"I don't know how I'm still standing" a Bakhtinian analysis of social housing and health narratives in East London.
Housing is a significant determinant of health and substandard housing is a public health issue. East London has long had a shortage of social and affordable housing, worsened in recent years by a combination of stressors. In one of East London's most deprived boroughs, Newham, changes brought about by the 2011 Localism Act and the unique demands of being the host Olympic borough in 2012 have brought considerable pressures to bear on social infrastructure. This paper examines how these pressures were experienced by local residents via their narratives of social housing and health. The data reported here are from a qualitative study comprising two waves of data collection. Narrative family interviews and go-along interviews were conducted with 40 Newham residents at wave one and 28 at wave two. A narrative analysis with a Bakhtinian interpretation was undertaken. This revealed that residents framed experiences of social housing in terms of an inherent system-level ideology based on notions of need and waiting. A particularly striking feature of this ideology was the extent to which descriptions of ill health and impairment were implicated in constructions of housing need; participants directly attributed a range of health complaints to their housing predicaments, including stress, depression, cancer scares, panic attacks and loss of sleep. Understanding the contested ideology of social housing can illuminate both the dynamic processes of social exclusion and the ways in which its subjects seek to resist it.


Bioavailability and allergoprotective capacity of milk-associated conjugated linoleic acid in a murine model of allergic airway inflammation.
Cross-sectional epidemiological studies have demonstrated that farm milk from traditional farm settings possesses allergoprotective properties. Up to now, it has not been clarified which milk ingredient is responsible for protection against allergic diseases. As farm milk is rich in conjugated linoleic acids (CLA), it is hypothesized that this n-3 polyunsaturated fatty acid family contributes to the allergoprotective capacity of farm milk. We aim to prove this hypothesis in a murine model of allergic airway inflammation. To prove the bioavailability and allergoprotective capacity of milk-associated CLA in a standardized protocol, milk batches that differed significantly in terms of their CLA content were spray dried and incorporated into a basic diet by substituting the regular sunflower fat fraction. Initially, the milk CLA uptake from the diet was monitored via measurement of the CLA content in plasma and erythrocyte membranes obtained from supplemented mice. To determine whether a milk CLA-enriched diet possesses allergoprotective properties, female Balb/c mice were fed the milk CLA-enriched diet ahead of sensitization and a challenge with ovalbumin (OVA) and the parameters of airway inflammation and eisosanoid pattern were measured. In animals, supplementation with a diet rich in milk CLA resulted in elevated CLA levels in plasma and erythrocyte membranes, indicating bioavailability of milk fatty acids. Though membrane-associated phospholipid patterns were affected by supplementation with milk CLA, this application neither reduced the hallmarks of allergic airway inflammation in sensitized and OVA-challenged mice nor modified the eiconsanoid pattern in the bronchoalveolar lavage fluid of these animals. Milk-associated CLA was not capable of preventing murine allergic airway inflammation in an animal model of OVA-induced allergic airway inflammation.


Allochronic isolation and incipient hybrid speciation in tiger swallowtail butterflies.
Hybridization leading to reproductively isolated, novel genotypes is poorly understood as a means of speciation and few empirical examples have been studied. In 1999, a previously non-existent delayed flight of what appeared to be the Canadian tiger swallowtail butterfly, Papilio canadensis, was observed in the Battenkill River Valley, USA. Allozyme frequencies and morphology suggest that this delayed flight was the product of hybridization between Papilio canadensis and its sibling species Papilio glaucus. The mitochondrial DNA (mtDNA) restriction fragment length polymorphisms presented here indicate that only P. canadensis-like mtDNA occurs in this population, suggesting that introgression likely occurred from hybrid males mating with P. canadensis females. Preliminary studies of this population indicated that delayed post-diapause pupal emergence in this hybrid genotype was the root cause behind the observed delayed flight, which suggests a potential empirical example of a mechanism leading to reproductive isolation. Here we provide further evidence of the role of adult pupal emergence as a reproductive barrier likely leading to reproductive isolation. In particular, we present results from pupal emergence studies using four different spring and two different winter temperature treatments. The results indicate a clear separation of adult emergences between the hybrid population and both parental species. However, our results indicate that exceptionally hot springs are likely to lead to greater potential for overlap between the local parental species, P. canadensis, and this delayed population with hybrid origins. Conversely, our results also show that warmer winters are likely to increase the temporal separation of the hybrid population and the parental species. Finally, we report recently collected evidence that this hybrid population remains morphologically distinct.


The Seriousness of Chronic Venous Disease: A Review of Real-World Evidence.
Chronic venous disease (CVD) is a prevalent condition that tends to worsen with age. Patients initially seek treatment to relieve symptoms of leg pain, discomfort, heaviness and swelling, all of which impact their quality of life. As the disease increases in severity to include varicose veins, skin changes, and venous ulcer, the demand for treatment increases while the quality of life further diminishes. The prevalence of CVD is highest in Western countries where it already consumes up to 2% of healthcare budgets. With the aging of the global population, the prevalences of CVD and severe CVD are projected to increase substantially, foretelling unsustainably large increases in the healthcare resources and costs needed to treat CVD patients in the coming decades. Effective venoactive drug treatments and ablation procedures are available that provide symptom relief, improve quality of life, slow disease progression, and promote ulcer healing. In addition, venoactive drug treatments may be highly cost-effective. However, there is evidence that physician awareness of CVD is suboptimal and that many patients with CVD are not being treated or referred to specialists according to established guidelines. To decrease this treatment gap and prevent unnecessary disease progression, international guidelines are available to help physicians consider CVD treatment options and refer patients when warranted. Improved disease awareness and appropriate early treatment may help reduce the coming burden of CVD.Funding: Servier.


A minimally invasive method for creating coronary stenosis in a swine model for MRI and SPECT imaging.
To develop a less-invasive method for creating coronary stenosis in an animal model for the study of myocardial perfusion defects by using magnetic resonance imaging (MRI) and single-photon-emission computed tomography (SPECT). Eleven farm pigs were instrumented with an MR-compatible coronary flow-reduction fitting in the left anterior descending coronary artery (LAD). These fittings were turned from a nylon rod, tapered from a maximum outer diameter of 3 mm, and drilled to a specified inner diameter (depending on the degree of coronary stenosis desired). The flow-reducing fittings were delivered over a coronary guidewire and advanced to a wedge position in the proximal LAD with an angioplasty catheter via a carotid artery approach. Perfusion determined by contrast-enhanced MRI at peak dipyridamole stress was compared with that obtained by 99mTc sestamibi SPECT. Radiolabeled microspheres were injected at rest, after stenosis implantation, and at peak pharmacological stress to establish the severity of the coronary lesion. Coronary stenosis was successfully created in seven animals. Mild coronary stenoses (<60%) were created in four animals. Significant coronary stenoses (80%-90%) were created in three animals. Thrombosis of the coronary flow-reducing fittings was observed in four animals, leading to sudden death in three animals and myocardial infarction in one animal. This method of angioplasty-guided, LAD coronary stenosis creation in a swine model presents a less-invasive alternative to open-chest techniques such as hydraulic occluders and ameroid constrictors.


Effect of site-specifically located aristolochic acid DNA adducts on in vitro DNA synthesis by human DNA polymerase alpha.
In order to examine the effect of purine adducts of the plant carcinogen aristolochic acid (AA) on DNA replication four 30-mer templates were prepared which contained single site-specific AA lesions. The oligonucleotides were isolated by HPLC and shown to contain the two known aristolochic acid I-DNA adducts (dA-AAI, dG-AAI) or the two known aristolochic acid II-DNA adducts (dA-AAII, dG-AAII) at position 27 from the 3' end by 32P-postlabeling. These adducts templates were replicated in primer (23-mer) extension reactions catalysed by human DNA polymerase alpha. Both AAI-DNA adducts (dA-AAI, dG-AAI) blocked DNA synthesis predominantly (80-95%) at the nucleotide 3' to the adduct, although primer extension to the full length of the template was found with unmodified control templates. Increasing dNTP concentrations had only a small effect on the DNA synthesis and translesional synthesis was negligible. In contrast, both AAII-DNA adducts showed marked differences in primer extension reactions. Blocking of DNA synthesis by the dA-AAII adduct was strongly dNTP dependent. With increasing dNTP concentrations 27 and 28 nucleotide products, indicating termination of DNA synthesis after incorporation of a nucleotide opposite this adduct and incorporation of an additional nucleotide accumulated. Only the dG-AAII adducted template allowed substantial translesional synthesis to the full length of the template (up to 25%). When a 26-mer primer was used to examine nucleotide incorporation directly across from the four purine adducts, we found no detectable incorporation of nucleotides for the dA-AAI adduct, whereas the dG-AAI adduct and both AAII-adducts (dA-AAII and dG-AAII) allowed preferential incorporation of the correct nucleotide. These results indicate that for human polymerase alpha three AA purine adducts (dA-AAI, dG-AAI and dA-AAII) provide severe blocks to DNA replication and that dG-AAII, which allows translesional synthesis, may not be a very efficient mutagenic lesion.


Closed-loop insulin therapy improves glycemic control in children aged <7 years: a randomized controlled trial.
To assess the possibility of improving nocturnal glycemic control as well as meal glycemic response using closed-loop therapy in children aged <7 years. This was a randomized controlled crossover trial comparing closed-loop with standard open-loop insulin pump therapy performed in an inpatient clinical research center. Ten subjects aged <7 years with type 1 diabetes for >6 months treated with insulin pump therapy were studied. Closed-loop therapy and standard open-loop therapy were compared from 10:00 p.m. to 12:00 p.m. on 2 consecutive days. The primary outcome was plasma glucose time in range (110-200 mg/dL) during the night (10:00 p.m.-8:00 a.m.). Secondary outcomes included peak postprandial glucose levels, incidence of hypoglycemia, degree of hyperglycemia, and prelunch glucose levels. A trend toward a higher mean nocturnal time within target range was noted for closed- versus open-loop therapy, although not reaching statistical significance (5.3 vs. 3.2 h, P = 0.12). There was no difference in peak postprandial glucose or number of episodes of hypoglycemia. There was significant improvement in time spent >300 mg/dL overnight with closed-loop therapy (0.18 vs. 1.3 h, P = 0.035) and the total area under the curve of glucose >200 mg/dL (P = 0.049). Closed-loop therapy returned prelunch blood glucose closer to target (189 vs. 273 mg/dL on open loop, P = 0.009). Closed-loop insulin delivery decreases the severity of overnight hyperglycemia without increasing the incidence of hypoglycemia. The therapy is better able to reestablish target glucose levels in advance of a subsequent meal. Younger children with type 1 diabetes may reap significant benefits from closed-loop therapy.


