#1 Richness of human gut microbiome correlates with metabolic markers Open access logo Link logo

Le Chatelier, Emmanuelle; Nielsen, Trine; Qin, Junjie; Prifti, Edi; Hildebrand, Falk; Falony, Gwen; Almeida, Mathieu; Arumugam, Manimozhiyan; Batto, Jean-Michel; Kennedy, Sean; Leonard, Pierre; Li, Junhua; Burgdorf, Kristoffer; Grarup, Niels; Jorgensen, T

Nature Volume 500, Issue 7464, Pages 541–546

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We are facing a global metabolic health crisis provoked by an obesity epidemic. Here we report the human gut microbial composition in a population sample of 123 non-obese and 169 obese Danish individuals. We find two groups of individuals that differ by the number of gut microbial genes and thus gut bacterial richness. They contain known and previously unknown bacterial species at different proportions; individuals with a low bacterial richness (23% of the population) are characterized by more marked overall adiposity, insulin resistance and dyslipidaemia and a more pronounced inflammatory phenotype when compared with high bacterial richness individuals. The obese individuals among the lower bacterial richness group also gain more weight over time. Only a few bacterial species are sufficient to distinguish between individuals with high and low bacterial richness, and even between lean and obese participants. Our classifications based on variation in the gut microbiome identify subsets of individuals in the general white adult population who may be at increased risk of progressing to adiposity-associated co-morbidities.

#2 Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile Open access logo Link logo

van Nood, Els; Vrieze, Anne; Nieuwdorp, Max; Fuentes, Susana; Zoetendal, Erwin G.; de Vos, Willem M.; Visser, Caroline E.; Kuijper, Ed J.; Bartelsman, Joep F. W. M.; Tijssen, Jan G. P.; Speelman, Peter; Dijkgraaf, Marcel G. W.; Keller, Josbert J.

New England Journal of Medicine Volume 368, Issue 5, Pages 130116140046009–415

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  • 1375 Mendeley readers

Recurrent Clostridium difficile infection is difficult to treat, and failure rates for antibiotic therapy are high. We studied the effect of duodenal infusion of donor feces in patients with recurrent C. difficile infection.

#3 Content analysis and thematic analysis: Implications for conducting a qualitative descriptive study Open access logo Link logo PDF logo

Vaismoradi Mojtaba, Turunen Hannele, Bondas Terese

Nursing & Health Sciences Volume 15, Issue 3, Pages 398–405

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Qualitative content analysis and thematic analysis are two commonly used approaches in data analysis of nursing research, but boundaries between the two have not been clearly specified. In other words, they are being used interchangeably and it seems difficult for the researcher to choose between them. In this respect, this paper describes and discusses the boundaries between qualitative content analysis and thematic analysis and presents implications to improve the consistency between the purpose of related studies and the method of data analyses. This is a discussion paper, comprising an analytical overview and discussion of the definitions, aims, philosophical background, data gathering, and analysis of content analysis and thematic analysis, and addressing their methodological subtleties. It is concluded that in spite of many similarities between the approaches, including cutting across data and searching for patterns and themes, their main difference lies in the opportunity for quantification of data. It means that measuring the frequency of different categories and themes is possible in content analysis with caution as a proxy for significance.

#4 Dynamic functional connectivity: promise, issues, and interpretations Open access logo Link logo

Hutchison, R. Matthew; Womelsdorf, Thilo; Allen, Elena A; Bandettini, Peter A; Calhound, Vince D; Corbettag, Maurizio; Della Penna, Stefania; Duyn, Jeff H; Glover, Gary H; Gonzalez-Castillo, Javier; Handwerker, Daniel A; Keilholz, Shella; Kiviniemi, Vesa;


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The brain must dynamically integrate, coordinate, and respond to internal and external stimuli across multiple time scales. Non-invasive measurements of brain activity with fMRI have greatly advanced our understanding of the large-scale functional organization supporting these fundamental features of brain function. Conclusions from previous resting-state fMRI investigations were based upon static descriptions of functional connectivity (FC), and only recently studies have begun to capitalize on the wealth of information contained within the temporal features of spontaneous BOLD FC. Emerging evidence suggests that dynamic FC metrics may index changes in macroscopic neural activity patterns underlying critical aspects of cognition and behavior, though limitations with regard to analysis and interpretation remain. Here, we review recent findings, methodological considerations, neural and behavioral correlates, and future directions in the emerging field of dynamic FC investigations.

