manage, 2013) for defining desertification risk was further analyzed to define the most important indicators related to the following degradation processes: water erosion in various land uses, tillage erosion, soil salinization, water stress, forest fires, and overgrazing. A correlation analysis was applied to the selected indicators in order to identify the most important variables contributing to each land degradation process. The analysis indicates that the most important indicators are: (i) rain seasonality affecting water erosion, water stress, and forest fires, (ii) slope gradient affecting water erosion, tillage erosion and water stress, and (iii) water scarcity soil salinization, water stress, and forest fires. Implementation of existing regulations or policies concerned with resources development and environmental sustainability was identified as the most important indicator of land protection.


Planar Junctionless Field-Effect Transistor for Detecting Biomolecular Interactions.
Label-free field-effect transistor-based immunosensors are promising candidates for proteomics and peptidomics-based diagnostics and therapeutics due to their high multiplexing capability, fast response time, and ability to increase the sensor sensitivity due to the short length of peptides. In this work, planar junctionless field-effect transistor sensors (FETs) were fabricated and characterized for pH sensing. The device with SiO2 gate oxide has shown voltage sensitivity of 41.8 ± 1.4, 39.9 ± 1.4, 39.0 ± 1.1, and 37.6 ± 1.0 mV/pH for constant drain currents of 5, 10, 20, and 50 nA, respectively, with a drain to source voltage of 0.05 V. The drift analysis shows a stability over time of -18 nA/h (pH 7.75), -3.5 nA/h (pH 6.84), -0.5 nA/h (pH 4.91), 0.5 nA/h (pH 3.43), corresponding to a pH drift of -0.45, -0.09, -0.01, and 0.01 per h. Theoretical modeling and simulation resulted in a mean value of the surface states of 3.8 × 1015/cm2 with a standard deviation of 3.6 × 1015/cm2. We have experimentally verified the number of surface sites due to APTES, peptide, and protein immobilization, which is in line with the theoretical calculations for FETs to be used for detecting peptide-protein interactions for future applications.


The presence of N-terminal methionine on nascent protein of rat liver and rabbit reticulocytes and its cleavage during polypeptide-chain elongation.
1. The size of nascent globin peptides from which the N-terminal methionine residue is cleaved has been investigated by comparing the proportion of N-terminal methionine and valine in short and long chains. Nascent chains were labelled in rabbit reticulocyte lysates, fractionated according to length by chromatography on Sephadex G-50, and analysed by the Edman degradation of selected pooled fractions. It was found that different peptide fractions contained either methionine or valine, but not both, as the N-terminal residue. Methionine was present at the N-terminus of globin chains containing up to approx. 50 amino acids whereas valine was found to be the N-terminal amino acid of longer peptides. 2. In similar experiments with nascent proteins of rat liver, labelled either in vivo or in a cell-free system containing microsomal material and cell sap, evidence was obtained for the presence of methionine at the N-terminus of nascent chains up to approx. 65 amino acid residues long. Thus protein synthesis in liver appears to be initiated also by methionine, but in this case cleavage takes place somewhat later during peptide elongation than in globin synthesis.


[Citrate influence on acetyl-CoA-carboxylase activation and phosphorylation in chicken liver with lipogenesis inhibited by nicotinic acid].
Nicotinic acid in vivo affects the citrate demand for acetyl-CoA-carboxylase activation in the chicken liver under conditions of alimentary lipogenesis stimulation. Stoichiometry of the citrate binding with the dissociation constant of the enzyme-allosteric activator complex is determined under experimental conditions. Endogenic phosphorylation of acetyl-CoA-carboxylase completely correlates with its inactivation and depends on the citrate level. cAMP is established to have an activating effect on phosphorylation of acetyl-CoA-carboxylase of test animals.


A Learning Health System for Pediatric Liver Transplant: The Starzl Network for Excellence in Pediatric Transplantation.
Learning health systems (LHS) integrate research, improvement, management, and patient care, such that every child receives "the right care at the right time...every time," that is, evidence-based, personalized medicine. Here, we report our efforts to establish a sustainable, productive, multicenter LHS focused on pediatric liver transplantation. The Starzl Network for Excellence in Pediatric Transplantation (SNEPT) is the first multicenter effort by pediatric liver transplant families and providers to develop shared priorities and a shared agenda for innovation in clinical care. This report outlines SNEPT's structure, accomplishments, and challenges as an LHS. We prioritized 4 initial projects: immunosuppression, perioperative anticoagulation, quality of life, and transition of care. We shared center protocols/management to identify areas of practice variability between centers. We prioritized actionable items that address barriers to providing "the right care at the right time" to every pediatric liver transplant recipient: facilitating transparency of practice variation and the connection of practices to patient outcomes, harnessing existing datasets to reduce the burden of tracking outcomes, incorporating patient-reported outcomes into outcome metrics, and accelerating the implementation of knowledge into clinical practice. This has allowed us to strengthen collaborative relationships, design quality improvement projects, and collect pilot data for each of our priority projects. The field of pediatric liver transplantation can be advanced through application of LHS principles. Going forward, SNEPT will continue to unite patient advocacy, big data, technology, and transplant thought leaders to deliver the best care, while developing new, scalable solutions to pediatric transplantation's most challenging problems.


Activity in human visual and parietal cortex reveals object-based attention in working memory.
Visual attention enables observers to select behaviorally relevant information based on spatial locations, features, or objects. Attentional selection is not limited to physically present visual information, but can also operate on internal representations maintained in working memory (WM) in service of higher-order cognition. However, only little is known about whether attention to WM contents follows the same principles as attention to sensory stimuli. To address this question, we investigated in humans whether the typically observed effects of object-based attention in perception are also evident for object-based attentional selection of internal object representations in WM. In full accordance with effects in visual perception, the key behavioral and neuronal characteristics of object-based attention were observed in WM. Specifically, we found that reaction times were shorter when shifting attention to memory positions located on the currently attended object compared with equidistant positions on a different object. Furthermore, functional magnetic resonance imaging and multivariate pattern analysis of visuotopic activity in visual (areas V1-V4) and parietal cortex revealed that directing attention to one position of an object held in WM also enhanced brain activation for other positions on the same object, suggesting that attentional selection in WM activates the entire object. This study demonstrated that all characteristic features of object-based attention are present in WM and thus follows the same principles as in perception.


Distinct inhibitory ATP-regulated modulatory domain (ARMi) in membrane guanylate cyclases.
Depending upon the cofactors Mg2+ or Mn2+, ATP stimulates or inhibits the signal transduction activities of the natriuretic factor receptor guanylate cyclases, ANF-RGC and CNP-RGC: there is stimulation in the presence of Mg2+ and inhibition in the presence of Mn2+. A defined core ATP-regulated modulatory (ARM) sequence motif within the intracellular 'kinase-like' domain of the cyclases is critical for stimulation, but the mechanism of the inhibitory transduction process is not known. In addition, ATP inhibits the basal cyclase activity of a rod outer segment membrane guanylate cyclase (ROS-GC). The mechanism of this inhibitory transduction process is also not known. These issues have been addressed in the present investigation through a program of deletion mutagenesis/expression studies of the cyclases. The study shows that the ATP-mediated inhibitory transduction processes of the natriuretic factor receptor cyclases and of ROS-GC are identical. The ATP-regulated inhibitory domain of all these cyclases resides within the C-terminal segment of the cyclase. This domain is in a different location from the one representing the ATP-stimulatory ARM. The identification of the inhibitory domain in the C-terminal segment of the cyclase indicates that this segment is composed of two separate domains: one representing a catalytic cyclase domain and the other an ATP-regulated inhibitory (ARMi) domain. These findings establish a novel ATP-mediated inhibitory transduction mechanism of the membrane guanylate cyclases which is distinct from that of its counterpart, the stimulatory ATP-mediated hormonal signal transduction mechanism. Thus, they define a new paradigm of guanylate cyclase-linked signal transduction pathways.


[Acceptance, empaty and emotional involvement in nurse-patient relationship].
In dealing with the patient, the nurse has always to have in mind that she is dealing with a human being. There are basic aspects in this personal relationship needed to the knowledge of the nurse to make this process therapeutic. Among these aspects we have acceptance, empaty and emotional involvement. These aspects we studied following bibliographical review, theorical conception and importance to the nurse-patient relationship. Situations that show accourance of those given aspects and the benefits brought to nurse-patient relationship are described.