Erlotinib attenuates homologous recombinational repair of chromosomal breaks in human breast cancer cells.
The epidermal growth factor receptor (EGFR) family has been implicated in several cancers, including breast, and its members have become the target of novel cancer therapies. In this report, we show a novel link between erlotinib, a potent EGFR inhibitor, DNA damage, and homology-directed recombinational repair (HDR) in human breast cancer cells. Erlotinib suppresses HDR. This is not secondary to erlotinib-mediated changes in cell cycle and is associated with increased gamma-H2AX foci, which is an in situ marker of chromosomal double-strand breaks. Both Rad51 and BRCA1 are essential components of the HDR machinery. Consistent with decreased HDR in erlotinib-treated cells, erlotinib also attenuates DNA damage-induced Rad51 foci and results in cytoplasmic retention of BRCA1. As BRCA1 is a shuttling protein and its nuclear function of promoting HDR is controlled by its subcellular localization, we further show that targeted translocation of BRCA1 to the cytoplasm enhances erlotinib sensitivity. These findings suggest a novel mechanism of action of erlotinib through its effects on the BRCA1/HDR pathway. Furthermore, BRCA1/HDR status may be an innovative avenue to enhance the sensitivity of cancer cells to erlotinib.


Genomic disorders 20 years on-mechanisms for clinical manifestations.
Genomic disorders result from copy-number variants (CNVs) or submicroscopic rearrangements of the genome rather than from single nucleotide variants (SNVs). Diverse technologies, including array comparative genomic hybridization (aCGH) and single nucleotide polymorphism (SNP) microarrays, and more recently, whole genome sequencing and whole-exome sequencing, have enabled robust genome-wide unbiased detection of CNVs in affected individuals and in reportedly healthy controls. Sequencing of breakpoint junctions has allowed for elucidation of upstream mechanisms leading to genomic instability and resultant structural variation, whereas studies of the association between CNVs and specific diseases or susceptibility to morbid traits have enhanced our understanding of the downstream effects. In this review, we discuss the hallmarks of genomic disorders as they were defined during the first decade of the field, including genomic instability and the mechanism for rearrangement defined as nonallelic homologous recombination (NAHR); recurrent vs nonrecurrent rearrangements; and gene dosage sensitivity. Moreover, we highlight the exciting advances of the second decade of this field, including a deeper understanding of genomic instability and the mechanisms underlying complex rearrangements, mechanisms for constitutional and somatic chromosomal rearrangements, structural intra-species polymorphisms and susceptibility to NAHR, the role of CNVs in the context of genome-wide copy number and single nucleotide variation, and the contribution of noncoding CNVs to human disease.


Dual role of the p75 tumor necrosis factor (TNF) receptor in TNF cytotoxicity.
Whereas there is ample evidence for involvement of the p55 tumor necrosis factor (TNF) receptor (p55-R) in the cytocidal effect of TNF, the role of the p75 TNF receptor (p75-R) in this effect is a matter of debate. In this study, we probed the function of p75-R in cells sensitive to the cytotoxicity of TNF using a wide panel of antibodies (Abs) against the receptor's extracellular domain. Two distinct Ab effects were observed. The Abs triggered signaling for cytotoxicity. This effect: (a) was correlated with the extent of p75-R expression by the cells; (b) was dependent on receptor cross-linking by the Abs; (c) occurred in HeLa cells, but not in A9 cells transfected with human p75-R or in HeLa cells expressing cytoplasmically truncated p75-R mutants, indicating that it involves cell-specific activities of the intracellular domain of the receptor; (d) was synergistic with the cytocidal effect of Abs against p55-R. Moreover, it seemed to reverse induced desensitization to the cytocidal effect of anti p55-R Abs, suggesting that it involves mechanisms different from those of the signaling by the p55 TNF-R. In addition, the Abs affected the response to TNF in a way that does not involve the signaling activity of p75-R. These effects: (a) could be observed also in cells in which only p55-R signaled for the cytocidal effect; (b) were not dependent on receptor cross-linking by the Abs; (c) varied according to the site at which the Abs bound to the receptor; and (d) were correlated inversely with the effects of the Abs on TNF binding to p75-R. That is, Abs binding to the membrane-distal part of the receptor's extracellular domain displaced TNF from the p75 receptor and enhanced cytocidal effect, whereas Abs that bind to the membrane-proximal part of the extracellular domain--a region at which a conformational change seems to take place upon TNF binding--decreased the dissociation of TNF from p75-R and inhibited its cytocidal effect. The above findings suggest that p75-R contributes to the cytocidal effect of TNF both by its own signaling and by regulating the access of TNF to p55-R.


Spatiotemporal DNA methylome dynamics of the developing mouse fetus.
Cytosine DNA methylation is essential for mammalian development but understanding of its spatiotemporal distribution in the developing embryo remains limited1,2. Here, as part of the mouse Encyclopedia of DNA Elements (ENCODE) project, we profiled 168 methylomes from 12 mouse tissues or organs at 9 developmental stages from embryogenesis to adulthood. We identified 1,808,810 genomic regions that showed variations in CG methylation by comparing the methylomes of different tissues or organs from different developmental stages. These DNA elements predominantly lose CG methylation during fetal development, whereas the trend is reversed after birth. During late stages of fetal development, non-CG methylation accumulated within the bodies of key developmental transcription factor genes, coinciding with their transcriptional repression. Integration of genome-wide DNA methylation, histone modification and chromatin accessibility data enabled us to predict 461,141 putative developmental tissue-specific enhancers, the human orthologues of which were enriched for disease-associated genetic variants. These spatiotemporal epigenome maps provide a resource for studies of gene regulation during tissue or organ progression, and a starting point for investigating regulatory elements that are involved in human developmental disorders.


Brevundimonas vancanneytii sp. nov., isolated from blood of a patient with endocarditis.
A Gram-negative, rod-shaped, non-spore-forming bacterial strain, designated LMG 2337(T), was isolated from the blood of a patient with endocarditis and characterized. The strain was affiliated with the alphaproteobacterial genus Brevundimonas, with Brevundimonas diminuta LMG 2089(T) (98.3 % 16S rRNA gene sequence similarity) and Brevundimonas terrae KSL-145(T) (97.5 %) as its closest relatives. This affiliation was supported by chemotaxonomic data: the G+C content was 66.3 mol %, the major polar lipids were phosphatidyl diacylglycerol, sulfoquinovosyl diacylglycerol and phosphatidyl glucopyranosyl diacylglycerol and the major fatty acids were summed feature 7 (one or more of C(18 : 1)ω 7c, C(18 : 1)ω 9t and C(18 : 1)ω 12t) and C(16 : 0). Strain LMG 2337(T) displayed an unusually broad substrate spectrum. The results from DNA-DNA hybridization and physiological and biochemical tests allowed the genotypic and phenotypic differentiation of strain LMG 2337(T) from all of the type strains of hitherto-described Brevundimonas species. The strain therefore represents a novel species, for which the name Brevundimonas vancanneytii sp. nov. is proposed, with type strain LMG 2337(T) (=CCUG 1797(T) =ATCC 14736(T)).


Mesenchymal Stem Cells and C-type Natriuretic Peptide Signaling: A Proposal for a New Treatment Approach for Skeletal Dysplasias.
Endochondral ossification is under the regulation of endocrine, paracrine and otocrine factors including transforming growth factor-β superfamily members, fibroblast growth factors, retinoids, products of hedgehog gene, parathyroid hormone-related peptide, molecules involved in cell adhesion, and extracellular matrix components. Natriuretic peptide receptor-B, and its ligand C-type natriuretic peptide have also been implicated in the regulation of limb bone development. Results of recent studies are promising in terms of systemic elevation of C-type natriuretic peptide level inducing growth. In addition, same strategy also overcomes the dwarf phenotype of achondroplasia, the most frequently seen skeletal dysplasia in human, in a mouse model. Based on this literature and a series of recent experiments discussed here, this perspective underlines the abundant C-type natriuretic peptide expression in trabecular bone derived mesenchymal stem cells of human, chicken, and rat origin, and proposes the potential use of mesenchymal stem cells as a part of growth inducing treatment strategy in osteochondrodisyplasias in the future.


Faecal Escherichia coli from patients with E. coli urinary tract infection and healthy controls who have never had a urinary tract infection.
Urinary tract infections (UTIs) are primarily caused by Escherichia coli with the patient's own faecal flora acting as a reservoir for the infecting E. coli. Here we sought to characterize the E. coli faecal flora of UTI patients and healthy controls who had never had a UTI. Up to 20 E. coli colonies from each rectal swab were random amplified polymorphic DNA (RAPD) typed for clonality, dominance in the sample and correlation to the infecting UTI isolate in patients. Each distinct clone was phylotyped and tested for antimicrobial susceptibility. Eighty-seven per cent of the UTI patients carried the infecting strain in their faecal flora, and faecal clones causing UTI were more often dominant in the faecal flora. Patients had a larger diversity of E. coli in their gut flora by carrying more unique E. coli clones compared to controls, and patient faecal clones were more often associated with multidrug resistance compared to controls. We found a similar phylotype distribution of faecal clones from UTI patients and healthy controls, including a large proportion of B2 isolates in the control group. Faecal-UTI isolates from patients were more often associated with multidrug resistance compared to faecal-only clones, indicating a link between UTI virulence and antimicrobial resistance. Intake of any antibiotic less than 6 months prior to inclusion in the experiment occurred significantly more in patients with UTI than in controls. In contrast, presence of an intrauterine device was significantly more common in controls indicating a protective effect against UTI. In conclusion, healthy controls have a large proportion of potentially pathogenic E. coli phylotypes in their faecal flora without this causing infection.


Aire-dependent production of XCL1 mediates medullary accumulation of thymic dendritic cells and contributes to regulatory T cell development.
Dendritic cells (DCs) in the thymus (tDCs) are predominantly accumulated in the medulla and contribute to the establishment of self-tolerance. However, how the medullary accumulation of tDCs is regulated and involved in self-tolerance is unclear. We show that the chemokine receptor XCR1 is expressed by tDCs, whereas medullary thymic epithelial cells (mTECs) express the ligand XCL1. XCL1-deficient mice are defective in the medullary accumulation of tDCs and the thymic generation of naturally occurring regulatory T cells (nT reg cells). Thymocytes from XCL1-deficient mice elicit dacryoadenitis in nude mice. mTEC expression of XCL1, tDC medullary accumulation, and nT reg cell generation are diminished in Aire-deficient mice. These results indicate that the XCL1-mediated medullary accumulation of tDCs contributes to nT reg cell development and is regulated by Aire.