#5 The International Classification of Headache Disorders, 3rd edition (beta version) Open access logo PDF logo

Bes A, Kunkel R, Lance JW, Nappi G, Pfaffenrath V, Rose FC, Schoenberg BS, Soyka D, Tfelt-Hansen P, Welch KMA, Wilkinson M, Olesen J, Bousser MG, Diener HC, Dodick D, First M, Goadsby PJ, Gobel H, Lainez MJA, Lance JW, Lipton RB, Nappi G, Sakai F, Schoenen J, Silberstein SD, Steiner TJ, Olesen J, Bendtsen L, Dodick D, Ducros A, Evers S, First M, Goadsby PJ, Hershey A, Katsarava Z, Levin M, Pascual J, Russell MB, Schwedt T, Steiner TJ, Tassorelli C, Terwindt GM, Vincent M, Wang SJ, Olesen J, Evers S, Charles

Cephalalgia (Sage Publications Inc.) Volume 33, Issue 9, Pages 629–808

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  • 880 Mendeley readers

#6 Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease Open access logo

Lambert JC,Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, Jun G, Destefano AL, Bis JC, Beecham GW, Grenier-Boley B, Russo G, Thornton-Wells TA, Jones N, Smith AV, Chouraki V, Thomas C, Ikram MA, Zelenika D, Vardarajan BN, ... Soininen H, ...

Nature Genetics Volume 45, Issue 12, Pages 1452–1458

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  • 879 Mendeley readers

Eleven susceptibility loci for late-onset Alzheimer's disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer's disease cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer's disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10(-8)) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.

#7 DNA-Binding Specificities of Human Transcription Factors Open access logo Link logo PDF logo

Jolma, Arttu; Yan, Jian; Whitington, Thomas; Toivonen, Jarkko; Nitta, Kazuhiro R.; Rastas, Pasi; Morgunova, Ekaterina; Enge, Martin; Taipale, Mikko Joonas Oskari; Wei, Gonghong; Palin, Kimmo; Vaquerizas, Juan M.; Vincentelli, Renaud; Luscombe, Nicholas M.


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Although the proteins that read the gene regulatory code, transcription factors (TFs), have been largely identified, it is not well known which sequences TFs can recognize. We have analyzed the sequence-specific binding of human TFs using high-throughput SELEX and ChIP sequencing. A total of 830 binding profiles were obtained, describing 239 distinctly different binding specificities. The models represent the majority of human TFs, approximately doubling the coverage compared to existing systematic studies. Our results reveal additional specificity determinants for a large number of factors for which a partial specificity was known, including a commonly observed A- or T-rich stretch that flanks the core motifs. Global analysis of the data revealed that homodimer orientation and spacing preferences, and base-stacking interactions, have a larger role in TF-DNA binding than previously appreciated. We further describe a binding model incorporating these features that is required to understand binding of TFs to DNA.

#8 The somatic genomic landscape of glioblastoma Open access logo PDF logo

Brennan Cameron W; Verhaak Roel G; McKenna Aaron; Campos Benito; Noushmehr Houtan; Salama Sofie R; Zheng Siyuan; Chakravarty Debyani; Sanborn J Zachary; Berman Samuel H; Beroukhim Rameen; Bernard Brady; Wu Cheng-Jiun; Genovese Giannicola; Shmulevich Ilya; Barnholtz-Sloan Jill; Zou Lihua; Vegesna Rahulsimham; Shukla Sachet A; Ciriello Giovanni

Cell Volume 155, Issue 2, Pages 462–477

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We describe the landscape of somatic genomic alterations based on multidimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors, including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer.

#9 Rapid Blood-Pressure Lowering in Patients with Acute Intracerebral Hemorrhage Open access logo Link logo

Anderson, Craig S.; Heeley, Emma; Huang, Yining; Wang, Jiguang; Stapf, Christian; Delcourt, Candice; Lindley, Richard; Robinson, Thompson; Lavados, Pablo; Neal, Bruce; Hata, Jun; Arima, Hisatomi; Parsons, Mark; Li, Yuechun; Wang, Jinchao; Heritier, Stepha