Louse comb versus direct visual examination for the diagnosis of head louse infestations.
The techniques used for diagnosis of head louse (Pediculosis capitis) infestation are a source of controversy. Most epidemiologic and diagnostic studies have been done using direct visual examination. The main objective of this study is to compare the efficacy of direct visual examination versus the louse comb method. The hair of each child was examined twice; one team used a screening stick and another team used a louse comb. Seventy-nine boys and 201 girls, 7-10 years old were examined. Examination with a louse comb found that 25.4% of the children were infested with both lice and nits, while another 31.3% had nits only. Boys were significantly less infested with lice and nits than girls (lice: 15.2 and 29.6%; nits: 21.5 and 35.4%, respectively). The infestation rate with lice and nits was significantly higher in children with long (68.9%) and medium-length (63.9%) hair than in children with short hair (44.0%) (p < 0.01). Direct visual examination found that 5.7% of the children were infested with both lice and nits, and another 49.0% with nits only. The average time until detection of the first louse was 57.0 seconds with the comb as compared to 116.4 seconds by direct visual examination. Diagnosis of louse infestation using a louse comb is four times more efficient than direct visual examination and twice as fast. The direct visual examination technique underestimates active infestation and detects past, nonactive infestations.


Adipose-tissue Mg2+-dependent phosphatidate phosphohydrolase. Control of activity and subcellular distribution in vitro and in vivo.
The subcellular distribution of Mg2+-dependent phosphatidate phosphohydrolase in rat adipocytes between a soluble and a membrane-bound fraction was measured by using both centrifugal fractionation and a novel Millipore-filtration method. The relative proportion of the phosphohydrolase associated with the particulate fraction was increased on incubation of cells with noradrenaline or palmitate. Insulin on its own decreased the proportion of the phosphohydrolase that was particulate and abolished the effect of noradrenaline, but not that of palmitate. The effect of noradrenaline on phosphohydrolase distribution was rapid, the effect being maximal within 10 min. Noradrenaline exerted this effect with a similar concentration-dependence to its lipolytic effect. Inclusion of albumin in homogenization buffers decreased the proportion of the phosphohydrolase that was particulate, but did not abolish the effect of noradrenaline. There was limited correlation between the proportion of the phosphohydrolase that was particulate and the measured rate of triacylglycerol synthesis in adipocytes incubated under a variety of conditions. Starvation, streptozotocin-diabetes and hypothyroidism decreased the specific activities of the phosphohydrolase and glycerolphosphate acyltransferase in homogenates from epididymal fat-pads. Restoration of these activities in the diabetic state was seen after administration of insulin over 2 days or, in the short term, within 2 h after a single administration of insulin. Administration of thyroxine over 3 days caused restoration of these activities in the hypothyroid state. Starvation and diabetes increased the proportion of the phosphohydrolase found in the microsomal fraction. This change was not seen when albumin was present in homogenization buffers. The possible role of fatty acids as regulators of the intracellular translocation of the phosphohydrolase, together with the role of this enzyme in the regulation of triacylglycerol synthesis in adipose tissue, is discussed.


Noxa in colorectal cancer: a study on DNA, mRNA and protein expression.
Noxa is a BH3-only member of the Bcl-2 family, upregulated by p53 as a response to DNA damage. Mutations in the BH3-only region of other BH3-only members lead to an inactive protein. We have investigated the mRNA expression of Noxa with real-time PCR in 94 unselected colorectal adenocarcinomas and the corresponding normal mucosa. Among them, Noxa protein expression was investigated with immunohistochemistry in 16 tumors and six corresponding normal mucosa samples. Further, we searched for Noxa mutations in all the cases using single-stranded conformation polymorphism and DNA sequencing. The mRNA expression of Noxa was weak in 9% and strong in 2% of the tumors, and decreased in 9% and increased in 16% of the tumors compared with the normal mucosa; however, these changes did not have any clinical or pathological significance. The protein level in most of the cases investigated was correlated with the mRNA level. We did not find any mutations in the Noxa gene. Thus, we suggest that Noxa may not be of importance in the development of colorectal cancer.


In-situ preparation of N-TiO2/graphene nanocomposite and its enhanced photocatalytic hydrogen production by H2S splitting under solar light.
Highly monodispersed nitrogen doped TiO2 nanoparticles were successfully deposited on graphene (N-TiO2/Gr) by a facile in-situ wet chemical method for the first time. N-TiO2/Gr has been further used for photocatalytic hydrogen production using a naturally occurring abundant source of energy i.e. solar light. The N-TiO2/Gr nanocomposite composition was optimized by varying the concentrations of dopant nitrogen and graphene (using various concentrations of graphene) for utmost hydrogen production. The structural, optical and morphological aspects of nanocomposites were studied using XRD, UV-DRS, Raman, XPS, FESEM, and TEM. The structural study of the nanocomposite shows existence of anatase N-TiO2. Further, the details of the components present in the composition were confirmed with Raman and XPS. The morphological study shows that very tiny, 7-10 nm sized, N-TiO2 nanoparticles are deposited on the graphene sheet. The optical study reveals a drastic change in absorption edge and consequent total absorption due to nitrogen doping and presence of graphene. Considering the extended absorption edge to the visible region, these nanocomposites were further used as a photocatalyst to transform hazardous H2S waste into eco-friendly hydrogen using solar light. The N-TiO2/Gr nanocomposite with 2% graphene exhibits enhanced photocatalytic stable hydrogen production i.e. ∼5941 μmol h(-1) under solar light irradiation using just 0.2 gm nanocomposite, which is much higher as compared to P25, undoped TiO2 and TiO2/Gr nanocomposite. The enhancement in the photocatalytic activity is attributed to 'N' doping as well as high specific surface area and charge carrier ability of graphene. The recycling of the photocatalyst shows a good stability of the nanocomposites. This work may provide new insights to design other semiconductor deposited graphene novel nanocomposites as a visible light active photocatalyst.


Early chronic low-level methylmercury poisoning in monkeys impairs spatial vision.
Five monkeys were treated from birth with oral doses of mercury as methylmercury (50 micrograms per kilogram of body weight per day); concentrations in the blood peaked at 1.2 to 1.4 parts per million; and declined after weaning from infant formula to a steady level of 0.6 to 0.9 part per million. There were no overt signs of toxicity. When tested between 3 and 4 years of age under conditions of both high and low luminance, treated monkeys exhibited spatial vision that was impaired compared with that of control monkeys.


Depth of conceptual knowledge modulates visual processes during word reading.
Recent evidence suggests that conceptual knowledge modulates early visual stages of object recognition. The present study investigated whether similar modulations can be observed also for the recognition of object names, that is, for symbolic representations with only arbitrary relationships between their visual features and the corresponding conceptual knowledge. In a learning paradigm, we manipulated the amount of information provided about initially unfamiliar visual objects while controlling for perceptual stimulus properties and exposure. In a subsequent test session with electroencephalographic recordings, participants performed several tasks on either the objects or their written names. For objects as well as names, knowledge effects were observed as early as about 120 msec in the P1 component of the ERP, reflecting perceptual processing in extrastriate visual cortex. These knowledge-dependent modulations of early stages of visual word recognition suggest that information about word meanings may modulate the perception of arbitrarily related visual features surprisingly early.


Alterations in DNA methylation associate with reduced migraine and headache days after medication withdrawal treatment in chronic migraine patients: a longitudinal study.
Chronic migraine, a highly disabling migraine subtype, affects nearly 2% of the general population. Understanding migraine chronification is vital for developing better treatment and prevention strategies. An important factor in the chronification of migraine is the overuse of acute headache medication. However, the mechanisms behind the transformation of episodic migraine to chronic migraine and vice versa have not yet been elucidated. We performed a longitudinal epigenome-wide association study to identify DNA methylation (DNAm) changes associated with treatment response in patients with chronic migraine and medication overuse as part of the Chronification and Reversibility of Migraine clinical trial. Blood was taken from patients with chronic migraine (n = 98) at baseline and after a 12-week medication withdrawal period. Treatment responders, patients with ≥ 50% reduction in monthly headache days (MHD), were compared with non-responders to identify DNAm changes associated with treatment response. Similarly, patients with ≥ 50% versus < 50% reduction in monthly migraine days (MMD) were compared. At the epigenome-wide significant level (p < 9.42 × 10-8), a longitudinal reduction in DNAm at an intronic CpG site (cg14377273) within the HDAC4 gene was associated with MHD response following the withdrawal of acute medication. HDAC4 is highly expressed in the brain, plays a major role in synaptic plasticity, and modulates the expression and release of several neuroinflammation markers which have been implicated in migraine pathophysiology. Investigating whether baseline DNAm associated with treatment response, we identified lower baseline DNAm at a CpG site (cg15205829) within MARK3 that was significantly associated with MMD response at 12 weeks. Our findings of a longitudinal reduction in HDAC4 DNAm status associated with treatment response and baseline MARK3 DNAm status as an early biomarker for treatment response, provide support for a role of pathways related to chromatin structure and synaptic plasticity in headache chronification and introduce HDAC4 and MARK3 as novel therapeutic targets.