Ensuring that COVID-19 research is inclusive: guidance from the NIHR INCLUDE project.
To provide guidance to researchers, funders, regulators and study delivery teams to ensure that research on COVID-19 is inclusive, particularly of groups disproportionately affected by COVID-19 and who may have been historically under-served by research. Groups who are disproportionately affected by COVID-19 include (but are not limited to) older people, people with multiple long-term conditions, people with disabilities, people from Black, Asian and Ethnic minority groups, people living with obesity, people who are socioeconomically deprived and people living in care homes. All these groups are under-served by clinical research, and there is an urgent need to rectify this if COVID-19 research is to deliver relevant evidence for these groups who are most in need. We provide a framework and checklists for addressing key issues when designing and delivering inclusive COVID-19 research, based on the National Institute for Health Research INnovations in CLinical trial design and delivery for the UnDEr-served project roadmap. Strong community engagement, codevelopment and prioritisation of research questions and interventions are essential. Under-served groups should be represented on funding panels and ethics committees, who should insist on the removal of barriers to participation. Exclusion criteria should be kept to a minimum; intervention delivery and outcome measurement should be simple, flexible and tailored to the needs of different groups, and local advice on the best way to reach and engage with under-served communities should be taken by study delivery teams. Data on characteristics that allow identification of under-served groups must be collected, analyses should include these data to enable subgroup comparisons and results should be shared with under-served groups at an early stage. Inclusive COVID-19 research is a necessity, not a luxury, if research is to benefit all the communities it seeks to serve. It requires close engagement with under-served groups and attention to aspects of study topic, design, delivery, analysis and dissemination across the research life cycle.


Detecting selection in population trees: the Lewontin and Krakauer test extended.
Detecting genetic signatures of selection is of great interest for many research issues. Common approaches to separate selective from neutral processes focus on the variance of F(ST) across loci, as does the original Lewontin and Krakauer (LK) test. Modern developments aim to minimize the false positive rate and to increase the power, by accounting for complex demographic structures. Another stimulating goal is to develop straightforward parametric and computationally tractable tests to deal with massive SNP data sets. Here, we propose an extension of the original LK statistic (T(LK)), named T(F-LK), that uses a phylogenetic estimation of the population's kinship (F) matrix, thus accounting for historical branching and heterogeneity of genetic drift. Using forward simulations of single-nucleotide polymorphisms (SNPs) data under neutrality and selection, we confirm the relative robustness of the LK statistic (T(LK)) to complex demographic history but we show that T(F-LK) is more powerful in most cases. This new statistic outperforms also a multinomial-Dirichlet-based model [estimation with Markov chain Monte Carlo (MCMC)], when historical branching occurs. Overall, T(F-LK) detects 15-35% more selected SNPs than T(LK) for low type I errors (P < 0.001). Also, simulations show that T(LK) and T(F-LK) follow a chi-square distribution provided the ancestral allele frequencies are not too extreme, suggesting the possible use of the chi-square distribution for evaluating significance. The empirical distribution of T(F-LK) can be derived using simulations conditioned on the estimated F matrix. We apply this new test to pig breeds SNP data and pinpoint outliers using T(F-LK), otherwise undetected using the less powerful T(LK) statistic. This new test represents one solution for compromise between advanced SNP genetic data acquisition and outlier analyses.


Food-web dynamics under climate change.
Climate change affects ecological communities through its impact on the physiological performance of individuals. However, the population dynamic of species well inside their thermal niche is also determined by competitors, prey and predators, in addition to being influenced by temperature changes. We use a trait-based food-web model to examine how the interplay between the direct physiological effects from temperature and the indirect effects due to changing interactions between populations shapes the ecological consequences of climate change for populations and for entire communities. Our simulations illustrate how isolated communities deteriorate as populations go extinct when the environment moves outside the species' thermal niches. High-trophic-level species are most vulnerable, while the ecosystem function of lower trophic levels is less impacted. Open communities can compensate for the loss of ecosystem function by invasions of new species. Individual populations show complex responses largely uncorrelated with the direct impact of temperature change on physiology. Such complex responses are particularly evident during extinction and invasion events of other species, where climatically well-adapted species may be brought to extinction by the changed food-web topology. Our results highlight that the impact of climate change on specific populations is largely unpredictable, and apparently well-adapted species may be severely impacted.


Where do teens go to get the 411 on sexual health? A teen intern in clinical research with teens.
Research Setting: The research for the study reported here was conducted in conjunction with the Biomedical and Health Sciences Internship for High School Students at the University of California, San Francisco, Department of Pediatrics. The eight-week intensive summer program promotes interest in science, medicine, and health among young people by introducing students to the professional world of science, broadly defined. Interns are expected to assist in a specific research project that addresses a scientific question. They participate in a variety of lectures and are exposed to faculty members, medical students, and college graduates working as research assistants in a rich academic and clinical research setting. This study was conducted within Kaiser Permanente (KP) of Northern California as part of a larger study aimed at increasing Chlamydia screening among sexually active adolescents. It was approved by Committee on Human Research, the institutional review board (IRB) for the University of California, San Francisco and the IRB for KP Northern California. There were two primary objectives of this study: first, we sought to identify where teenagers obtain information about sexual health; second, we examined whether aspects of a clinician's communication style with a teen during a health care visit were associated with the teen choosing that clinician as a primary source of sexual health information (as compared with parents, peers, teachers, the news media, and other sources). Teens who perceived that their clinician communicated with respect and explained information in ways that they could understand were more likely to cite their clinician as a source of sexual health information. Having time alone (confidentiality) with a physician was also associated with teens' selection of a clinician as a primary information source. Whether the clinician asked about sex during the health care visit was significantly associated with males selecting the clinician as a primary source of sexual health information. An important finding, at least for males, because teens do not always bring up the topic.


Acute transcranial magnetic stimulation of frontal brain regions selectively modulates the release of vasopressin, biogenic amines and amino acids in the rat brain.
Using intracerebral microdialysis in urethane-anaesthetized adult male Wistar rats, we monitored the effects of acute repetitive transcranial magnetic stimulation (rTMS; 20 trains of 20 Hz, 2.5 s) on the intrahypothalamic release of arginine vasopressin (AVP) and selected amino acids (glutamate, glutamine, aspartate, serine, arginine, taurine, gamma-aminobutyric acid) and the intrahippocampal release of monoamines (dopamine, noradrenaline, serotonin) and their metabolites (homovanillic acid, 3,4-dihydroxyphenylacetic acid, 5-hydroxyindoleacetic acid). The stimulation parameters were adjusted according to the results of accurate computer reconstructions of the current density distributions induced by rTMS in the rat and human brains, ensuring similar stimulation patterns in both cases. There was a continuous reduction in AVP release of up to 50% within the hypothalamic paraventricular nucleus in response to rTMS. In contrast, the release of taurine, aspartate and serine was selectively stimulated within this nucleus by rTMS. Furthermore, in the dorsal hippocampus the extracellular concentration of dopamine was elevated in response to rTMS. Taken together, these data provide the first in vivo evidence that acute rTMS of frontal brain regions has a differentiated modulatory effect on selected neurotransmitter/neuromodulator systems in distinct brain areas.


The crystal structure of bluetongue virus VP7.
Bluetongue virus (BTV), a representative of the orbivirus genus of the Reoviridae, is considerably larger (at 80 nm across), and structurally more complex, than any virus for which we have comprehensive structural information. Orbiviruses infect mammalian hosts through insect vectors and cause economically important diseases of domesticated animals. They possess a segmented double-stranded RNA genome within a capsid composed of four major types of polypeptide chains. An outer layer of VP2 and VP5 is removed as the virus enters the target cell, to leave an intact core within the cell. This core is 70 nm across and composed of 780 copies of VP7 (M(r) 38K) that, as trimers, form 260 'bristly' capsomeres clothing an inner scaffold constructed from VP3 (M(r) 103K). We report here the crystal structure of VP7 from BTV serotype 10, which reveals a molecular architecture not seen previously in viral structural proteins. Each subunit consists of two domains, one a beta-sandwich, the other a bundle of alpha-helices, and a short carboxy-terminal arm which might tie trimers together during capsid formation. A concentration of methionine residues at the core of the molecule could provide plasticity, relieving structural mismatches during assembly.


Fibroblast growth factors 7 and 10 are involved in ameloblastoma proliferation via the mitogen-activated protein kinase pathway.
Ameloblastoma is an epithelial benign tumor of the odontogenic apparatus and its growth mechanisms are not well understood. Fibroblast growth factor (FGF) 3, FGF7 and FGF10, which are expressed by the neural crest-derived ectomesenchymal cells, induce the proliferation of odontogenic epithelial cells during tooth development. Therefore, we examined the expression and function of these FGFs in ameloblastoma. We examined 32 cases of ameloblastoma as well as AM-1 cells (an ameloblastoma cell line) and studied the expression of FGF3, FGF7, FGF10 and their specific receptors, namely, FGF receptor (FGFR) 1 and FGFR2. Proliferation, mitogen-activated protein kinase (MAPK) signaling and PI3K signaling were examined in AM-1 cells after the addition of FGF7, FGF10 and these neutralizing antibodies. The expression of FGF7, FGF10, FGFR1 and FGFR2 was detected in ameloblastoma cells and AM-1 cells, while that of FGF3 was not. FGF7 and FGF10 stimulated AM-1 cell proliferation and phosphorylation of p44/42 MAPK. However, Akt was not phosphorylated. Blocking the p44/42 MAPK pathway by using a specific mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitor (U0126) completely neutralized the effects of FGF7 and FGF10 on AM-1 cell proliferation. However, Anti FGF7 and FGF10 neutralizing antibodies did not decrease cell proliferation and MAPK phosphorylation of AM-1 cells. These results suggested that FGF7 and FGF10 are involved in the proliferation of ameloblastoma cells through the MAPK pathway.