New England Journal of Medicine Volume 368, Issue 25, Pages 130529040010006–2365

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Whether rapid lowering of elevated blood pressure would improve the outcome in patients with intracerebral hemorrhage is not known. We randomly assigned 2839 patients who had had a spontaneous intracerebral hemorrhage within the previous 6 hours and who had elevated systolic blood pressure to receive intensive treatment to lower their blood pressure (with a target systolic level of <140 mm Hg within 1 hour) or guideline-recommended treatment (with a target systolic level of <180 mm Hg) with the use of agents of the physician's choosing. The primary outcome was death or major disability, which was defined as a score of 3 to 6 on the modified Rankin scale (in which a score of 0 indicates no symptoms, a score of 5 indicates severe disability, and a score of 6 indicates death) at 90 days. A prespecified ordinal analysis of the modified Rankin score was also performed. The rate of serious adverse events was compared between the two groups. Among the 2794 participants for whom the primary outcome could be determined, 719 of 1382 participants (52.0%) receiving intensive treatment, as compared with 785 of 1412 (55.6%) receiving guideline-recommended treatment, had a primary outcome event (odds ratio with intensive treatment, 0.87; 95% confidence interval [CI], 0.75 to 1.01; P=0.06). The ordinal analysis showed significantly lower modified Rankin scores with intensive treatment (odds ratio for greater disability, 0.87; 95% CI, 0.77 to 1.00; P=0.04). Mortality was 11.9% in the group receiving intensive treatment and 12.0% in the group receiving guideline-recommended treatment. Nonfatal serious adverse events occurred in 23.3% and 23.6% of the patients in the two groups, respectively. In patients with intracerebral hemorrhage, intensive lowering of blood pressure did not result in a significant reduction in the rate of the primary outcome of death or severe disability. An ordinal analysis of modified Rankin scores indicated improved functional outcomes with intensive lowering of blood pressure. (Funded by the National Health and Medical Research Council of Australia; INTERACT2 ClinicalTrials.gov number, NCT00716079.).

#10 Systematic identification of trans eQTLs as putative drivers of known disease associations Open access logo Link logo

Westra, Harm-Jan; Peters, Marjolein J.; Esko, Tonu; Yaghootkar, Hanieh; Schurmann, Claudia; Kettunen, Johannes; Christiansen, Mark W.; Fairfax, Benjamin P.; Schramm, Katharina; Powell, Joseph E.; Zhernakova, Alexandra; Zhernakova, Daria V.; Veldink, Jan H

Nature Genetics Volume 45, Issue 10, Pages 1238–1243

  • 16 tweets
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Identifying the downstream effects of disease-associated SNPs is challenging. To help overcome this problem, we performed expression quantitative trait locus (eQTL) meta-analysis in non-transformed peripheral blood samples from 5,311 individuals with replication in 2,775 individuals. We identified and replicated trans eQTLs for 233 SNPs (reflecting 103 independent loci) that were previously associated with complex traits at genome-wide significance. Some of these SNPs affect multiple genes in trans that are known to be altered in individuals with disease: rs4917014, previously associated with systemic lupus erythematosus (SLE), altered gene expression of C1QB and five type I interferon response genes, both hallmarks of SLE. DeepSAGE RNA sequencing showed that rs4917014 strongly alters the 3' UTR levels of IKZF1 in cis, and chromatin immunoprecipitation and sequencing analysis of the trans-regulated genes implicated IKZF1 as the causal gene. Variants associated with cholesterol metabolism and type 1 diabetes showed similar phenomena, indicating that large-scale eQTL mapping provides insight into the downstream effects of many trait-associated variants.

#11 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD Open access logo Link logo PDF logo

Rydén, Lars; Grant, Peter J; Anker, Stefan D; Berne, Christian; Cosentino, Francesco; Danchin, Nicolas; Deaton, Christi; Escaned, Javier; Hammes, Hans-Peter; Huikuri, Heikki; Marre, Michel; Marx, Nikolaus; Mellbin, Linda; Ostergren, Jan; Patrono, Carlo; S

European Heart Journal Volume 34, Issue 39

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  • 507 Mendeley readers

#12 Metagenomic species profiling using universal phylogenetic marker genes Open access logo Link logo

Sunagawa, Shinichi; Mende, Daniel R.; Zeller, Georg; Izquierdo-Carrasco, Fernando; Berger, Simon A.; Kultima, Jens Roat; Coelho, Luis Pedro; Arumugam, Manimozhiyan; Tap, Julien; Nielsen, Henrik Bjorn; Rasmussen, Simon; Brunak, Soren; Pedersen, Oluf; Guarn

Nature Methods Volume 10, Issue 12

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To quantify known and unknown microorganisms at species-level resolution using shotgun sequencing data, we developed a method that establishes metagenomic operational taxonomic units (mOTUs) based on single-copy phylogenetic marker genes. Applied to 252 human fecal samples, the method revealed that on average 43% of the species abundance and 58% of the richness cannot be captured by current reference genome-based methods. An implementation of the method is available at http://www.bork.embl.de/software/mOTU/.