Antioxidant factors in plant foods and selected oilseeds.
The effect of dietary factors on health promotion and disease prevention has been an issue of interest since antiquity and has become a subject of renewed research activity in recent years. Many of the components involved are antioxidative in nature and include phenolic compounds. These phenolics exist in the free, esterified, glycosylated and polymeric forms. Scrutiny of the source materials, their subsequent extraction under optimized conditions and evaluation of activity, followed by fractionation and structure elucidation of active components is generally necessary. Meals obtained from oilseeds, such as canola, mustard, flax, borage, and evening primrose, after oil extraction, contained a variety of antioxidative factors. The antioxidative effect of source materials, their extracts or fractions thereof, depended on the seed type, the content and chemical nature of their active components.


Free energy of conformational isomers: The case of gapped DNA duplexes.
Liquid-crystalline phases in all-DNA systems have been extensively studied in the past and although nematic, cholesteric and columnar mesophases have been observed, the smectic phase remained elusive. Recently, it has been found evidence of a smectic-A ordering in an all-DNA system, where the constituent particles, which are gapped DNA duplexes, resemble chain-sticks. It has been argued that in the smectic-A phase these DNA chain-sticks should be folded as a means to suppress aggregate polydispersity and excluded volume. Nevertheless, if initial crystalline configurations are prepared in silico with gapped DNA duplexes either fully unfolded or fully folded by carrying out computer simulations one can end up with two different phases having at the same concentration and temperature the majority of gapped DNA duplexes either folded or unfolded. This result suggests that these two phases have a small free energy difference, since no transition is observed from one to the other within the simulation time span. In the present manuscript, we assess which of these two phases is thermodynamically stable through a suitable protocol based on thermodynamic integration. Our method is rather general and it can be used to discriminate stable states from metastable ones of comparable free energy.


Evaluation of Lonicera etrusca var. etrusca Santi (Caprifoliaceae) Stem and Leaf in Terms of Anatomical Structures and Some Phenolic Compounds.
The genus Lonicera includes medicinally important plants. Two varieties of L. etrusca have been recorded in Türkiye. Anatomical structures and phytochemical contents are important in the diagnosis and identification of medicinal plants. This study included stem and leaf anatomy of L. etrusca var. etrusca and high performance liquid chromatography (HPLC) analysis of the methanol extracts obtained from these parts. Plant materials were collected from Ankara. Methanol extracts were prepared from the stems and leaves by ultrasonic bath. The amounts of chlorogenic acid and caffeic acid that are major compounds in the stem and leaves, were determined by HPLC. For anatomical studies, specimens were preserved in 70% alcohol. Transverse and surface sections were prepared by hand. Detection of tissues was performed using Sartur reagent. Anatomical specimens were examined using a light microscope and microphotographed. In HPLC analysis, the highest amount of chlorogenic acid was determined in the leaf (1.148%), and the highest amount of caffeic acid (0.156%) was determined in the stem. In the anatomical analysis, it was observed that the stem was disc-shaped and hollow; pericycle is in a ring form, consists of fibre-like cells with thick walls and wide lumina; cork occurs adjoining pericyclic fibers; thin-walled pith cells containing dense druse crystals. The leaf lamina is bifacial in the transverse section; palisade and spongy parenchyma, both contain abundant starch grains; solitary druse crystals are sparse in the leaf mesophyll; the stomata were observed only on the lower surface with 3-5 subsidiary cells. With this study, L. etrusca var. etrusca has been clarified in terms of its anatomical structures and phenolic compounds. The chemical contents and anatomical structures of the plant may contain important information that can be used in classification. This study may support in taxonomically classification for the L. etrusca var. etrusca.


Evidence for the anorexia of aging: gastrointestinal transit and hunger in healthy elderly vs. young adults.
Animal studies suggest that aging is associated with anorexia and disordered gastrointestinal transit. To determine whether there is a relationship between the effects of aging on appetite and gastrointestinal transit in humans, 19 young (age 23-50 yr) and 14 elderly (age 70-84 yr) normal volunteers underwent measurements of 1) desire to eat, hunger, and fullness (visual analog scales); 2) gastric emptying (scintigraphy); 3) orocecal transit (breath hydrogen); 4) total gut transit (radiopaque markers); and 5) autonomic nerve function (cardiovascular reflexes). We found that, postprandially, elderly subjects had less desire to eat (P < 0.05) and less hunger (P < 0.05), but not a significantly greater fullness than younger subjects. Gastric emptying (50% emptying time) for solid (182 +/- 26 vs. 127 +/- 13 min, P < 0.05) and liquid (47 +/- 4 vs. 35 +/- 3 min, P < 0.05) meal components was slower in elderly subjects. Postprandial hunger was inversely related (r = -0.39, P < 0.05) to solid gastric emptying. There were no significant differences in orocecal and total gut transit times between the two groups. Autonomic nerve function was abnormal in 11 elderly but none of the young subjects (P < 0.01). We conclude that aging is associated with 1) diminished desire to eat and hunger, 2) slowing of solid and liquid gastric emptying, 3 no change in orocecal and total gut transit, and 4) autonomic nerve dysfunction. The slowing of gastric emptying may contribute to anorexia in aging subjects.


Securing a diagnosis in patients presenting with suspected paracetamol (acetaminophen) poisoning: A retrospective cohort study.
Paracetamol (acetaminophen) is the most commonly ingested drug in self-poisoning. The correlation between an ingested self-reported dose of paracetamol and plasma paracetamol concentration is moderate. The usefulness of this correlation to rule out paracetamol ingestion has to be investigated. The objective of this study is to evaluate the performance of medical history in diagnosis of paracetamol ingestion in patients admitted to the Emergency Department (ED) for deliberate self-poisoning. This retrospective cohort study was carried out in two EDs at an urban university hospital in Toulouse, France, from January 1 to June 30, 2018. All patients older than 15 years of age attending the ED for suspected deliberate self-poisonings who underwent blood testing were included. Medical history was considered positive for paracetamol intoxication if patients directly reported the use of paracetamol for deliberate self-poisoning during their ED admission or if paramedics reported the presence of paracetamol packages at the patient's home. We defined paracetamol ingestion as any concentration of paracetamol > 5 mg/L measured on presentation. We included 709 patients. 151 (21%) patients had a positive plasma paracetamol concentration. 165 (23%) patients revealed a positive medical history in terms of paracetamol ingestion. 29 (4%) patients had a false-negative medical history, and 45 (6%) patients had a false-positive history. The sensitivity of the medical history (95% confidence interval) was 79% (72 - 87), and its specificity was 92% (89 - 94). Diagnosis of self-poisoning involving paracetamol cannot be made using patient's medical history alone. Screening for paracetamol intoxication is proposed.


3'UTRs of glutathione peroxidases differentially affect selenium-dependent mRNA stability and selenocysteine incorporation efficiency.
Selenoprotein mRNAs are particular in several aspects. They contain a specific secondary structure in their 3'UTR, called Secis (selenocysteine inserting sequence), which is indispensable for selenocysteine incorporation, and they are degraded under selenium-limiting conditions according to their ranking in the hierarchy of selenoproteins. In the familiy of selenium-dependent glutathione peroxidases (GPx) the ranking is GI-GPx > or = PHGPx > cGPx = pGPx. This phenomenon was studied by mutually combining the coding regions of GI-GPx, PHGPx and cGPx with their 3'UTRs. HepG2 cells were stably transfected with the resulting constructs. Expression of glutathione peroxidases was estimated by activity measurement and Western blotting, the selenium-dependent mRNA stability by real-time PCR. Whereas 3'UTRs from stable PHGPx and GI-GPx could be exchanged without loss of stability, they were not able to stabilize cGPx mRNA. cGPx 3'UTR rendered GI-GPx and PHGPx mRNA unstable. Thus, cGPx mRNA contains selenium-responsive instability elements in both the translated and the untranslated region, which cannot be compensated by one of the stable homologs. Stabilizing efficiency of an individual GPx 3'UTR did not correlate with the efficiency of selenocysteine incorporation. PHGPx 3'UTR was equally effective as cGPx 3'UTR in enhancing GPx activity in all constructs, while GI-GPx 3'UTR showed a markedly lower efficacy. We conclude that different mRNA sequences and/or RNA-binding proteins might regulate mRNA stability and translation of selenoprotein mRNA.