Assessing rheumatologists' attitudes and utilization of classification criteria for ankylosing spondylitis and axial spondyloarthritis: a global effort.
This study aims to assess rheumatologists' perceptions, utilization patterns, and attitudes towards the modified New York (mNY) criteria for ankylosing spondylitis (AS) and Assessment of SpondyloArthritis International Society (ASAS) criteria for axial spondyloarthritis (axSpA). Members of the national rheumatology societies in five countries (United States of America (USA), Canada, India, Turkey, and Brazil) were invited to participate in a survey containing questions regarding rheumatologists' familiarity, and use of AS and axSpA classification criteria in daily practice, perceived specificity of spondyloarthritis features in making the diagnosis, patterns of imaging tests performed in daily practice, and their opinion about the need for modification of current classification criteria. The responses were analyzed by gender, age, years in practice, as well as by country of practice. Descriptive statistics, t test, and chi-square test were used for comparison of groups. Approximately 6% rheumatologists (478 out of 8021 professional association members) from five countries completed the survey. The country-specific response rates were Brazil 4%, USA 4.3%, India 11%, Canada 14%, and Turkey 29%, though the overall contributions from individual countries were USA 47%, India 14.9%, Brazil 13.8%, Turkey 12.8%, and Canada 8.8%. The mean age of respondents was 50 years (± 11.8), 31% were females and 90% spent majority (> 75%) of their time in clinical practice. The mNY and ASAS criteria were regularly used in clinical practice by 44 and 66% of responders, respectively. Those reporting "always" using ASAS criteria were more likely to be women (p = 0.006), and within 5 years of completing rheumatology training. Vast majority (74%) regarded Inflammatory Back Pain (IBP) as a specific feature for axSpA. Majority (50 and 60%, respectively) regarded uveitis and dactylitis as "very specific" features helping them make the diagnosis of axSpA, whereas heel enthesitis, peripheral inflammatory arthritis, and response to NSAIDs were considered "somewhat specific" by 50% of the responders. Less than half (47%) of the responders used the mNY grading for X-ray of SI joints. In the case of normal X-ray of SI joint, the use of MRI was more frequent than CT scan (83.6 vs. 10.9%) in assessing for sacroiliitis. If sacroiliitis was not seen on X-rays, the likelihood of ordering MRI was significantly higher among rheumatologists completing training within < 15 years versus > 25 years prior (90 vs. 75%, p = 0.007). Overall, 70% thought that ASAS criteria were adequately specific for clinical trials. However, 42% respondents still felt a need to modify ASAS classification criteria for axSpA. Also, 46% respondents felt that mNY criteria should be modified. In the absence of diagnostic criteria, majority of rheumatologists are using the classification criteria for diagnosis of axSpA. Though axSpA classification criteria are perceived to be specific for clinical trials, 40% rheumatologists feel the need to modify these criteria. Key Points • This study informs how rheumatologists in five countries spread over four different continents diagnose axSpA in clinical practice. • Since majority rheumatologists among survey respondents across the countries use ASAS criteria for diagnosis of axSpA, more specific criteria may be required to avoid overdiagnosis. • MRI is commonly used to rule out sacroiliitis in case of normal X-ray of sacroiliac joints.


Mutations in SETD2 and genes affecting histone H3K36 methylation target hemispheric high-grade gliomas.
Recurrent mutations affecting the histone H3.3 residues Lys27 or indirectly Lys36 are frequent drivers of pediatric high-grade gliomas (over 30% of HGGs). To identify additional driver mutations in HGGs, we investigated a cohort of 60 pediatric HGGs using whole-exome sequencing (WES) and compared them to 543 exomes from non-cancer control samples. We identified mutations in SETD2, a H3K36 trimethyltransferase, in 15% of pediatric HGGs, a result that was genome-wide significant (FDR = 0.029). Most SETD2 alterations were truncating mutations. Sequencing the gene in this cohort and another validation cohort (123 gliomas from all ages and grades) showed SETD2 mutations to be specific to high-grade tumors affecting 15% of pediatric HGGs (11/73) and 8% of adult HGGs (5/65) while no SETD2 mutations were identified in low-grade diffuse gliomas (0/45). Furthermore, SETD2 mutations were mutually exclusive with H3F3A mutations in HGGs (P = 0.0492) while they partly overlapped with IDH1 mutations (4/14), and SETD2-mutant tumors were found exclusively in the cerebral hemispheres (P = 0.0055). SETD2 is the only H3K36 trimethyltransferase in humans, and SETD2-mutant tumors showed a substantial decrease in H3K36me3 levels (P < 0.001), indicating that the mutations are loss-of-function. These data suggest that loss-of-function SETD2 mutations occur in older children and young adults and are specific to HGG of the cerebral cortex, similar to the H3.3 G34R/V and IDH mutations. Taken together, our results suggest that mutations disrupting the histone code at H3K36, including H3.3 G34R/V, IDH1 and/or SETD2 mutations, are central to the genesis of hemispheric HGGs in older children and young adults.


Leptin and soluble leptin receptor in risk of colorectal cancer in the European Prospective Investigation into Cancer and Nutrition cohort.
Leptin, a peptide hormone produced primarily by the adipocytes, is hypothesized to play a role in the pathogenesis of colorectal cancer (CRC). Soluble leptin receptor (sOB-R) may regulate leptin's physiologic functions; however its relation to CRC risk is unknown. This study explored the association of leptin and sOB-R with risk of CRC in a prospective nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. A total of 1,129 incident CRC cases (713 colon, 416 rectal) were matched within risk sets to 1,129 controls. Conditional logistic regression was used to calculate relative risks (RR) and 95% confidence intervals (CI). After multivariable adjustment including body mass index (BMI), waist circumference, and baseline leptin concentrations, sOB-R was strongly inversely associated with CRC (RR comparing the highest quintile vs. the lowest, 0.55; 95% CI, 0.40-0.76; P(trend) = 0.0004) and colon cancer (RR, 0.42; 95% CI, 0.28-0.63, P(trend) = 0.0001); whereas no association was seen for rectal cancer (RR adjusted for BMI and waist circumference, 0.83; 95% CI, 0.48-1.44, P(trend) = 0.38). In contrast, leptin was not associated with risk of CRC (RR adjusted for BMI and waist circumference, 0.85; 95% CI, 0.56-1.29, P(trend) = 0.23). Additional adjustments for circulating metabolic biomarkers did not attenuate these results. These novel findings suggest a strong inverse association between circulating sOB-R and CRC risk, independent of obesity measures, leptin concentrations, and other metabolic biomarkers. Further research is needed to confirm the potentially important role of sOB-R in CRC pathogenesis.


Copper plasmonics and catalysis: role of electron-phonon interactions in dephasing localized surface plasmons.
Copper metal can provide an important alternative for the development of efficient, low-cost and low-loss plasmonic nanoparticles, and selective nanocatalysts. However, poor chemical stability and lack of insight into photophysics and plasmon decay mechanisms has impeded study. Here, we use smooth conformal ALD coating on copper nanoparticles to prevent surface oxidation, and study dephasing time for localized surface plasmons on different sized copper nanoparticles. Using dephasing time as a figure of merit, we elucidate the role of electron-electron, electron-phonon, impurity, surface and grain boundary scattering on the decay of localized surface plasmon waves. Using our quantitative analysis and different temperature dependent measurements, we show that electron-phonon interactions dominate over other scattering mechanisms in dephasing plasmon waves. While interband transitions in copper metal contributes substantially to plasmon losses, tuning surface plasmon modes to infrared frequencies leads to a five-fold enhancement in the quality factor. These findings demonstrate that conformal ALD coatings can improve the chemical stability for copper nanoparticles, even at high temperatures (>300 °C) in ambient atmosphere, and nanoscaled copper is a good alternative material for many potential applications in nanophotonics, plasmonics, catalysis and nanoscale electronics.


Reshaping the gut microbiome with bacterial transplantation and antibiotic intake.
The intestinal microbiota consists of over 1000 species, which play key roles in gut physiology and homeostasis. Imbalances in the composition of this bacterial community can lead to transient intestinal dysfunctions and chronic disease states. Understanding how to manipulate this ecosystem is thus essential for treating many disorders. In this study, we took advantage of recently developed tools for deep sequencing and phylogenetic clustering to examine the long-term effects of exogenous microbiota transplantation combined with and without an antibiotic pretreatment. In our rat model, deep sequencing revealed an intestinal bacterial diversity exceeding that of the human gut by a factor of two to three. The transplantation produced a marked increase in the microbial diversity of the recipients, which stemmed from both capture of new phylotypes and increase in abundance of others. However, when transplantation was performed after antibiotic intake, the resulting state simply combined the reshaping effects of the individual treatments (including the reduced diversity from antibiotic treatment alone). Therefore, lowering the recipient bacterial load by antibiotic intake prior to transplantation did not increase establishment of the donor phylotypes, although some dominant lineages still transferred successfully. Remarkably, all of these effects were observed after 1 mo of treatment and persisted after 3 mo. Overall, our results indicate that the indigenous gut microbial composition is more plastic that previously anticipated. However, since antibiotic pretreatment counterintuitively interferes with the establishment of an exogenous community, such plasticity is likely conditioned more by the altered microbiome gut homeostasis caused by antibiotics than by the primary bacterial loss.


Increased dopamine tone during meditation-induced change of consciousness.
This is the first in vivo demonstration of an association between endogenous neurotransmitter release and conscious experience. Using 11C-raclopride PET we demonstrated increased endogenous dopamine release in the ventral striatum during Yoga Nidra meditation. Yoga Nidra is characterized by a depressed level of desire for action, associated with decreased blood flow in prefrontal, cerebellar and subcortical regions, structures thought to be organized in open loops subserving executive control. In the striatum, dopamine modulates excitatory glutamatergic synapses of the projections from the frontal cortex to striatal neurons, which in turn project back to the frontal cortex via the pallidum and ventral thalamus. The present study was designed to investigate whether endogenous dopamine release increases during loss of executive control in meditation. Participants underwent two 11C-raclopride PET scans: one while attending to speech with eyes closed, and one during active meditation. The tracer competes with endogenous dopamine for access to dopamine D2 receptors predominantly found in the basal ganglia. During meditation, 11C-raclopride binding in ventral striatum decreased by 7.9%. This corresponds to a 65% increase in endogenous dopamine release. The reduced raclopride binding correlated significantly with a concomitant increase in EEG theta activity, a characteristic feature of meditation. All participants reported a decreased desire for action during meditation, along with heightened sensory imagery. The level of gratification and the depth of relaxation did not differ between the attention and meditation conditions. Here we show increased striatal dopamine release during meditation associated with the experience of reduced readiness for action. It is suggested that being in the conscious state of meditation causes a suppression of cortico-striatal glutamatergic transmission. To our knowledge this is the first time in vivo evidence has been provided for regulation of conscious states at a synaptic level.