#13 History of gene therapy Open access logo

Wirth T, Parker N, Ylä-Herttuala S


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Two decades after the initial gene therapy trials and more than 1700 approved clinical trials worldwide we not only have gained much new information and knowledge regarding gene therapy in general, but also learned to understand the concern that has persisted in society. Despite the setbacks gene therapy has faced, success stories have increasingly emerged. Examples for these are the positive recommendation for a gene therapy product (Glybera) by the EMA for approval in the European Union and the positive trials for the treatment of ADA deficiency, SCID-X1 and adrenoleukodystrophy. Nevertheless, our knowledge continues to grow and during the course of time more safety data has become available that helps us to develop better gene therapy approaches. Also, with the increased understanding of molecular medicine, we have been able to develop more specific and efficient gene transfer vectors which are now producing clinical results. In this review, we will take a historical view and highlight some of the milestones that had an important impact on the development of gene therapy. We will also discuss briefly the safety and ethical aspects of gene therapy and address some concerns that have been connected with gene therapy as an important therapeutic modality.

#14 Transcription Factor Binding in Human Cells Occurs in Dense Clusters Formed around Cohesin Anchor Sites Open access logo Link logo PDF logo

Yan, Jian; Enge, Martin; Whitington, Thomas; Dave, Kashyap; Liu, Jianping; Sur, Inderpreet; Schmierer, Bernhard; Jolma, Arttu; Kivioja, Teemu; Taipale, Minna; Taipale, Jussi

Cell Volume 154, Issue 4, Pages 801–813

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During cell division, transcription factors (TFs) are removed from chromatin twice, during DNA synthesis and during condensation of chromosomes. How TFs can efficiently find their sites following these stages has been unclear. Here, we have analyzed the binding pattern of expressed TFs in human colorectal cancer cells. We find that binding of TFs is highly clustered and that the clusters are enriched in binding motifs for several major TF classes. Strikingly, almost all clusters are formed around cohesin, and loss of cohesin decreases both DNA accessibility and binding of TFs to clusters. We show that cohesin remains bound in S phase, holding the nascent sister chromatids together at the TF cluster sites. Furthermore, cohesin remains bound to the cluster sites when TFs are evicted in early M phase. These results suggest that cohesin-binding functions as a cellular memory that promotes re-establishment of TF clusters after DNA replication and chromatin condensation.

#15 Arthroscopic Partial Meniscectomy versus Sham Surgery for a Degenerative Meniscal Tear Open access logo Link logo

Sihvonen, Raine; Paavola, Mika; Malmivaara, Antti; Itala, Ari; Joukainen, Antti; Nurmi, Heikki; Kalske, Juha; Järvinen, Teppo L. N.

New England Journal of Medicine Volume 369, Issue 26, Pages 2515–2524

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Arthroscopic partial meniscectomy is one of the most common orthopedic procedures, yet rigorous evidence of its efficacy is lacking.

#16 Discovery and refinement of loci associated with lipid levels Open access logo Link logo

Willer, Cristen J.; Schmidt, Ellen M.; Sengupta, Sebanti; Peloso, Gina M.; Gustafsson, Stefan; Kanoni, Stavroula; Ganna, Andrea; Chen, Jin; Buchkovich, Martin L.; Mora, Samia; Beckmann, Jacques S.; Bragg-Gresham, Jennifer L.; Chang, Hsing-Yi; Demirkan, Ay

Nature Genetics Volume 45, Issue 11, Pages 1274–1283

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Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.