Overexpression of parathyroid hormone-related protein or parathyroid hormone in transgenic mice impairs branching morphogenesis during mammary gland development.
Parathyroid hormone-related protein (PTHrP) was originally discovered as the tumor product that causes humoral hypercalcemia of malignancy. PTHrP is now known to be widely expressed in many normal fetal tissues where it may participate in the regulation of organogenesis. In this report, we document that overexpression of PTHrP in myoepithelial cells in the mammary glands of transgenic mice resulted in a form of breast hypoplasia characterized by a profound defect in branching morphogenesis of the developing mammary duct system. In addition, transgenic mice manifested a defect in lobuloalveolar development during pregnancy that seemed to be, in part, the consequence of an impaired ability to form terminal ducts in response to estrogen and progesterone stimulation. The effects of PTHrP on branching morphogenesis during breast development appeared to be the result of amino-terminal PTH-like sequences that signal through the PTH/PTHrP receptor, since overexpression of parathyroid hormone itself in the mammary glands of transgenic mice caused a similar development phenotype, and delivery of PTHrP (1-36) via locally implanted slow-release pellets impaired breast development in normal mice. These results suggest that PTHrP, which is a native product of mammary epithelial and myoepithelial cells may participate in normal breast development, perhaps as a locally secreted growth inhibitor.


Emotion regulation strategies on psychological distress and psychological well-being of caregivers of mentally challenged children: moderating role of social support.
This study investigates the moderating role of social support in the relationship between emotion regulation, psychological distress, and psychological well-being of caregivers of mentally challenged children. A total of 315 caregivers aged 18-62 (Mage = 36.99, SD = 9.90; 38.7% male, 61.3% female) completed the Emotion Regulation Questionnaire, Multidimensional Scale of Perceived Social Support, Depression Anxiety Stress Scale, and Psychological Well-being Scale. The results indicated that social support significantly moderated the relationship between cognitive reappraisal, expressive suppression, and psychological well-being. However, the moderating effect of social support in the relationship between cognitive reappraisal, expressive suppression, and psychological distress was insignificant. The findings suggest that caregivers of mentally challenged children with high social support will report higher psychological well-being when they adopt cognitive reappraisal and expressive suppression strategies.


Binding of nuclear factor κB to noncanonical consensus sites reveals its multimodal role during the early inflammatory response.
Mammalian cells have developed intricate mechanisms to interpret, integrate, and respond to extracellular stimuli. For example, tumor necrosis factor (TNF) rapidly activates proinflammatory genes, but our understanding of how this occurs against the ongoing transcriptional program of the cell is far from complete. Here, we monitor the early phase of this cascade at high spatiotemporal resolution in TNF-stimulated human endothelial cells. NF-κB, the transcription factor complex driving the response, interferes with the regulatory machinery by binding active enhancers already in interaction with gene promoters. Notably, >50% of these enhancers do not encode canonical NF-κB binding motifs. Using a combination of genomics tools, we find that binding site selection plays a key role in NF-κΒ-mediated transcriptional activation and repression. We demonstrate the latter by describing the synergy between NF-κΒ and the corepressor JDP2. Finally, detailed analysis of a 2.8-Mbp locus using sub-kbp-resolution targeted chromatin conformation capture and genome editing uncovers how NF-κΒ that has just entered the nucleus exploits pre-existing chromatin looping to exert its multimodal role. This work highlights the involvement of topology in cis-regulatory element function during acute transcriptional responses, where primary DNA sequence and its higher-order structure constitute a regulatory context leading to either gene activation or repression.


[Experimental study of human umbilical cord blood derived stromal cells transfected with recombinant adenoviral vector co-expressing VCAM-1 and GFP].
This study was aimed to investigate the effect of vcam-1 gene-modified human umbilical cord blood derived stromal cells (CBDSCs) on hematopoietic regulation so as to establish the experimental foundation for further study. The target gene vcam-1 was cloned into the shuttle plasmid with the report gene GFP. The recombinant shuttle plasmid was transformed into BJ5183 bacteria to recombine with backbone vector pAdeasy-l, and the recombinant adenoviral vector ad-vcam-1-gfp was confirmed after transfection with CBDSCs. The results indicated that two fragments of about 9 kb and 2 kb were obtained after digestion of recombinant plasmid pAdTrack-vcam-1 with NotIand XhoI, and single fragment of 600 bp was obtained after amplification with PCR; two fragments of about 31 kb and 4 kb were obtained after digestion of recombinant plasmid pad-vcam-1-gfp with PacI, which suggested a successful homologous recombination. The expression of vcam-1 gene in ad-vcam-1-gfp transfected CBDSCs could be detected by immunocytochemistry, RT-PCR and fluorescent microscopy. It is concluded that the recombinant adenoviral vector ad-vcam-1-gfp has been constructed successfully, and the expression of vcam-1 is up-regulated in CBDSCs transfected by gene ad-vcam-1-gfp.


Comparison of sensitometric and diagnostic performance of two films.
The sensitometric properties of Kodak Ektaspeed Plus and Flow E-speed film as well as their diagnostic efficacy for detecting proximal surface caries were compared. Flow and Kodak E-speed films were exposed and processed according to American National Standards Institute and American Dental Association (ADA) specifications, and film speed, contrast, and density of base plus fog were measured. Additionally, 80 premolar and molar teeth were imaged and their proximal surfaces scored by 12 dentists for the presence of caries. The actual depth of the caries was determined by microscopic examination of the teeth after sectioning. Kodak Ektaspeed Plus and Flow E-speed films, although labeled E-speed by the manufacturers, are both slow F-speed films. They have comparable base plus fog densities and comparable contrast curves. Dentists detected carious lesions equally well using both film types. The sensitivity, specificity, accuracy, and receiver operating characteristic area for detecting enamel and dentinal caries were not significantly different between the two films. Kodak Ektaspeed Plus and Flow E-speed films both meet or exceed the ADA performance specifications in terms of sensitometric properties. Both offer equal diagnostic utility for detecting caries.


[Transcranial Doppler ultrasonography (normal values, function tests and results)].
During an examination of 60 healthy subjects (from 5 to 75 years) and 195 patients with cerebrovascular diseases, the authors have established the age-associated values of blood velocity in the basal cerebral arteries and specified the role of the compression tests in evaluating collateral cerebral circulation. The data obtained permitted one to assess the diagnostic potentialities of transcranial dopplerosonography in cerebrovascular diseases.


Effect of high-pressure torsion on microstructure, mechanical properties and corrosion resistance of cast pure Mg.
High-pressure torsion (HPT) processing was applied to cast pure magnesium, and the effects of the deformation on the microstructure, hardness, tensile properties and corrosion resistance were evaluated. The microstructures of the processed samples were examined by electron backscatter diffraction, and the mechanical properties were determined by Vickers hardness and tensile testing. The corrosion resistance was studied using electrochemical impedance spectroscopy in a 3.5% NaCl solution. The results show that HPT processing effectively refines the grain size of Mg from millimeters in the cast structure to a few micrometers after processing and also creates a basal texture on the surface. It was found that one or five turns of HPT produced no significant difference in the grain size of the processed Mg and the hardness was a maximum after one turn due to recovery in some grains. Measurements showed that the yield strength of the cast Mg increased by about seven times whereas the corrosion resistance was not significantly affected by the HPT processing.


Reproducibility of ear cytology in dogs with otitis externa.
Eighty-three dogs with clinical signs of otitis externa and with ear cytology revealing microbial organisms were studied. Samples were collected from both ears of each dog by inserting two swabs successively into each ear canal, rotating each once through 360 degrees and then rolling it out in a line on to a glass slide. For each animal, four single parallel smears (SPS) were made on one slide, which was then appropriately labelled to identify the animal as well as the order of the samples. The slides, one representing each animal, were subsequently stained with modified Wright's stain. Six high-power fields of every SPS were counted. Golden retrievers and West Highland white terriers were found to be predisposed to developing otitis externa (P=0.0006 and P=0.0123, respectively). Otitis externa occurred significantly more frequently in dogs with pendulous pinnae than in dogs with erect pinnae (P=0.0009). There was no significant difference between the first and the second samples with respect to the number of microorganisms found (P>0.1 for cocci and P>0.5 for rods and yeasts), and there was a substantial agreement between the results of the two successive swabs for the presence of cocci (kappa=0.765) and rods (kappa=0.705). For yeasts, the agreement was only moderate (kappa=0.581).


Academic Stress May Contribute to the Onset of Pediatric Inflammatory Bowel Diseases.
It is currently unclear whether seasonality affects the onset of inflammatory bowel diseases (IBDs: Crohn disease and ulcerative colitis) in children. Here, we examined the records of pediatric patients with IBD diagnosed between 2009 and 2015 in a discovery cohort of 169 cases and a validation cohort of 122 subjects, where the month of symptoms onset could be determined. No seasonal patterns could be identified in respect to conception, birth, and disease onset. An annual rhythm of symptomatic onset, however, correlating with academic semesters was identified. IBD symptoms in the discovery cohort presented significantly more (P = 0.0218) during 5 months including the initiation (August, September, January) and the termination of academic semesters (December, May) compared to any other 5 months of the year. This observation was validated in the independent cohort (P < 0.0001). Our findings imply that academic stress may contribute to disease onset in pediatric IBD, which may improve timely diagnosis.