Multiparametric MRI in rectal cancer.
MRI has a pivotal role in both pretreatment staging and posttreatment evaluation of rectal cancer. The accuracy of MRI in pretreatment staging is higher compared with posttreatment evaluation. This occurs due to similar signal intensities of tumoral and posttreatment fibrotic, necrotic, and inflamed tissue. This limitation occurs with conventional MRI of the rectum with morphologic sequences. There is a need towards increasing the accuracy of MRI, especially for posttreatment evaluation. The term multiparametric MRI implies addition of functional sequences, namely, diffusion and perfusion to the routine protocol. This review summarizes the technique, potential implications and previously published studies about multiparametric MRI of rectal cancer.


Thiazide-Associated Hypercalcemia: Incidence and Association With Primary Hyperparathyroidism Over Two Decades.
Thiazide diuretics, the antihypertensive agent prescribed most frequently worldwide, are commonly associated with hypercalcemia. However, the epidemiology and clinical features are poorly understood. To update the incidence of thiazide-associated hypercalcemia and clarify its clinical features. In a population-based descriptive study, Olmsted County, Minnesota, residents with thiazide-associated hypercalcemia were identified through the Rochester Epidemiology Project and the Mayo Clinic Laboratory Information System from 2002-2010 and were added to the historical cohort beginning in 1992. Incidence rates were adjusted to the 2010 United States white population. Overall, 221 Olmsted County residents were identified with thiazide-associated hypercalcemia an average of 5.2 years after initiation of treatment. Subjects were older (mean age, 67 years) and primarily women (86.4%). The incidence of thiazide-associated hypercalcemia increased after 1997 and peaked in 2006 with an annual incidence of 20 per 100,000, compared to an overall rate of 12 per 100,000 in 1992-2010. Severe hypercalcemia was not observed in the cohort despite continuation of thiazide treatment in 62.4%. Of patients discontinuing thiazides, 71% continued to have hypercalcemia. Primary hyperparathyroidism was diagnosed in 53 patients (24%), including five patients who underwent parathyroidectomy without thiazide discontinuation. Many patients with thiazide-associated hypercalcemia have underlying primary hyperparathyroidism. Additionally, a sharp rise in thiazide-associated hypercalcemia incidence began in 1998, paralleling the increase observed in primary hyperparathyroidism in this community. Case ascertainment bias from targeted osteoporosis screening is the most likely explanation.


Design Equations for Mixed-Mode Fracture of Dental Ceramic-Cement Interfaces Using the Brazil-Nut-Sandwich Test.
Dental interfaces are subject to mixed-mode loading. This study provides practical guidance for determining interfacial fracture toughness of dental ceramic systems. We address interfacial fracture of a composite resin cement sandwiched between two dental ceramic materials. Emphasis is placed on sandwich disc specimens with cracks originating from elliptical-shaped flaws near the center, for which analytical fracture mechanics methods fail to predict. The interaction integral method is used to provide accurate finite element solutions for cracks with elliptical-shaped flaws in a Brazil-nut-sandwich specimen. The developed model was first validated with existing experimental data and then used to evaluate the three most widely used dental ceramic systems: polycrystalline ceramics (zirconia), glass-ceramics (lithium disilicate), and feldspathic ceramics (porcelain). Contrary to disc specimens with ideal cracks, those with cracks emanating from elliptical-shaped flaws do not exhibit a monotonic increase in interfacial toughness. Also, interfacial fracture toughness is seen to have a direct relationship with the aspect ratio of elliptical-shaped flaws and an inverse relationship with the modulus ratio of the constituents. The presence of an elliptical-shaped flaw significantly changes the interfacial fracture behavior of sandwich structures. Semi-empirical design equations are provided for fracture toughness and stress intensity factors for interfacial cracks. The developed design equations provide practical guidance for determining interfacial fracture toughness of selected dental ceramic material systems. Those equations take into account four critical factors: size of the elliptical flaw, modulus ratio of constituent materials, loading angle, and applied load.


A Combination of Podophyllotoxin and Rutin Attenuates Radiation Induced Gastrointestinal Injury by Negatively Regulating NF-κB/p53 Signaling in Lethally Irradiated Mice.
Development of an effective radio protector to minimise radiation-inflicted damages have largely failed owing to inherent toxicity of most of the agents examined so far. This study is centred towards delivering protection to lethally irradiated mice by pre-administration of a safe formulation G-003M (combination of podophyllotoxin and rutin) majorly through regulation of inflammatory and cell death pathways in mice. Single intramuscular dose of G-003M injected 60 min prior to 9 Gy exposure rescued 89% of whole body lethally irradiated C57BL/6J mice. Studies have revealed reduction in radiation induced reactive oxygen species (ROS), nitric oxide (NO) generation, prostaglandin E2 (PGE2) levels and intestinal apoptosis in G-003M pre-treated mice intestine. Restricted nuclear translocation of redox-sensitive Nuclear factor-κB (NF-κB) and subsequent downregulation of cyclo-oxygenase 2 (COX-2), inducible nitric oxide synthase (iNOS; EC 18.104.22.168) and tumor necrosis factor (TNF-α) levels demonstrated the anti-inflammatory effect that G-003M exerts. Support to early hematopoietic recovery was exhibited through G-003M mediated induction of granulocyte colony stimulating factor (G-CSF) and interleukin (IL-6) levels in lethally irradiated mice. Considerable attenuation in radiation induced morphological damage to the intestinal villi, crypts and mucosal layers was observed in G-003M pre-treated mice. Additionally, our formulation did not reduce the sensitivity of tumor tissue to radiation. Altogether, these results suggest that G-003M ameliorates the deleterious effects of radiation exposure by minimising ROS and NO generation and effectively regulating inflammatory and cell death pathways. Mechanism of protection elucidated in the current study demonstrates that G-003M can be used as a safe and effective radio protective agent in radiotherapy for human application.


Nitrogen-bisphosphonates block retinoblastoma phosphorylation and cell growth by inhibiting the cholesterol biosynthetic pathway in a keratinocyte model for esophageal irritation.
The surprising discovery that nitrogen-containing bisphosphonates (N-BPs) act via inhibition of the mevalonate-to-cholesterol pathway raised the possibility that esophageal irritation by N-BPs is mechanism-based. We used normal human epidermal keratinocytes (NHEKs) to model N-BP effects on stratified squamous epithelium of the esophagus. The N-BPs alendronate and risedronate inhibited NHEK growth in a dose-dependent manner without inducing apoptosis. N-BPs (30 microM) caused accumulation of cells in S phase and increased binucleation (inhibited cytokinesis). Consistent with N-BP inhibition of isoprenylation, geranylgeraniol or farnesol prevented accumulation in S phase. Binucleation was also induced by the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor lovastatin and by the squalene synthase inhibitor zaragozic acid A and was prevented by adding low-density lipoprotein. At 300 microM, N-BPs reduced expression of cyclin-dependent kinase (cdk) 2 and cdk4 and enhanced expression of p21(waf1) and p27(kip1) and their binding to cdks with corollary hypophosphorylation of retinoblastoma. Lovastatin and zaragozic acid A produced similar effects, except that p21(waf1) expression and binding to cdks was not induced. Growth inhibition, but not binucleation, was also caused by the geranylgeranyl transferase I inhibitor, GGTI-298, which also enhanced cdk2 and cdk4 association with p27(kip1). These findings are consistent with suppression of epithelial cell growth by N-BPs via inhibition of the mevalonate pathway and the consequent reduction in cholesterol synthesis, which blocks cytokinesis, and in geranylgeranylation, which interferes with progression through the cell cycle.


Assisted autogenic drainage in infants and young children hospitalized with uncomplicated pneumonia, a pilot study.
Pneumonia is the most important respiratory problem in low-to-middle income countries. Airway clearance therapy continues to be used in children with pneumonia and secretion retention; however, there is lack of evidence to support or reject this treatment. This study aimed to investigate the feasibility of a randomized controlled trial (RCT) on the efficacy and safety of assisted autogenic drainage (AAD) compared to standard nursing care in children hospitalized with uncomplicated pneumonia. A single-blinded pilot RCT was conducted on 29 children (median age 3.5 months, IQR 1.5-9.4) hospitalized with uncomplicated pneumonia. The intervention group received standard nursing care with additional bi-daily AAD, for 10 to 30 min. The control group only received standard nursing care, unless otherwise deemed necessary by the physician or physiotherapist. The primary outcome measure was duration of hospitalization. The secondary outcome measures included days of fever and supplemental oxygen support; respiratory rate (RR) and heart rate adjusted for age; RR and oxygen saturation pre-, post-, and 1-hr post-treatment; oxygen saturation; adverse events; and mortality. No difference was found for duration of hospitalization (median 7.5 and 7.0 days for the control and intervention groups, respectively); however, Kaplan-Meier analysis revealed a strong tendency towards a shorter time to discharge in the intervention group (p = .06). No significant differences were found for the other outcome measures at time of discharge. No adverse events were reported. Within the intervention group, a significant reduction in RR adjusted for age was found. As no adverse events were reported, and AAD did not prolong hospitalization; AAD might be considered as safe and effective in young children with uncomplicated pneumonia. However, a larger multicentred RCT is warranted to determine the efficacy of AAD compared to standard nursing care.


Molecular basis of tubulin transport within the cilium by IFT74 and IFT81.
Intraflagellar transport (IFT) of ciliary precursors such as tubulin from the cytoplasm to the ciliary tip is involved in the construction of the cilium, a hairlike organelle found on most eukaryotic cells. However, the molecular mechanisms of IFT are poorly understood. Here, we found that the two core IFT proteins IFT74 and IFT81 form a tubulin-binding module and mapped the interaction to a calponin homology domain of IFT81 and a highly basic domain in IFT74. Knockdown of IFT81 and rescue experiments with point mutants showed that tubulin binding by IFT81 was required for ciliogenesis in human cells.