#17 2013 ESC guidelines on the management of stable coronary artery disease : the Task Force on the management of stable coronary artery disease of the European Society of Cardiology Open access logo Link logo PDF logo

Sechtem, Udo; Achenbach, Stephan; Andreotti, Felicita; Budaj, Andrzej; Bugiardini, Raffaele; Crea, Filippo; Cuisset, Thomas; Di Mario, Carlo; Rafael Ferreira, J.; Gersh, Bernard J.; Gitt, Anselm K.; Hulot, Jean-Sebastien; Marx, Nikolaus; Opie, Lionel H.;

European Heart Journal

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#18 Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population:guidance for clinicians to prevent coronary heart disease Link logo PDF logo

Nordestgaard, Borge G.; Chapman, M. John; Humphries, Steve E.; Ginsberg, Henry N.; Masana, Luis; Descamps, Olivier S.; Wiklund, Olov; Hegele, Robert A.; Raal, Frederick J.; Defesche, Joep C.; Wiegman, Albert; Santos, Raul D.; Watts, Gerald F.; Parhofer, K

European Heart Journal

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The first aim was to critically evaluate the extent to which familial hypercholesterolaemia (FH) is underdiagnosed and undertreated. The second aim was to provide guidance for screening and treatment of FH, in order to prevent coronary heart disease (CHD).

#19 Effect of natural genetic variation on enhancer selection and function Open access logo

Heinz S, Romanoski CE, Benner C, Allison KA, Kaikkonen MU, Orozco LD, Glass CK

Nature Volume 503, Issue 7477

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The mechanisms by which genetic variation affects transcription regulation and phenotypes at the nucleotide level are incompletely understood. Here we use natural genetic variation as an in vivo mutagenesis screen to assess the genome-wide effects of sequence variation on lineage-determining and signal-specific transcription factor binding, epigenomics and transcriptional outcomes in primary macrophages from different mouse strains. We find substantial genetic evidence to support the concept that lineage-determining transcription factors define epigenetic and transcriptomic states by selecting enhancer-like regions in the genome in a collaborative fashion and facilitating binding of signal-dependent factors. This hierarchical model of transcription factor function suggests that limited sets of genomic data for lineage-determining transcription factors and informative histone modifications can be used for the prioritization of disease-associated regulatory variants.

#20 RNA Toxicity from the ALS/FTD C9ORF72 Expansion Is Mitigated by Antisense Intervention Open access logo Link logo PDF logo

Donnelly, Christopher J.; Zhang, Ping-Wu; Pham, Jacqueline T.; Heusler, Aaron R.; Mistry, Nipun A.; Vidensky, Svetlana; Daley, Elizabeth L.; Poth, Erin M.; Hoover, Benjamin; Fines, Daniel M.; Maragakis, Nicholas; Tienari, Pentti J.; Petrucelli, Leonard; T

Neuron Volume 80, Issue 2

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A hexanucleotide GGGGCC repeat expansion in the noncoding region of the C9ORF72 gene is the most common genetic abnormality in familial and sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The function of the C9ORF72 protein is unknown, as is the mechanism by which the repeat expansion could cause disease. Induced pluripotent stem cell (iPSC)-differentiated neurons from C9ORF72 ALS patients revealed disease-specific (1) intranuclear GGGGCCexp RNA foci, (2) dysregulated gene expression, (3) sequestration of GGGGCCexp RNA binding protein ADARB2, and (4) susceptibility to excitotoxicity. These pathological and pathogenic characteristics were confirmed in ALS brain and were mitigated with antisense oligonucleotide (ASO) therapeutics to the C9ORF72 transcript or repeat expansion despite the presence of repeat-associated non-ATG translation (RAN) products. These data indicate a toxic RNA gain-of-function mechanism as a cause of C9ORF72 ALS and provide candidate antisense therapeutics and candidate human pharmacodynamic markers for therapy.

#21 Intra-abdominal hypertension and the abdominal compartment syndrome: updated consensus definitions and clinical practice guidelines from the World Society of the Abdominal Compartment Syndrome Open access logo Link logo PDF logo

Kirkpatrick, Andrew W.; Roberts, Derek J.; De Waele, Jan; Jaeschke, Roman; Malbrain, Manu L. N. G.; De Keulenaer, Bart; Duchesne, Juan; Bjorck, Martin; Leppäniemi, Ari; Ejike, Janeth C.; Sugrue, Michael; Cheatham, Michael; Ivatury, Rao; Ball, Chad G.; Bla

Intensive Care Medicine Volume 39, Issue 7, Pages 1190–1206

  • 17 tweets
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To update the World Society of the Abdominal Compartment Syndrome (WSACS) consensus definitions and management statements relating to intra-abdominal hypertension (IAH) and the abdominal compartment syndrome (ACS).