Search for CP Violation in D_{s}^{+}→K_{S}^{0}π^{+}, D^{+}→K_{S}^{0}K^{+}, and D^{+}→ϕπ^{+} Decays.
A search for charge-parity (CP) violation in Cabibbo-suppressed D_{s}^{+}→K_{S}^{0}π^{+}, D^{+}→K_{S}^{0}K^{+}, and D^{+}→ϕπ^{+} decays is reported using proton-proton collision data, corresponding to an integrated luminosity of 3.8 fb^{-1}, collected at a center-of-mass energy of 13 TeV with the LHCb detector. High-yield samples of kinematically and topologically similar Cabibbo-favored D_{(s)}^{+} decays are analyzed to subtract nuisance asymmetries due to production and detection effects, including those induced by CP violation in the neutral kaon system. The results areA_{CP}(D_{s}^{+}→K_{S}^{0}π^{+})=(1.3±1.9±0.5)×10^{-3},A_{CP}(D^{+}→K_{S}^{0}K^{+})=(-0.09±0.65±0.48)×10^{-3},A_{CP}(D^{+}→ϕπ^{+})=(0.05±0.42±0.29)×10^{-3},where the first uncertainties are statistical and the second systematic. They are the most precise measurements of these quantities to date, and are consistent with CP symmetry. A combination with previous LHCb measurements, based on data collected at 7 and 8 TeV, is also reported.


Chinese and African Euphorbiaceae plant extracts: markedly enhancing effect on Epstein-Barr virus-induced transformation.
Chinese and African Euphorbiaceae plant extracts were shown to have a markedly enhancing effect on Epstein-Barr virus (EBV)-induced transformation of human lymphocytes. When 5 X 10(5) cord blood lymphocytes were seeded into the semisolid agar medium immediately after EBV exposure, 3-10 times more colonies developed in the presence of the plant extracts at their optimal doses. When a smaller number of 5 X 10(4) cells were seeded, transformed colonies were also observed in the presence of the plant extracts but not in their absence. All of the colonies picked up from the agar medium were EBV-determined nuclear antigen (EBNA)-positive and showed the typical blastoid morphology. There were no colonies detected in the EBV-uninfected cultures with the extracts, indicating that the virus was required for the promotion by these plant extracts of this lymphocyte transformation. Euphorbiaceae plants are known to be employed as local herbal drugs in southern China and tropical Africa, and the possible role as a co-factor of the plant extracts in the development of nasopharyngeal carcinoma (NPC) and African Burkitt's lymphoma (BL) is discussed.


Ability of predator odour exposure to elicit conditioned versus sensitised post traumatic stress disorder-like behaviours, and forebrain deltaFosB expression, in rats.
At present, exposure of a rodent to the odour of a predator is one of the most common animal models of post traumatic stress disorder (PTSD). Despite this, the model remains incompletely characterized, particularly in regard to within subject assessment of major PTSD-like behaviours. In an attempt to redress this situation, we have extensively characterized the two broad categories of behaviour that are considered to characterize PTSD, that is sensitized behaviours such as social withdrawal and hypervigilance and conditioned behaviours such as avoidance of trauma linked cues. Specifically, we determined the presence and duration of both conditioned and sensitized behaviours, in the same cohort of animals, after three exposures to predator odour. Conditioned fear was assessed on the basis of inhibition of locomotor activity upon return to context 2, 7, 14, 21, and 28 days after the last odour exposure session. To assess the impact on sensitization behaviours, we monitored acoustic startle responses and social interaction behaviour 4, 9, 16, 23, and 30 days after the last exposure session. In addition to examining the behavioural consequences associated with odour exposure, we also determined the key brain regions that were activated using DeltaFosB immunohistochemistry. Our results show that the two groups of behaviours thought to characterize PTSD (conditioned and sensitized) do not travel together in the predator odour model, with clear evidence of enduring changes in conditioned fear but little evidence of changes in social interaction or acoustic startle. With regard to associated patterns of activity in the brain, we observed that odour-exposed animals exhibited significantly higher numbers of FosB-positive nuclei in only the medial prefrontal cortex (mPFC), a finding that can be viewed as being consistent with the observed behavioural changes.


Severe hemihypotrophy in a female infant with mosaic Turner syndrome: a variant of Russell-Silver syndrome?
Russell-Silver syndrome is a genetically heterogeneous condition. For most affected individuals, it represents a phenotype rather than a specific disorder. Although chromosomal anomalies, imprinting disorder, maternal uniparental disomy 7 as well as familial autosomal dominant and X-linked forms have been reported, the diagnosis remains determined on clinical grounds. Russell-Silver syndrome is characterized by asymmetric intrauterine growth retardation, postnatal failure to thrive, distinct facial features, limb asymmetry, excessive sweating and minor skin lesions. We report here a female infant who had a karyotype of 45,X on prenatal amniocytes. After delivery she was noted to have features not explainable on the basis of Turner syndrome. Her phenotype actually was quite consistent with Russell-Silver syndrome. She had a triangular face with prominent forehead, large eyes, a thin nose, malar hypoplasia, thin upper lip with down-turned corner of the mouth and a pointed chin. Marked body asymmetry was evident at birth, with the left side significantly smaller than the right side. She has a diphalangeal left fifth finger. Skin fibroblast culture and analysis showed a karyotype of 45,X on the right side and 45,X/46,XX on the left side. The case is another illustration of the genetic heterogeneity of Russell-Silver phenotype.


A GDSL Esterase/Lipase Catalyzes the Esterification of Lutein in Bread Wheat.
Xanthophylls are a class of carotenoids that are important micronutrients for humans. They are often found esterified with fatty acids in fruits, vegetables, and certain grains, including bread wheat (Triticum aestivum). Esterification promotes the sequestration and accumulation of carotenoids, thereby enhancing stability, particularly in tissues such as in harvested wheat grain. Here, we report on a plant xanthophyll acyltransferase (XAT) that is both necessary and sufficient for xanthophyll esterification in bread wheat grain. XAT contains a canonical Gly-Asp-Ser-Leu (GDSL) motif and is encoded by a member of the GDSL esterase/lipase gene family. Genetic evidence from allelic variants of wheat and transgenic rice (Oryza sativa) calli demonstrated that XAT catalyzes the formation of xanthophyll esters. XAT has broad substrate specificity and can esterify lutein, β-cryptoxanthin, and zeaxanthin using multiple acyl donors, yet it has a preference for triacylglycerides, indicating that the enzyme acts via transesterification. A conserved amino acid, Ser-37, is required for activity. Despite xanthophylls being synthesized in plastids, XAT accumulated in the apoplast. Based on analysis of substrate preferences and xanthophyll ester formation in vitro and in vivo using xanthophyll-accumulating rice callus, we propose that disintegration of the cellular structure during wheat grain desiccation facilitates access to lutein-promoting transesterification.plantcell;31/12/3092/FX1F1fx1.


Substance or space? The relative importance of substance properties and environmental characteristics in modeling the fate of chemicals in Europe.
The relative influence of substance properties and of environmental characteristics on the variation in the environmental fate of chemicals was studied systematically and comprehensively. This was done by modeling environmental concentrations for 200 sets of substance properties, representative of organic chemicals used, and 137 sets of environmental characteristics, representative of regions in Europe of 250 x 250 km. Since it was expected that the model scale has an influence on the predicted concentration variations, the calculations were repeated for regions with a 100 x 100 km and 50 x 50 km area. Stepwise multiple regression analysis was performed to determine the contribution of each of the individual input parameters on the total concentration variation. Depending on the scenario, the range in predicted environmental concentrations spreads from two up to nine orders of magnitude. In accord with earlier studies, variation in the fate of chemicals in the environment appeared to depend mainly on substance-specific partition coefficients and degradation rates. For the estimation of soil and water concentrations with direct emissions to these compartments, however, the influence of spatial variation in environmental characteristics can mount up to two orders of magnitude, a range that can be significant to account for in certain model applications. Concentration differences in water and soil are predicted to be larger if a smaller region is applied in the model calculations, and the relative influence of environmental characteristics on the total variation increases on a more detailed spatial scale. It is argued that the influence of environmental characteristics as predictors of exposure concentrations of chemicals deserves better attention in comparative risk assessment with conventional nonspatial multimedia box models.


Food Allergen-induced IgE Response Mouse Model Created by Injection of in vitro Differentiated Th2 Cell Culture and Oral Antigen Intake.
Immunoglobulin (Ig) E is a mediator of food allergic reaction; however, the mechanisms of its production in response to an ingested antigen are not fully understood. For analysis of IgE production, here we propose an IgE response mouse model created by injection of a Th2 cell culture and feeding of an egg white diet. According to this manipulation, total and ovalbumin specific IgE production were elevated in this model. We think our model enables us to analyze IgE induction by Th2 cells in food allergy and can contribute to the development of a treatment for food allergy.