Intracranial hemangiomas in a patient with POEMS syndrome.
POEMS syndrome is a rare multi-system disease with typical features of polyneuropathy, organomegaly, endocrinopathy, monoclonal plasmaproliferative disorder and skin changes. We describe a 44-year-old woman with polyneuropathy, hepatomegaly, IgA lambda-plasmacytoma, thrombocytosis, papilledema with elevated protein levels in cerebrospinal fluid and multiple cutaneous hemangiomas who was diagnosed with three intracranial lesions. Histology revealed capillary hemangiomas, one of them displaying partially glomeruloid features.


Effects of ferulic acid on fertile and asthenozoospermic infertile human sperm motility, viability, lipid peroxidation, and cyclic nucleotides.
The capacity of human sperm fertilization principally depends on sperm motility and membrane integrity. Reactive oxygen species, such as superoxide anion and hydrogen peroxide, are known to impair sperm motility and membrane integrity by inducing membrane lipid peroxidation (LPO). Ferulic acid (FA), an effective constituent in various medicinal herbs, has recently been shown to scavenge oxygen free radicals and increase the intracellular cAMP and cGMP. The aim of this study is to investigate the effects of FA on human sperm motility, viability, lipid peroxidation, and cyclic nucleotides in fertile and asthenozoospermic infertile individuals in vitro. The sperm samples were obtained from 10 fertile volunteers and 10 asthenozoospermic infertile patients. Washed spermatozoa were incubated at 37 degrees C in Ham's F-10 medium with 0, 0.1, 0.2, 0.4, 0.8, or 1.6 mM of FA. Samples were analyzed for viability, determined by eosin-Y dye exclusion method at 0, 1, 2, 3, 5, and 6 h of incubation; motility, determined by the trans-membrane migration method within 2 h of incubation; LPO, determined by thiobarbituric acid (TBA) method at 3 h of incubation and the intracellular cAMP and cGMP, determined, respectively, by 3H-cAMP and 125I-cGMP radioimmunoassay at 3 h of incubation. The results showed: in both fertile and infertile spermatozoa, the viability, trans-membrane migration ratio (TMMR) and the levels of intracellular cAMP and cGMP in FA-treated spermatozoa were significantly higher than those of spermatozoa in control groups, while TBA-reactive substances contents in treated spermatozoa were significantly lower than those in control spermatozoa. The effects of FA on these processes were concentration dependent. These data suggested that FA is beneficial to sperm viability and motility in both fertile and infertile individuals, and that reduction of lipid peroxidative damage to sperm membranes and increase of intracellular cAMP and cGMP may be involved in these benefits. It is possible that FA may be used for cure of asthenozoospermic infertility.


Current variations in childhood cancer supportive care in the Netherlands.
Current treatment strategies in pediatric oncology are intensive and lead to high survival rates but also to treatment-related complications. Therefore, supportive care plays an increasingly important role. This study was designed to evaluate variations in supportive care practice in children with cancer in the Netherlands and adherence to selected existing international guidelines through an in-depth review of local guidelines and protocols at all 6 Dutch pediatric cancer centers. Based on shared expert opinion, a questionnaire regarding current supportive care practice was compiled. For each center, the required information was extracted from local supportive care guidelines, and the list was sent to a pediatric oncologist of that center to verify its correspondence with local daily practice. Subsequently, it was determined whether clinical practice was concordant (same in ≥ 5 of 6 centers), partly concordant (highly overlapping in ≥ 5 of 6 centers), or discordant (same in < 5 of 6 centers). Local practices were compared with strong recommendations from high-quality, evidence-based guidelines. The questionnaire comprised 67 questions regarding supportive care practice. Concordance was observed for 11 of 67 practice items (16%), partial concordance was observed for 6 of 67 practice items (9%), and discordance was observed for 50 of 67 practice items (75%). Adherence to strong recommendations of 4 high-quality, evidence-based guidelines varied but was generally low. Large variations exist in pediatric oncology supportive care practice, and this could negatively influence care. Adherence to existing evidence-based guidelines and the development and implementation of new clinical practice guidelines have the potential of standardizing supportive care practice and thereby improving outcomes for children with cancer.


Maternal periconceptional folic acid intake and risk of autism spectrum disorders and developmental delay in the CHARGE (CHildhood Autism Risks from Genetics and Environment) case-control study.
Periconceptional folate is essential for proper neurodevelopment. Maternal folic acid intake was examined in relation to the risk of autism spectrum disorder (ASD) and developmental delay (DD). Families enrolled in the CHARGE (CHildhood Autism Risks from Genetics and Environment) Study from 2003 to 2009 were included if their child had a diagnosis of ASD (n = 429), DD (n = 130), or typical development (TD; n = 278) confirmed at the University of California Davis Medical Investigation of Neurodevelopmental Disorders Institute by using standardized clinical assessments. Average daily folic acid was quantified for each mother on the basis of dose, brands, and intake frequency of vitamins, supplements, and breakfast cereals reported through structured telephone interviews. Mean (±SEM) folic acid intake was significantly greater for mothers of TD children than for mothers of children with ASD in the first month of pregnancy (P1; 779.0 ± 36.1 and 655.0 ± 28.7 μg, respectively; P < 0.01). A mean daily folic acid intake of ≥600 μg (compared with <600 μg) during P1 was associated with reduced ASD risk (adjusted OR: 0.62; 95% CI: 0.42, 0.92; P = 0.02), and risk estimates decreased with increased folic acid (P-trend = 0.001). The association between folic acid and reduced ASD risk was strongest for mothers and children with MTHFR 677 C>T variant genotypes. A trend toward an association between lower maternal folic acid intake during the 3 mo before pregnancy and DD was observed, but not after adjustment for confounders. Periconceptional folic acid may reduce ASD risk in those with inefficient folate metabolism. The replication of these findings and investigations of mechanisms involved are warranted.


Changes in brain transcripts related to Alzheimer's disease in a model of HFE hemochromatosis are not consistent with increased Alzheimer's disease risk.
Iron abnormalities are observed in the brains of Alzheimer's disease (AD) patients, but it is unclear whether common disorders of systemic iron overload such as hemochromatosis alter risks of AD. We used microarrays and real-time reverse transcription-PCR to investigate changes in the brain transcriptome of adult Hfe-/- mice, a model of hemochromatosis, relative to age- and gender-matched wildtype controls. Classification by functional pathway analysis revealed transcript changes for various genes important in AD. There were decreases of up to 9-fold in transcripts for amyloid-β protein precursor, tau, apolipoprotein E, presenilin 1, and various other γ-secretase components, as well as Notch signaling pathway molecules. This included decreased transcripts for 'hairy and enhancer of split' Hes1 and Hes5, downstream targets of Notch canonical signaling. The reductions in Hes1 and Hes5 transcripts provide evidence that the changes in levels of transcripts for γ-secretase components and Notch signaling genes have functional consequences. The effects appeared relatively specific for AD in that few genes pertaining to other important neurodegenerative diseases, notably Parkinson's disease and Huntington's disease, or to inflammation, oxidative stress, or apoptosis, showed altered transcript levels. The observed effects on AD-related gene transcripts do not appear to be consistent with increased AD risk in HFE hemochromatosis and might, if anything, be predicted to protect against AD to some extent. As Hfe-/- mice did not have higher brain iron levels than wildtype controls, these studies highlight the need for further research in models of more severe hemochromatosis with brain iron loading.


Contribution of molecular typing methods and antifungal susceptibility testing to the study of a candidemia cluster in a burn care unit.
We investigated a cluster of cases of Candida septicemia diagnosed in four burn patients. Twenty clinical isolates of Candida albicans and two of Candida parapsilosis, plus eight isolates of C. albicans recovered from nurses' clothes, were analyzed by antifungal susceptibility testing and three genotyping methods (restriction fragment length polymorphism analysis with EcoRI and HinfI, arbitrarily primed PCR, and karyotyping). The high MICs of the azoles for all of the C. albicans isolates tested suggest either a natural resistance of the endogenous flora or the transmission of isolates with acquired resistance. The genotyping methods demonstrated the involvement of four different strains, cross-infections with one C. albicans strain and one C. parapsilosis strain, and identity between some of the strains from the patients and nurses. The origins of the strains remain unclear. Our results show that the use of a combination of at least two different methods such as those used in the present study is recommended for C. albicans typing.


Subcellular localization and hormone sensitivity of adipocyte cyclic AMP phosphodiesterase.
Treatment of intact adipocytes with either or both insulin and adrenaline stimulated membrane cyclic AMP phosphodiesterase activity only in the endoplasmic reticulum subfraction. The cyclic GMP-inhibited cyclic AMP phosphodiesterase activity was also found in this fraction. Quantitative Western blotting using a specific polyclonal antibody, raised against the homogeneous 'dense-vesicle' cyclic AMP phosphodiesterase from rat liver, identified a single 63 kDa species which was localized in the adipocyte endoplasmic reticulum fraction. The ability of adrenaline to stimulate adipocyte membrane cyclic AMP phosphodiesterase was shown to be mediated via beta-adrenoceptors and not alpha 1-adrenoceptors. Membrane cyclic AMP phosphodiesterase was stimulated by glucagon but not by vasopressin, A23187 or 12-O-tetradecanoylphorbol 13-acetate (TPA). Treatment of adipocytes with either chloroquine or dansyl cadaverine failed to affect the ability of insulin to stimulate cyclic AMP phosphodiesterase activity. Treatment of an isolated adipocyte endoplasmic reticulum membrane fraction with purified protein kinase A increased its cyclic AMP phosphodiesterase activity some 2-fold. When this fraction was treated with purified protein kinase A and [32P]ATP, label was incorporated into a 63 kDa protein which was specifically immunoprecipitated with the antiserum against the liver 'dense-vesicle' cyclic AMP phosphodiesterase.


The transcriptional programme of antibody class switching involves the repressor Bach2.
Activated B cells differentiate to plasma cells to secrete IgM or, after undergoing class switch recombination (CSR), to secrete other classes of immunoglobulins. Diversification of antibody function by CSR is important for humoral immunity. However, it remains unclear how the decision for the bifurcation is made. Bach2 is a B-cell-specific transcription repressor interacting with the small Maf proteins whose expression is high only before the plasma cell stage. Here we show that Bach2 is critical for CSR and somatic hypermutation (SHM) of immunoglobulin genes. Genetic ablation of Bach2 in mice revealed that Bach2 was required for both T-cell-independent and T-cell-dependent IgG responses and SHM. When stimulated in vitro, Bach2-deficient B cells produced IgM, as did wild-type cells, and abundantly expressed Blimp-1 (refs 9, 10) and XBP-1 (ref. 11), critical regulators of the plasmacytic differentiation, indicating that Bach2 was not required for the plasmacytic differentiation itself. However, they failed to undergo efficient CSR. These findings define Bach2 as a key regulator of antibody response and provide an insight into the orchestration of CSR and SHM during plasma cell differentiation.