#22 Burden and aetiology of diarrhoeal disease in infants and young children in developing countries (the Global Enteric Multicenter Study, GEMS): a prospective, case-control study Open access logo Link logo PDF logo

Kotloff Karen L; Nataro James P; Blackwelder William C; Nasrin Dilruba; Farag Tamer H; Panchalingam Sandra; Wu Yukun; Sow Samba O; Sur Dipika; Breiman Robert F; Faruque Abu S; Zaidi Anita K; Saha Debasish; Alonso Pedro L; Tamboura Boubou; Sanogo Doh; Onwuchekwa Uma; Manna Byomkesh; Ramamurthy Thandavarayan; Kanungo Suman; Ochieng John B; Omore Richard et al

The Lancet

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Diarrhoeal diseases cause illness and death among children younger than 5 years in low-income countries. We designed the Global Enteric Multicenter Study (GEMS) to identify the aetiology and population-based burden of paediatric diarrhoeal disease in sub-Saharan Africa and south Asia.

#23 European Stroke Organization Guidelines for the Management of Intracranial Aneurysms and Subarachnoid Haemorrhage Open access logo Link logo PDF logo

Steiner, Thorsten; Juvela, Seppo; Unterberg, Andreas; Jung, Carla; Forsting, Michael; Rinkel, Gabriel

Cerebrovascular Diseases Volume 35, Issue 2, Pages 93–112

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Intracranial aneurysm with and without subarachnoid haemorrhage (SAH) is a relevant health problem: The overall incidence is about 9 per 100,000 with a wide range, in some countries up to 20 per 100,000. Mortality rate with conservative treatment within the first months is 50-60%. About one third of patients left with an untreated aneurysm will die from recurrent bleeding within 6 months after recovering from the first bleeding. The prognosis is further influenced by vasospasm, hydrocephalus, delayed ischaemic deficit and other complications. The aim of these guidelines is to provide comprehensive recommendations on the management of SAH with and without aneurysm as well as on unruptured intracranial aneurysm.

#24 Rev-Erbs repress macrophage gene expression by inhibiting enhancer-directed transcription Open access logo

Lam MT, Cho H, Lesch HP, Gosselin D, Heinz S, Tanaka-Oishi Y, Benner C, Kaikkonen MU, Kim AS, Kosaka M, Lee CY, Watt A, Grossman TR, Rosenfeld MG, Evans RM, Glass CK

Nature Volume 498, Issue 7455, Pages 511–515

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Rev-Erb-α and Rev-Erb-β are nuclear receptors that regulate the expression of genes involved in the control of circadian rhythm, metabolism and inflammatory responses. Rev-Erbs function as transcriptional repressors by recruiting nuclear receptor co-repressor (NCoR)-HDAC3 complexes to Rev-Erb response elements in enhancers and promoters of target genes, but the molecular basis for cell-specific programs of repression is not known. Here we present evidence that in mouse macrophages Rev-Erbs regulate target gene expression by inhibiting the functions of distal enhancers that are selected by macrophage-lineage-determining factors, thereby establishing a macrophage-specific program of repression. Remarkably, the repressive functions of Rev-Erbs are associated with their ability to inhibit the transcription of enhancer-derived RNAs (eRNAs). Furthermore, targeted degradation of eRNAs at two enhancers subject to negative regulation by Rev-Erbs resulted in reduced expression of nearby messenger RNAs, suggesting a direct role of these eRNAs in enhancer function. By precisely defining eRNA start sites using a modified form of global run-on sequencing that quantifies nascent 5' ends, we show that transfer of full enhancer activity to a target promoter requires both the sequences mediating transcription-factor binding and the specific sequences encoding the eRNA transcript. These studies provide evidence for a direct role of eRNAs in contributing to enhancer functions and suggest that Rev-Erbs act to suppress gene expression at a distance by repressing eRNA transcription.

#25 GWAS of 126,559 Individuals Identifies Genetic Variants Associated with Educational Attainment Open access logo Link logo PDF logo

Rietveld, Cornelius A.; Medland, Sarah E.; Derringer, Jaime; Yang, Jian; Esko, Tonu; Martin, Nicolas W.; Westra, Harm-Jan; Shakhbazov, Konstantin; Abdellaoui, Abdel; Agrawal, Arpana; Albrecht, Eva; Alizadeh, Behrooz Z.; Amin, Najaf; Bamard, John; Baumeist

Science Volume 340, Issue 6139, Pages 1467–1471

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A genome-wide association study (GWAS) of educational attainment was conducted in a discovery sample of 101,069 individuals and a replication sample of 25,490. Three independent single-nucleotide polymorphisms (SNPs) are genome-wide significant (rs9320913, rs11584700, rs4851266), and all three replicate. Estimated effects sizes are small (coefficient of determination R(2) ≈ 0.02%), approximately 1 month of schooling per allele. A linear polygenic score from all measured SNPs accounts for ≈2% of the variance in both educational attainment and cognitive function. Genes in the region of the loci have previously been associated with health, cognitive, and central nervous system phenotypes, and bioinformatics analyses suggest the involvement of the anterior caudate nucleus. These findings provide promising candidate SNPs for follow-up work, and our effect size estimates can anchor power analyses in social-science genetics.