Discovery of 4-anilinofuro[2,3-b]quinoline derivatives as selective and orally active compounds against non-small-cell lung cancers.
We have reported the preparation and anticancer evaluation of certain 4-anilinofuro[2,3-b]quinolines. However, drawbacks such as lack of selective cytotoxicity, poor oral bioavailability, and poor water solubility exhibited by these compounds prompted us to search for newer derivatives. Among them, (E)-1-(4-(furo[2,3-b]quinolin-4-ylamino)phenyl)ethanone O-2-aminoethyloxime (13a) is selectively active against the growth of NCI-H460 and is highly water-soluble (63 μg/mL). Its hydrochloride salt, 13a·HCl exhibited not only excellent water solubility (1049 μg/mL) but also a high oral bioavailability (57.1%). Compound 13a may cause cancer cell apoptosis through inducing mitotic arrest and mitotic catastrophe mechanism. Xenographic studies indicated the tumor size with 13a·HCl treated nude mice was significantly lower than control. Further evaluation in an orthotopic lung cancer model indicated that 13a·HCl can be absorbed readily through oral administration, distributed to lung tissue, and exhibited significant efficacy in inhibiting the growth of lung cancers.


Exercise Training in a Patient With a Left Ventricular Assist Device and Large Aortic Valve Thrombus.
An aortic valve thrombus (AVT) is a rare complication after HeartMate II implantation. In a 44-year-old man, a large AVT was discovered 6 weeks after implantation of a HeartMate II for severe dilated cardiomyopathy. The aortic valve was permanently closed. After a followup of 3 months without embolic events, the patient started a cardiac rehabilitation (CR) program involving aerobic exercise, resistance exercises, group gymnastics, and relaxation exercise, and completed the program without any complications, resulting in a significant functional benefit. CR might not be systematically contraindicated in patients with HeartMate II and an AVT, in particular, if there is no opening of the aortic valve at rest.


Effects of demographic stochasticity on biological community assembly on evolutionary time scales.
We study the effects of demographic stochasticity on the long-term dynamics of biological coevolution models of community assembly. The noise is induced in order to check the validity of deterministic population dynamics. While mutualistic communities show little dependence on the stochastic population fluctuations, predator-prey models show strong dependence on the stochasticity, indicating the relevance of the finiteness of the populations. For a predator-prey model, the noise causes drastic decreases in diversity and total population size. The communities that emerge under influence of the noise consist of species strongly coupled with each other and have stronger linear stability around the fixed-point populations than the corresponding noiseless model. The dynamics on evolutionary time scales for the predator-prey model are also altered by the noise. Approximate 1/f fluctuations are observed with noise, while 1/f2 fluctuations are found for the model without demographic noise.


Is Chios mastic gum effective in the treatment of functional dyspepsia? A prospective randomised double-blind placebo controlled trial.
Herbal remedies are increasingly popular for the treatment of functional dyspepsia. Chios mastic gum is a resinous exudate from the stem of Pistacia lentiscus var. chia. It is a traditional natural remedy used throughout the eastern Mediterranean. The aim of this study was to assess the efficacy of Chios mastic gum in patients with functional dyspepsia. One hundred and forty eight patients fulfilling Rome II criteria for functional dyspepsia were randomly assigned to receive either Chios mastic gum 350 mg three times daily or placebo. After 3 weeks of treatment the change from baseline in the severity of symptoms of functional dyspepsia was assessed using the Hong Kong index of dyspepsia. Patients' global assessment of efficacy was also evaluated. The symptom score after treatment was significantly lower in the Chios mastic gum than in the placebo group ((14.78+/-1.78) vs (19.96+/-1.83)) (p<0.05). There was a marked improvement of symptoms in 40% of patients receiving placebo and in 77% of patients receiving Chios mastic gum (p<0.02). Individual symptoms that showed significant improvement with Chios mastic gum were: stomach pain in general, stomach pain when anxious, dull ache in the upper abdomen and heartburn (<0.05 for all four symptoms). Chios mastic gum significantly improves symptoms in patients with functional dyspepsia compared to placebo.


[The effect of blue light on mitochondrial membrane potential and cytochrome C of cultured human retinal pigment epithelium cells].
To answer the question whether mitochondrial permeability transition (MPT) participates in blue light-induced damage to human retinal pigment epithelium (RPE) cells, this study was directed at assessing the effect of blue light on mitochondrial membrane potential (delta psi(m)) and cytochrome C (Cyt C) of cultured human RPE cells. Human RPE cells were exposed to blue light (wave length 470-490 nm); delta psi(m) was measured by rhodamine 123 staining and subsequent flow cytometry. Three groups were investigated: Group A (exposure to different intensity of blue light); group B (exposure to identical intensity for different duration); group C (exposure to identical intensity and duration, different prolongation of post-exposure culture). Cyt C activity was assayed by ELISA. Caspase-3 was detected by colorimetric assay. In these aspects, two groups were investigated: Group I [(2000+/-500) 1x for 6 h]; Group II [(2000+/-500) 1x for 12 h]. When human RPE cells were exposed to blue light, the more pronounced decrease of delta psi(m) was consistent with the increase of light intensity in group A. Pronounced decrease of delta psi(m) was seen at 6 h and 12 h of exposure duration in group B. At 6 h prolongation of post-exposure culture in group C, the decrease of delta psi(m) was observed, lasting 48 h. The concentration of Cyt C was detected; no significant changes were found at 6 h and 12 h prolongation of post-exposure culture, but a significant increase was found at 24 h and 36 h post-exposure in the two groups. The increase was more significant in Group II than in Group I at 24 h post-exposure. The activity change of caspase-3 was not found in the two groups. Blue light exposure over threshold can induce damage to human RPE cells, probably by triggering the mitochondrial permeability transition, which results in the decrease of delta psi(m) and the release of cytochrome C.


Risk of asthma and allergic outcomes in the offspring in relation to maternal food consumption during pregnancy: a Finnish birth cohort study.
Epidemiological and immunological studies suggest that maternal diet during pregnancy might affect the development of allergic diseases in the offspring. The authors set out to study the effect of maternal food consumption during pregnancy on the emergence of the International Study of Asthma and Allergies in Childhood (ISAAC)-based allergic outcomes: asthma, allergic rhinitis, and wheeze by the 5 yr of age. Data from 2441 children at 5 yr of age were analyzed within the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) Nutrition Study, a population-based birth cohort study. Maternal diet was assessed with a validated food frequency questionnaire. In multiple regression models adjusted for known confounders, low maternal consumption of leafy vegetables (adjusted odds ratio [aOR]: 1.55; 95% CI: 1.21, 1.98), malaceous fruits (aOR: 1.45; 95% CI: 1.15, 1.84), and chocolate (aOR: 1.36; 95% CI: 1.09, 1.70) were positively associated with the risk of wheeze in children. High maternal consumption of fruit and berry juices was positively associated with the risk of allergic rhinitis (aOR: 1.40; 95% CI: 1.03, 1.90) in children. No associations were observed between maternal food consumption and asthma. Development of allergic diseases in preschool children may be influenced by intrauterine exposure to maternal diet.


Intracellular trapping of cycloSal-pronucleotides: modification of prodrugs with amino acid esters.
A new class of d4TMP- cycloSal-pronucleotides bearing enzymatically cleavable amino acid esters is reported. These compounds are designed to trap the pronucleotide inside the cell by a fast conversion of a nonpolar ester group into a charged carboxylate. This should prevent efficient diffusion equilibrium across the cell membrane to the extracellular environment, leading to an intracellular accumulation of the compounds. This initial conversion is followed by a slow release of the nucleoside monophosphate (i.e., d4TMP). The concept is proven by hydrolysis studies in phosphate buffer, cell extracts, and human serum. These investigations revealed a high sensitivity of some amino acid ester modifications to conversion by cellular extracts, resulting in the fast release of a charged intermediate, whereas no cleavage of the modification is found in phosphate buffer. In addition, antiviral activities against HIV are presented.


[Nutrition and physical activity: two targets for cancer prevention].
The links between nutrition and cancer onset are now well established by epidemiological studies. The scientific evidence is presented in a report of the World Cancer Research Foundation (WCRF). Protective factors towards overall cancer risk are fruit and vegetable consumption and physical activity. Overweight and obesity, intakes of alcoholic beverage, fat, salt, high temperature cooked and processed red meat, increase cancer risk. In addition, beta-carotene systematic supplementation could increase lung cancer risk in smokers. As optimal controlling of these risk factors can decrease cancer mortality by 25%, nutritional counselling must be integrated in the global strategy of primary and secondary prevention of cancers.