Efflux of noradrenaline from platelets in normotensive members of hypertensive families.
1. Platelets have been used as a model of sympathetic neurons to study the storage of noradrenaline in normotensive individuals belonging to families with essential hypertension for at least two generations. 2. The initial efflux rate (k) of noradrenaline was determined in 44 young relatives (mean age 29.2 years), in 18 middle-aged relatives (mean age 46.7 years) and in 31 young controls with no known family history of essential hypertension (mean age 29.8 years). From the groups of relatives all those with definite hypertension had been excluded a priori. 3. k was significantly higher in the young relatives (22.7 +/- 7.9) than in the middle-aged relatives (17.7 +/- 6.4) and in the controls (15.6 +/- 5.1). Of the relatives 27.3% had higher k values than any of the controls. A significant correlation was found between k and diastolic blood pressure in controls but not in young relatives.


Orthostatic Intolerance and Postural Orthostatic Tachycardia Syndrome in Joint Hypermobility Syndrome/Ehlers-Danlos Syndrome, Hypermobility Type: Neurovegetative Dysregulation or Autonomic Failure?
Background. Joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type (JHS/EDS-HT), is a hereditary connective tissue disorder mainly characterized by generalized joint hypermobility, skin texture abnormalities, and visceral and vascular dysfunctions, also comprising symptoms of autonomic dysfunction. This study aims to further evaluate cardiovascular autonomic involvement in JHS/EDS-HT by a battery of functional tests. Methods. The response to cardiovascular reflex tests comprising deep breathing, Valsalva maneuver, 30/15 ratio, handgrip test, and head-up tilt test was studied in 35 JHS/EDS-HT adults. Heart rate and blood pressure variability was also investigated by spectral analysis in comparison to age and sex healthy matched group. Results. Valsalva ratio was normal in all patients, but 37.2% of them were not able to finish the test. At tilt, 48.6% patients showed postural orthostatic tachycardia, 31.4% orthostatic intolerance, 20% normal results. Only one patient had orthostatic hypotension. Spectral analysis showed significant higher baroreflex sensitivity values at rest compared to controls. Conclusions. This study confirms the abnormal cardiovascular autonomic profile in adults with JHS/EDS-HT and found the higher baroreflex sensitivity as a potential disease marker and clue for future research.


Behavioral activation is an evidence-based treatment for depression.
Recent reviews of evidence-based treatment for depression did not identify behavioral activation as an evidence-based practice. Therefore, this article conducted a systematic review of behavioral activation treatment of depression, which identified three meta-analyses, one recent randomized controlled trial and one recent follow-up of an earlier randomized control trial. Behavioral activation was consistently superior to wait list and treatment as usual control groups. Effect sizes were not different from cognitive behavior therapy or cognitive therapy, both post-treatment and at follow-up. Indeed, behavioral activation may be more effective than cognitive therapy and cognitive behavior therapy in terms of lower dropout. Behavioral activation, like cognitive behavior therapy, may be superior to paroxitine because it results in less relapse and recurrence, may be substantially cheaper, and does not have risks of pharmacotherapy. There is some evidence that behavioral activation may also be useful with some people for whom cognitive and cognitive-behavior therapy is less effective, such as those with severe, lifelong depression, people with substance abuse and people with dementia and severe depression. There is now sufficient evidence to conclude that behavioral activation is an evidence-based therapy.


Learning the topological properties of brain tumors.
This work presents a graph-based representation (a.k.a., cell-graph) of histopathological images for automated cancer diagnosis by probabilistically assigning a link between a pair of cells (or cell clusters). Since the node set of a cell-graph can include a cluster of cells as well as individual ones, it enables working with low-cost, low-magnification photomicrographs. The contributions of this work are twofold. First, it is shown that without establishing a pairwise spatial relation between the cells (i.e., the edges of a cell-graph), neither the spatial distribution of the cells nor the texture analysis of the images yields accurate results for tissue level diagnosis of brain cancer called malignant glioma. Second, this work defines a set of global metrics by processing the entire cell-graph to capture tissue level information coded into the histopathological images. In this work, the results are obtained on the photomicrographs of 646 archival brain biopsy samples of 60 different patients. It is shown that the global metrics of cell-graphs distinguish cancerous tissues from noncancerous ones with high accuracy (at least 99 percent accuracy for healthy tissues with lower cellular density level, and at least 92 percent accuracy for benign tissues with similar high cellular density level such as nonneoplastic reactive/inflammatory conditions).


Overview and analysis of animal use in North America.
The Canadian Council on Animal Care (CCAC) publishes data on over 25 species of animals used in science, and the US Department of Agriculture publishes data on six of those species. Between 1980 and 1999, the reduction in animal use was found to be correlated between Canada and the USA for dogs (r = 0.944, p < 0.001), cats (r = 0.839, p < 0.001), rabbits (r = 0.852, p < 0.001) and hamsters (r = 0.716, p < 0.01), with no significant correlation found for non-human primates and guinea-pigs. On the basis of the four species where correlation between the two countries was found for reduction in use, the mean ratio of the number of animals used in the USA compared to the number used in Canada was 17.0 +/- 7.5. The CCAC data for these six US-regulated species were used in an analysis of regression with multiple predictors to test whether they could be used to predict the total number of animals used. No significant correlation was found. However, using the same analysis, rats, mice, fish and birds were found to be highly correlated with the total number of animals used (r2 = 0.9835, p < 0.005). The regression equation developed by using Canadian data was validated using UK animal use numbers. An almost perfect fit between the estimated values provided the evidence that total animal use in Canada and the UK decreased at about the same pace during the 1990s. Animal use data can be a useful tool to monitor the implementation of reduction measures. However, their use for the monitoring of refinement measures requires care and analysis. For example, the sustained downward trend in the number of experiments causing severe pain in unanaesthetised animals (category of invasiveness [CI] E) observed in Canada and the USA between 1996 and 1999 is indicative of effective refinement, but it would be misleading to interpret the increase in the number of animals used in Canada under CI D in 1997 as an indication of greater pain and distress. In fact, the larger number of animals in CI D resulted at least in part from the implementation of new CCAC guidelines designed to ensure better monitoring of transgenic animal care and use.


Malaria and Nutritional Status Among Children With Severe Acute Malnutrition in Niger: A Prospective Cohort Study.
The relationship between malaria infection and nutritional status is complex. Previous studies suggest malaria may increase the incidence and severity of malnutrition, while malnutrition may increase the risk of malaria infection. Here, we report bidirectional associations between malaria and nutritional status among children with uncomplicated severe acute malnutrition (SAM). This study is a secondary analysis of a randomized, controlled trial for the treatment of uncomplicated SAM in Niger. Children aged 6-59 months were enrolled and followed for 12 weeks. Malaria infection was assessed using an histidine-rich protein 2 (HRP2) rapid diagnostic test at admission and at any follow-up visit with fever. We assessed the association of nutritional status at admission on malaria incidence using Cox proportional hazards regression and malaria infection at admission on nutritional recovery and weight and height gain using linear regression. Of 2399 children included in the analysis, 1327 (55.3%) were infected with malaria at admission. Malaria incidence was 12.1 cases/100 person-months among those without malaria infection at admission. Nutritional status at admission was not associated with malaria incidence. Children with malaria infection at admission and subsequently treated with an artemisinin-based combination therapy had increased weight gain (0.38 g/kg/day; 95% confidence interval [CI], 0.07 to 0.69) and reduced height gain (-0.002 mm/day; 95% CI, -0.004 to -0.0008). Malaria infection was common among children treated for uncomplicated SAM. Malaria infection may impair height gain. Proper medical and nutritional management should be ensured to prevent adverse effects of malaria infection. NCT01613547.


Data Augmentation for Deep Neural Networks Model in EEG Classification Task: A Review.
Classification of electroencephalogram (EEG) is a key approach to measure the rhythmic oscillations of neural activity, which is one of the core technologies of brain-computer interface systems (BCIs). However, extraction of the features from non-linear and non-stationary EEG signals is still a challenging task in current algorithms. With the development of artificial intelligence, various advanced algorithms have been proposed for signal classification in recent years. Among them, deep neural networks (DNNs) have become the most attractive type of method due to their end-to-end structure and powerful ability of automatic feature extraction. However, it is difficult to collect large-scale datasets in practical applications of BCIs, which may lead to overfitting or weak generalizability of the classifier. To address these issues, a promising technique has been proposed to improve the performance of the decoding model based on data augmentation (DA). In this article, we investigate recent studies and development of various DA strategies for EEG classification based on DNNs. The review consists of three parts: what kind of paradigms of EEG-based on BCIs are used, what types of DA methods are adopted to improve the DNN models, and what kind of accuracy can be obtained. Our survey summarizes the current practices and performance outcomes that aim to promote or guide the deployment of DA to EEG classification in future research and development.


Regulation of MBK-2/DYRK by CDK-1 and the pseudophosphatases EGG-4 and EGG-5 during the oocyte-to-embryo transition.
DYRKs are kinases that self-activate in vitro by autophosphorylation of a YTY motif in the kinase domain, but their regulation in vivo is not well understood. In C. elegans zygotes, MBK-2/DYRK phosphorylates oocyte proteins at the end of the meiotic divisions to promote the oocyte-to-embryo transition. Here we demonstrate that MBK-2 is under both positive and negative regulation during the transition. MBK-2 is activated during oocyte maturation by CDK-1-dependent phosphorylation of serine 68, a residue outside of the kinase domain required for full activity in vivo. The pseudotyrosine phosphatases EGG-4 and EGG-5 sequester activated MBK-2 until the meiotic divisions by binding to the YTY motif and inhibiting MBK-2's kinase activity directly, using a mixed-inhibition mechanism that does not involve tyrosine dephosphorylation. Our findings link cell-cycle progression to MBK-2/DYRK activation and the oocyte-to-embryo transition.