#26 The Keap1-Nrf2 pathway: Mechanisms of activation and dysregulation in cancer Open access logo

Kansanen Emilia, Kuosmanen Suvi M, Leinonen Hanna, Levonen Anna-Liisa

Redox Biology Volume 1, Issue 1, Pages 45–49

  • 2 tweets
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The Keap1-Nrf2 pathway is the major regulator of cytoprotective responses to oxidative and electrophilic stress. Although cell signaling pathways triggered by the transcription factor Nrf2 prevent cancer initiation and progression in normal and premalignant tissues, in fully malignant cells Nrf2 activity provides growth advantage by increasing cancer chemoresistance and enhancing tumor cell growth. In this graphical review, we provide an overview of the Keap1-Nrf2 pathway and its dysregulation in cancer cells. We also briefly summarize the consequences of constitutive Nrf2 activation in cancer cells and how this can be exploited in cancer gene therapy.

#27 Large-scale genotyping identifies 41 new loci associated with breast cancer risk Open access logo Link logo

Michailidou, Kyriaki; Hall, Per; Gonzalez-Neira, Anna; Ghoussaini, Maya; Dennis, Joe; Milne, Roger L.; Schmidt, Marjanka K.; Chang-Claude, Jenny; Bojesen, Stig E.; Bolla, Manjeet K.; Wang, Qin; Dicks, Ed; Lee, Andrew; Turnbull, Clare; Rahman, Nazneen; Fle

Nature Genetics Volume 45, Issue 4, Pages 353–361

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Breast cancer is the most common cancer among women. Common variants at 27 loci have been identified as associated with susceptibility to breast cancer, and these account for ∼9% of the familial risk of the disease. We report here a meta-analysis of 9 genome-wide association studies, including 10,052 breast cancer cases and 12,575 controls of European ancestry, from which we selected 29,807 SNPs for further genotyping. These SNPs were genotyped in 45,290 cases and 41,880 controls of European ancestry from 41 studies in the Breast Cancer Association Consortium (BCAC). The SNPs were genotyped as part of a collaborative genotyping experiment involving four consortia (Collaborative Oncological Gene-environment Study, COGS) and used a custom Illumina iSelect genotyping array, iCOGS, comprising more than 200,000 SNPs. We identified SNPs at 41 new breast cancer susceptibility loci at genome-wide significance (P < 5 × 10(-8)). Further analyses suggest that more than 1,000 additional loci are involved in breast cancer susceptibility.

#28 Descending modulation and persistent pain Open access logo Link logo

Pertovaara, Antti

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#29 Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes Open access logo PDF logo

Glauser T, Ben-Menachem E, Bourgeois B, Cnaan A, Guerreiro C, Kälviäinen R, Mattson R, French JA, Perucca E, Tomson T