L- and M-cone isolating ERGs: LED versus CRT stimulation.
Using double silent substitution, it is possible to generate L-cone and M-cone isolating electroretinograms (ERGs) on a CRT. A major limitation of the technique is that the depth of modulation of cone classes is limited by the restricted luminance of the phosphors and their spectral overlap. To address this problem we have ported the technique to a four-color LED Ganzfeld stimulus (Diagnosis ColorDome). This allows higher retinal illuminances, higher contrasts, and triple silent substitution. With careful control over the retinal area stimulated, we show that the same data can be recorded from both CRT and LED stimuli when luminance, size and cone contrast are kept constant. Importantly, the different temporal profiles of the two devices do not influence the ERG amplitude and phase plots. We present data over a much wider range of luminances (up to about 10,000 trolands) and contrasts with the LED stimulator than previously reported with CRT screens. We conclude that the close resemblance between data obtained with an LED stimulator and with a CRT screen indicate that the differences have a purely physiological origin.


[Degree of aggregation of Ascaris lumbricoides according to age groups after a massive antihelmilthic intervention].
The degree of aggregation is determined for the whole population and for different age-specific strata and is used for assessing the reinfection rate after a mass antihelminthic chemotherapeutic intervention. The degree of aggregation of Ascaris lumbricoides is derived from prevalence and intensity of infection date obtained from an epidemiological study of ascariasis carried out in Coatzacoalcos, Veracruz, México by means of maximum likelihood estimation of the negative binomial distribution. The results show that the distribution of the parasite for the whole population differs from the distribution of the parasite within each age-specific stratum; the reinfection rate is not uniform, the dynamics of the host-parasite association exhibits a clear destabilization of its endemic equilibrium after a first round of mass treatment. It is suggested that the aggregation among the different age-groups is highly variable and hence the infection and reinfection rates are heterogeneous with regard to age; these states of the host-parasite system are transient. Given the heterogeneity of the infection, the selective treatment seems to be the most adequate strategy to diminish helminth infection rates.


Effects of the fertility transition on birth seasonality in the Netherlands.
Synchronous with the decline in fertility that took place in the post-war period in the Netherlands, patterns of birth seasonality changed as well. In this paper seasonal fluctuations in fertility in the Netherlands are examined using population register data for the period 1952 to 2005. The peak in births has changed from spring to summer and subsequently to August/September, thereby shifting from the European to the American pattern. The seasonal shift can be attributed to parity-specific changes. Before the transition, birth seasonality did not differ much between the different parities. In the transition period from higher to low fertility, differences between parities increased which persist up to today. At present, the overall seasonality pattern is determined by first births. Moreover, birth seasonality varies by maternal age. The findings stimulate the discussion on the role of planning as a cause of birth seasonality.


Long noncoding RNA GAPLINC regulates CD44-dependent cell invasiveness and associates with poor prognosis of gastric cancer.
It is increasingly evident that long noncoding RNAs (lncRNA) have causative roles in carcinogenesis. In this study, we report findings implicating a novel lncRNA in gastric cancer, termed GAPLINC (gastric adenocarcinoma predictive long intergenic noncoding RNA), based on the use of global microarray and in situ hybridization (ISH) analyses to identify aberrantly expressed lncRNA in human gastric cancer specimens. GAPLINC is a 924-bp-long lncRNA that is highly expressed in gastric cancer tissues. GAPLINC suppression and with gene expression profiling in gastric cancer cells revealed alterations in cell migration pathways, with CD44 expression the most highly correlated. Manipulating GAPLINC expression altered CD44 mRNA abundance and the effects of GAPLINC on cell migration and proliferation were neutralized by suppressing CD44 expression. Mechanistic investigations revealed that GAPLINC regulates CD44 as a molecular decoy for miR211-3p, a microRNA that targets both CD44 and GAPLINC. Tissue ISH analysis suggested that GAPLINC overexpression defines a subgroup of patients with gastric cancer with very poor survival. Taken together, our results identify a noncoding regulatory pathway for the CD44 oncogene, shedding new light on the basis for gastric cancer cell invasiveness.


[The effect of ischemic and cardioplegic heart standstill on the myocard metabolism in normal and less perfused heart (author's transl)].
The tolerance of ischemia in normal and less perfused myocard during an ischemic and cardioplegic heart standstill was investigated. A decrease of ATP and ADP and an increase of the lactate, pyruvate and AMP was established during an ischemia of 20 minutes. The less perfused hearts gave considerably worse results regarding the energy transformation than normal hearts. In less perfused hearts the energy reserve of myocardial metabolism showed a considerably better behaviour during a cardioplegic heart standstill of 45 minutes than an ischemic one of 20 minutes. During the recuperation period this trend was emphasised.


Spinal cord injury I: A synopsis of the basic science.
Substantial knowledge has been gained in the pathological findings following naturally occurring spinal cord injury (SCI) in dogs and cats. The molecular mechanisms involved in failure of neural regeneration within the central nervous system, potential therapeutics including cellular transplantation therapy, neural plasticity, and prognostic indicators of recovery from SCI have been studied. This 2-part review summarizes 1) basic science perspectives regarding treating and curing spinal cord injury, 2) recent studies that shed light on prognosis and recovery from SCI, 3) current thinking regarding standards of care for dogs with SCI, 4) experimental approaches in the laboratory setting, and 5) current clinical trials being conducted in veterinary medicine. Part I presents timely information on the pathophysiology of spinal cord injury, challenges associated with promoting regeneration of neurons of the central nervous system, and experimental approaches aimed at developing treatments for spinal cord injury.


Study protocol for investigating the impact of community home modification services on hospital utilisation for fall injuries: a controlled longitudinal study using data linkage.
This study will evaluate the effectiveness of home adaptations, both in preventing hospital admissions due to falls for older people, and improving timely discharge. Results will provide evidence for services at the interface between health and social care, informing policies seeking to promote healthy ageing through prudent healthcare and fall prevention. All individuals living in Wales, UK, aged 60 years and over, will be included in the study using anonymised linked data from the Secure Anonymised Information Linkage Databank. We will use a national database of home modifications implemented by the charity organisation Care & Repair Cymru (C&R) from 2009 to 2017 to define an intervention cohort. We will use the electronic Frailty Index to assign individual levels of frailty (fit, mild, moderate or severe) and use these to create a comparator group (non-C&R) of people who have not received a C&R intervention. Coprimary outcomes will be quarterly numbers of emergency hospital admissions attributed to falls at home, and the associated length of stay. Secondary outcomes include the time in moving to a care home following a fall, and the indicative financial costs of care for individuals who had a fall. We will use appropriate multilevel generalised linear models to analyse the number of hospital admissions related to falls. We will use Cox proportional hazard models to compare the length of stay for fall-related hospital admissions and the time in moving to a care home between the C&R and non-C&R cohorts. We will assess the impact per frailty group, correct for population migration and adjust for confounding variables. Indicative costs will be calculated using financial codes for individual-level hospital stays. Results will provide evidence for services at the interface between health and social care, informing policies seeking to promote healthy ageing through prudent healthcare and prevention. Information governance requirements for the use of record-linked data have been approved and only anonymised data will be used in our analysis. Our results will be submitted for publication in peer-reviewed journals. We will also work with lay members and the knowledge transfer team at Swansea University to create communication and dissemination materials on key findings.


Exploration and trapping of mortal random walkers.
Exploration and trapping properties of random walkers that may evanesce at any time as they walk have seen very little treatment in the literature, and yet a finite lifetime is a frequent occurrence, and its effects on a number of random walk properties may be profound. For instance, whereas the average number of distinct sites visited by an immortal walker grows with time without bound, that of a mortal walker may, depending on dimensionality and rate of evanescence, remain finite or keep growing with the passage of time. This number can in turn be used to calculate other classic quantities such as the survival probability of a target surrounded by diffusing traps. If the traps are immortal, the survival probability will vanish with increasing time. However, if the traps are evanescent, the target may be spared a certain death. We analytically calculate a number of basic and broadly used quantities for evanescent random walkers.


Metalloproteinases and their inhibitors in angiogenesis.
Angiogenesis, the formation of new blood vessels from the pre-existing vasculature, is an integral part of physiological processes such as embryonic development, the female reproductive cycle and wound healing. Angiogenesis is also central to a variety of pathologies including cancer, where it is recognised as being crucial for the growth of solid tumours. Matrix metalloproteinases (MMPs) are a family of soluble and membrane-anchored proteolytic enzymes that can degrade components of the extracellular matrix (ECM) as well as a growing number of modulators of cell function. Several of the MMPs, most notably MMP-2 and -9 and membrane-type-1 MMP (MT1-MMP), have been linked to angiogenesis. Potential roles for these proteases during the angiogenic process include degradation of the basement membrane and perivascular ECM components, liberation of angiogenic factors, production of endogenous angiogenic inhibitors, and the unmasking of cryptic biologically relevant sites in ECM components. This review brings together what is currently known about the functions of the MMPs and the closely related adamalysin metalloproteinase (ADAM) family in angiogenesis, and discusses how this information might be useful in manipulation of the angiogenic process, with a view to controlling aberrant neovascularisation.