Iron reduction response and demographic differences between diabetics and non-diabetics with cardiovascular disease entered into a controlled clinical trial.
Iron-catalyzed oxygen-free radical-induced oxidative stress mediates the pathogenesis of diabetes and cardiovascular disease (CVD). Diabetics (n = 473) and non-diabetics (n = 804) with CVD entered into a randomized trial of iron (ferritin) reduction by calibrated phlebotomy (, Identifier NCT00032357) had comparable iron measures at entry but diabetics had a greater burden of CVD and comorbidities, lower hemoglobin and hematocrit levels, and higher glucose levels than non-diabetics. Entry iron measures were lower in diabetics on hypoglycemic therapy compared to previously untreated diabetics. Diabetics and non-diabetics had comparable iron measures during follow-up. The Loess analysis of paired ferritin and hemoglobin, and paired ferritin and glucose levels in diabetics randomized to phlebotomy showed higher ferritin levels associated with lower hemoglobin and higher glucose levels. Progressive ferritin reduction in diabetics correlated with increasing hemoglobin and decreasing glucose levels, neither of which reached levels observed in non-diabetics. We postulate that phlebotomy-triggered autophagy (ferritinophagy) released redox-active iron sequestered intracellularly, worsening anemia and glucose utilization that corrected partially with ferritin reduction. Intracellular redox-active iron levels contributory to disease, not reflected in peripheral iron measures, may persist because of glycation of iron transport proteins in diabetes. These findings suggest novel strategies for disease prevention and improving outcomes in diabetes and CVD.


Microbiome Signatures Associated With Steatohepatitis and Moderate to Severe Fibrosis in Children With Nonalcoholic Fatty Liver Disease.
The intestinal microbiome might affect the development and severity of nonalcoholic fatty liver disease (NAFLD). We analyzed microbiomes of children with and without NAFLD. We performed a prospective, observational, cross-sectional study of 87 children (age range, 8-17 years) with biopsy-proven NAFLD and 37 children with obesity without NAFLD (controls). Fecal samples were collected and microbiome composition and functions were assessed using 16S ribosomal RNA amplicon sequencing and metagenomic shotgun sequencing. Microbial taxa were identified using zero-inflated negative binomial modeling. Genes contributing to bacterial pathways were identified using gene set enrichment analysis. Fecal microbiomes of children with NAFLD had lower α-diversity than those of control children (3.32 vs 3.52, P = .016). Fecal microbiomes from children with nonalcoholic steatohepatitis (NASH) had the lowest α-diversity (control, 3.52; NAFLD, 3.36; borderline NASH, 3.37; NASH, 2.97; P = .001). High abundance of Prevotella copri was associated with more severe fibrosis (P = .036). Genes for lipopolysaccharide biosynthesis were enriched in microbiomes from children with NASH (P < .001). Classification and regression tree model with level of alanine aminotransferase and relative abundance of the lipopolysaccharide pathway gene encoding 3-deoxy-d-manno-octulosonate 8-phosphate-phosphatase identified patients with NASH with an area under the receiver operating characteristic curve value of 0.92. Genes involved in flagellar assembly were enriched in the fecal microbiomes of patients with moderate to severe fibrosis (P < .001). Classification and regression tree models based on level of alanine aminotransferase and abundance of genes encoding flagellar biosynthesis protein had good accuracy for identifying case children with moderate to severe fibrosis (area under the receiver operating characteristic curve, 0.87). In an analysis of fecal microbiomes of children with NAFLD, we associated NAFLD and NASH with intestinal dysbiosis. NAFLD and its severity were associated with greater abundance of genes encoding inflammatory bacterial products. Alterations to the intestinal microbiome might contribute to the pathogenesis of NAFLD and be used as markers of disease or severity.


Employers' views of promoting walking to work: a qualitative study.
Physical inactivity increases the risk of many chronic diseases including coronary heart disease, type 2 diabetes, obesity and some cancers. It is currently recommended that adults should undertake at least 150 minutes of moderate physical activity in bouts of 10 minutes or more throughout the week. One way for adults in employment to incorporate exercise into their daily routine is to walk during the commute to and from work. Schemes to promote active travel require the support of employers and managers but there is a lack of research focusing on their views and experiences of promoting walk to work schemes. This study presents the findings from in-depth, digitally recorded interviews with 29 employers from a range of small, medium and large workplaces who participated in a feasibility study to develop and test an employer-led scheme to promote walking to work. All recordings were fully transcribed. The Framework approach for data management was used to aid qualitative analysis. Interview transcripts were read and reread, and textual data were placed in charts focusing on facilitators, barriers, and possibilities for employers to promote walking to work. A range of perspectives were identified, from active support through uncertainty and cynicism to resistance. The majority of employers who took part in the study were unclear about how to give practical support for employees who walk to work, but appeared more confident about ideas to promote cycling. Some employers were concerned about how their attempts to promote walking might be perceived by employees. Furthermore, the main business of their organisation took priority over other activities. It is clear that employers need more evidence of the effectiveness of walk to work schemes, and the benefits to employers of committing resources to them. Furthermore, employers need support in creating an authentic, health promoting ethos within the workplace to enhance positive relationships and reduce tensions that may arise when promoting active travel initiatives.


Normobaric, intermittent hypoxia conditioning is cardio- and vasoprotective in rats.
Favorable versus detrimental cardiovascular responses to intermittent hypoxia conditioning (IHC) are heavily dependent on experimental or pathological conditions, including the duration, frequency and intensity of the hypoxia exposures. Recently, we demonstrated that a program of moderate, normobaric IHC (FIO2 9.5-10% for 5-10 min/cycle, with intervening 4 min normoxia, 5-8 cycles/day for 20 days) in dogs afforded robust cardioprotection against infarction and arrhythmias induced by coronary artery occlusion-reperfusion, but this protection has not been verified in other species. Accordingly, in this investigation cardio- as well as vasoprotection were examined in male Wistar rats completing the normobaric IHC program or a sham program in which the rats continuously breathed atmospheric air. Myocardial ischemia and reperfusion (IR) was imposed by occlusion and reperfusion of the left anterior descending coronary artery in in situ experiments and by subjecting isolated, perfused hearts to global ischemia-reperfusion. Cardiac arrhythmias and myocardial infarct size were quantified in in situ experiments. Endothelial function was evaluated from the relaxation to acetylcholine of norepinephrine-precontracted aortic rings taken from in situ IR experiments, and from the increase in coronary flow produced by acetylcholine in isolated hearts. IHC sharply reduced cardiac arrhythmias during ischemia and decreased infarct size by 43% following IR. Endothelial dysfunction in aorta was marked after IR in sham rats, but not significant in IHC rats. Similar findings were found for the coronary circulations of isolated hearts. These findings support the hypothesis that moderate, normobaric IHC is cardio- and vasoprotective in a rat model of IR.


CULTURE OF DISSOCIATED DROSOPHILA EMBRYOS: AGGREGATED CELLS DIFFERENTIATE AND SORT OUT.
When the cells of Drosophila embryos are dissociated and cultured in vitro, aggregation of the cells begins rapidly and movements of the cells continue for at least 5 days. Oenocytes, hypoderm, nerve, muscle, and trachea cells take up characteristic positions in the aggregates. Cells from X2 mutant embryos sort out in identically the same way as do cells from normal embryos.


The transcriptional network for mesenchymal transformation of brain tumours.
The inference of transcriptional networks that regulate transitions into physiological or pathological cellular states remains a central challenge in systems biology. A mesenchymal phenotype is the hallmark of tumour aggressiveness in human malignant glioma, but the regulatory programs responsible for implementing the associated molecular signature are largely unknown. Here we show that reverse-engineering and an unbiased interrogation of a glioma-specific regulatory network reveal the transcriptional module that activates expression of mesenchymal genes in malignant glioma. Two transcription factors (C/EBPbeta and STAT3) emerge as synergistic initiators and master regulators of mesenchymal transformation. Ectopic co-expression of C/EBPbeta and STAT3 reprograms neural stem cells along the aberrant mesenchymal lineage, whereas elimination of the two factors in glioma cells leads to collapse of the mesenchymal signature and reduces tumour aggressiveness. In human glioma, expression of C/EBPbeta and STAT3 correlates with mesenchymal differentiation and predicts poor clinical outcome. These results show that the activation of a small regulatory module is necessary and sufficient to initiate and maintain an aberrant phenotypic state in cancer cells.


Effect of a 902 MHz electromagnetic field emitted by mobile phones on human cognitive function: A replication study.
Our study was a replication and extension with methodological improvements to a previous study on effects of the electromagnetic field (EMF) emitted by a 902 MHz mobile phone on human cognitive functioning. Improvements on the previous study included multicentre testing and a double blind design. A total of 64 subjects (32 men and 32 women) in two independent laboratories performed a battery of 9 cognitive tasks twice: while the EMF was on and while it was off. Reaction times (RTs) and accuracy were recorded. The order of exposure and tasks was counterbalanced across subjects and gender. There were no statistically significant differences in performance between genders or laboratories. Although the RTs and the accuracy of answers were very similar to those of our previous study, our previous results were not replicated. We concluded that EMF had no effect on RTs or on the accuracy of the subjects' answers. Further, our results indicate that our EMF had no immediate effect on human cognitive functioning or that such effects are so small that they are observed on behavior only occasionally.


Hypoxia favors myosin heavy chain beta gene expression in an Hif-1alpha-dependent manner.
The potentiation of the naturally limited regenerative capacity of the heart is dependent on an understanding of the mechanisms that are activated in response to pathological conditions such as hypoxia. Under these conditions, the expression of genes suggested to support cardiomyocyte survival and heart adaptation is triggered. Particularly important are changes in the expression of myosin heavy chain (MHC) isoforms. We propose here that alterations in the expression profiles of MHC genes are induced in response to hypoxia and are primarily mediated by hypoxia inducible factor (HIF). In in vitro models of mouse embryonic stem cell-derived cardiomyocytes, we showed that hypoxia (1% O2) or the pharmacological stabilization of HIFs significantly increased MHCbeta (Myh7) gene expression. The key role of HIF-1alpha is supported by the absence of these effects in HIF-1alpha-deficient cells, even in the presence of HIF-2alpha. Interestingly, ChIP analysis did not confirm the direct interaction of HIF-1alpha with putative HIF response elements predicted in the MHCalpha and beta encoding DNA region. Further analyses showed the significant effect of the mTOR signaling inhibitor rapamycin in inducing Myh7 expression and a hypoxia-triggered reduction in the levels of antisense RNA transcripts associated with the Myh7 gene locus. Overall, the recognized and important role of HIF in the regulation of heart regenerative processes could be highly significant for the development of novel therapeutic interventions in heart failure.