Non-pathogenic rhizobacteria interfere with the attraction of parasitoids to aphid-induced plant volatiles via jasmonic acid signalling.
Beneficial soil-borne microbes, such as mycorrhizal fungi or rhizobacteria, can affect the interactions of plants with aboveground insects at several trophic levels. While the mechanisms of interactions with herbivorous insects, that is, the second trophic level, are starting to be understood, it remains unknown how plants mediate the interactions between soil microbes and carnivorous insects, that is, the third trophic level. Using Arabidopsis thaliana Col-0 and the aphid Myzus persicae, we evaluate here the underlying mechanisms involved in the plant-mediated interaction between the non-pathogenic rhizobacterium Pseudomonas fluorescens and the parasitoid Diaeretiella rapae, by combining ecological, chemical and molecular approaches. Rhizobacterial colonization modifies the composition of the blend of herbivore-induced plant volatiles. The volatile blend from rhizobacteria-treated aphid-infested plants is less attractive to an aphid parasitoid, in terms of both olfactory preference behaviour and oviposition, than the volatile blend from aphid-infested plants without rhizobacteria. Importantly, the effect of rhizobacteria on both the emission of herbivore-induced volatiles and parasitoid response to aphid-infested plants is lost in an Arabidopsis mutant (aos/dde2-2) that is impaired in jasmonic acid production. By modifying the blend of herbivore-induced plant volatiles that depend on the jasmonic acid-signalling pathway, root-colonizing microbes interfere with the attraction of parasitoids of leaf herbivores.


Requirement of mitogen-activated protein kinases and I kappa B phosphorylation for induction of proinflammatory cytokines synthesis by macrophages indicates functional similarity of receptors triggered by glycosylphosphatidylinositol anchors from parasitic protozoa and bacterial lipopolysaccharide.
In the present study, we evaluated the ability of GPI-anchored mucin-like glycoproteins purified from Trypanosoma cruzi trypomastigotes (tGPI-mucin) to trigger phosphorylation of different mitogen-activated protein kinases (MAPKs) and related transcription factors in inflammatory macrophages. Kinetic experiments show that the peak of extracellular signal-related kinase (ERK)-1/ERK-2, stress-activated protein kinase (SAPK) kinase-1/mitogen-activated protein kinase (MAPK) kinase-4, and p38/SAPK-2, phosphorylation occurs between 15 and 30 min after macrophage stimulation with tGPI-mucin or GPI anchors highly purified from tGPI-mucins (tGPI). The use of the specific inhibitors of ERK-1/ERK-2 (PD 98059) and p38/SAPK-2 (SB 203580) phosphorylation also indicates the role of MAPKs, with possible involvement of cAMP response element binding protein, in triggering TNF-alpha and IL-12 synthesis by IFN-gamma-primed-macrophages exposed to tGPI or tGPI-mucin. In addition, tGPI-mucin and tGPI were able to induce phosphorylation of I kappa B, and the use of SN50 peptide, an inhibitor of NF-kappa B translocation, resulted in 70% of TNF-alpha synthesis by macrophages exposed to tGPI-mucin. Finally, the similarity of patterns of MAPK and I kappa B phosphorylation, the concentration of drugs required to inhibit cytokine synthesis, as well as cross-tolerization exhibited by macrophages exposed to tGPI, tGPI-mucin, or bacterial LPS, suggest that receptors with the same functional properties are triggered by these different microbial glycoconjugates.


Angiogenic molecules in Hodgkin's disease: results from sequential serum analysis.
Increased angiogenic activity has been demonstrated in lymphoproliferative diseases including Hodgkin's disease. In the current study, the levels of circulating angiogenic molecules in 60 Hodgkin's patients were determined prior to and after treatment and correlated to disease stage and prognostic score. Hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were increased in Hodgkin's patients in comparison to healthy controls (p<0.001). Angiogenin and angiopoietin-2 levels did not differ from controls. HGF, VEGF, TNF-alpha and angiogenin decreased significantly in Hodgkin's patients after standard treatment (p<0.001 for HGF, p<0.05 for VEGF, TNF-alpha and angiogenin). Furthermore, HGF and TNF-alpha increased with advancing stage of disease (p<0.05). HGF and VEGF correlated significantly with IL-6 (r=0.56, p<0.0005 and r=0.57, p<0.001 respectively). In conclusion, Hodgkin's disease displays an angiogenic activity as depicted by the increased serum levels of a number of angiogenic cytokines. HGF seems to be the prominent molecule in Hodgkin's disease, which may be used to monitor the disease status and the response to treatment.


Transforming Nanomedicines From Lab Scale Production to Novel Clinical Modality.
The use of nanoparticles as anticancer drug carriers has been studied for over 50 years. These nanoparticles that can carry drugs are now termed "nanomedicines". Since the approval of the first FDA "nanodrug", DOXIL in 1995, tremendous efforts have been made to develop hundreds of nanomedicines based on different materials. The development of drug nanocarriers (NCs) for cancer therapy is especially challenging and requires multidisciplinary approach. Not only is the translation from a lab scale production of the NCs to clinical scale a challenge, but tumor biology and its unique physiology also possess challenges that need to be overcome with cleverer approaches. Yet, with all the efforts made to develop new strategies to deliver drugs (including small molecules and biologics) for cancer therapy, the number of new NCs that are reaching clinical trials is extremely low. Here we discuss the reasons most of the NCs loaded with anticancer drugs are not likely to reach the clinic and emphasize the importance of understanding tumor physiology and heterogeneity, the use of predictive animal models, and the importance of sharing data as key denominators for potential successful translation of NCs from a bench scale into clinical modality for cancer care.


Inhibition of Trichoderma reesei cellulase by sugars and solvents.
Inhibition of Trichoderma reesei cellulase by sugars (glucose, delta-gluconolactone, and cellobiose) and solvents (ethanol, butanol, and acetone) was studied using cellulose azure. Glucose, cellobiose, ethanol, and butanol were noncompetitive inhibitors, delta-gluconolactone was a mixed inhibitor, and acetone was a noncompetitive activator. Converting cellobiose to glucose reduces the effective inhibitor binding constant by 6 times and converting cellobiose to ethanol reduces it by 16 times.


Effectiveness of Disc 'O' Sit cushions on attention to task in second-grade students with attention difficulties.
This study investigated the effectiveness of a type of dynamic seating system, the Disc 'O' Sit cushion (Gymnic, Osoppo, Italy), for improving attention to task among second-grade students with attention difficulties. Sixty-three second-grade students participated in the study. Using a randomized controlled trial design, 31 students were assigned to a treatment group, and 32 were assigned to a control group. Treatment group participants used Disc 'O' Sit cushions throughout the school day for a 2-week period. The teachers completed the Behavior Rating Inventory of Executive Functioning (Gioia, Isquith, Guy, & Kenworthy, 1996) for each participant before and after the intervention. An analysis of variance identified a statistically significant difference in the attention to task before and after the intervention for the treatment group. The results of the study provide preliminary evidence for the use of the Disc 'O' Sit cushion as an occupational therapy intervention to improve attention in the school setting.


Predictors of outcome and long-term survival in patients with pleural infection.
In pleural infection, medical treatment failure (chest-tube drainage and antibiotics) requires surgery and increases mortality. It would be helpful to predict which patients will fail this approach. We examined clinical predictors in 85 consecutive patients with pleural infection receiving chest drainage and intrapleural fibrinolytics, and recorded age, length of history, antibiotic delay and choice, time to drainage, blood/pleural fluid (PF) bacteriology, PF pH, lactate dehydrogenase (LDH), glucose and appearance, effusion size, pleural thickness on computed tomographic (CT) scan, and survival from time of drainage. Failures (surgery/death) were compared with successes. There were 13 (15%) medical failures. PF purulence was more frequent in medical failures (10 of 13 versus 29 of 72 successes, p < 0.02 chi-square). Absence of purulence was a useful predictor of success (positive predictive value [PPV] 93%). Purulence was not useful in predicting medical failure (PPV 26%). There was a trend for positive blood culture to predict failure (5 of 13 failures versus 11 of 72 successes, p = 0.05 chi-square), but no significant differences in other endpoints. Twelve (14%) patients died in follow-up, all with comorbidity within 400 d after drainage. Probability of survival at 4 yr was 86%. Of endpoints considered in this study, PF purulence was the only useful predictor of outcome with medical therapy in pleural infection. There is good long-term survival from pleural infection.