Epilepsia (Series 4) Volume 54, Issue 3, Pages 551–563

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The purpose of this report was to update the 2006 International League Against Epilepsy (ILAE) report and identify the level of evidence for long-term efficacy or effectiveness for antiepileptic drugs (AEDs) as initial monotherapy for patients with newly diagnosed or untreated epilepsy. All applicable articles from July 2005 until March 2012 were identified, evaluated, and combined with the previous analysis (Glauser et al., 2006) to provide a comprehensive update. The prior analysis methodology was utilized with three modifications: (1) the detectable noninferiority boundary approach was dropped and both failed superiority studies and prespecified noninferiority studies were analyzed using a noninferiority approach, (2) the definition of an adequate comparator was clarified and now includes an absolute minimum point estimate for efficacy/effectiveness, and (3) the relationship table between clinical trial ratings, level of evidence, and conclusions no longer includes a recommendation column to reinforce that this review of efficacy/evidence for specific seizure types does not imply treatment recommendations. This evidence review contains one clarification: The commission has determined that class I superiority studies can be designed to detect up to a 20% absolute (rather than relative) difference in the point estimate of efficacy/effectiveness between study treatment and comparator using an intent-to-treat analysis. Since July, 2005, three class I randomized controlled trials (RCT) and 11 class III RCTs have been published. The combined analysis (1940-2012) now includes a total of 64 RCTs (7 with class I evidence, 2 with class II evidence) and 11 meta-analyses. New efficacy/effectiveness findings include the following: levetiracetam and zonisamide have level A evidence in adults with partial onset seizures and both ethosuximide and valproic acid have level A evidence in children with childhood absence epilepsy. There are no major changes in the level of evidence for any other subgroup. Levetiracetam and zonisamide join carbamazepine and phenytoin with level A efficacy/effectiveness evidence as initial monotherapy for adults with partial onset seizures. Although ethosuximide and valproic acid now have level A efficacy/effectiveness evidence as initial monotherapy for children with absence seizures, there continues to be an alarming lack of well designed, properly conducted epilepsy RCTs for patients with generalized seizures/epilepsies and in children in general. These findings reinforce the need for multicenter, multinational efforts to design, conduct, and analyze future clinically relevant adequately designed RCTs. When selecting a patient's AED, all relevant variables and not just efficacy and effectiveness should be considered.

#30 Large-scale association analysis identifies new risk loci for coronary artery disease Open access logo Link logo

Deloukas, Panos; Kanoni, Stavroula; Willenborg, Christina; Farrall, Martin; Assimes, Themistocles L.; Thompson, John R.; Ingelsson, Erik; Saleheen, Danish; Erdmann, Jeanette; Goldstein, Benjamin A.; Stirrups, Kathleen; Koenig, Inke R.; Cazier, Jean-Baptis

Nature Genetics Volume 40, Issue 11

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At present, transgenes in Caenorhabditis elegans are generated by injecting DNA into the germline. The DNA assembles into a semistable extrachromosomal array composed of many copies of injected DNA. These transgenes are typically overexpressed in somatic cells and silenced in the germline. We have developed a method that inserts a single copy of a transgene into a defined site. Mobilization of a Mos1 transposon generates a double-strand break in noncoding DNA. The break is repaired by copying DNA from an extrachromosomal template into the chromosomal site. Homozygous single-copy insertions can be obtained in less than 2 weeks by injecting approximately 20 worms. We have successfully inserted transgenes as long as 9 kb and verified that single copies are inserted at the targeted site. Single-copy transgenes are expressed at endogenous levels and can be expressed in the female and male germlines.

#31 Foul play is associated with injury incidence: an epidemiological study of three FIFA World Cups (2002-2010) Open access logo Link logo PDF logo

Ryynänen, Jaakko; Junge, Astrid; Dvorak, Jiri; Peterson, Lars; Kautiainen, Hannu; Karlsson, Jon; Borjesson, Mats

British Journal of Sports Medicine

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Foul play has been considered as one of the most important known extrinsic risk factors for injuries in football.

#32 Evidence for two types of brown adipose tissue in humans Open access logo

Lidell ME, Betz MJ, Leinhard OD, Heglind M, Elander L, Slawik M, Mussack T, Nilsson D, Romu T, Nuutila P, Virtanen KA, Beuschlein F, Persson A, Borga M, Enerback S

Nature Medicine Volume 19, Issue 5

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The previously observed supraclavicular depot of brown adipose tissue (BAT) in adult humans was commonly believed to be the equivalent of the interscapular thermogenic organ of small mammals. This view was recently disputed on the basis of the demonstration that this depot consists of beige (also called brite) brown adipocytes, a newly identified type of brown adipocyte that is distinct from the classical brown adipocytes that make up the interscapular thermogenic organs of other mammals. A combination of high-resolution imaging techniques and histological and biochemical analyses showed evidence for an anatomically distinguishable interscapular BAT (iBAT) depot in human infants that consists of classical brown adipocytes, a cell type that has so far not been shown to exist in humans. On the basis of these findings, we conclude that infants, similarly to rodents, have the bona fide iBAT thermogenic organ consisting of classical brown adipocytes that is essential for the survival of small mammals in a cold environment.

#33 Critical assessment of automated flow cytometry data analysis techniques Open access logo

Aghaeepour N; Finak G; Dougall D; Khodabakhshi AH; Mah P; Obermoser G; Spidlen J; Taylor I; Wuensch SA; Bramson J; Eaves C; Weng AP; Fortuno ES 3rd; Ho K; Kollmann TR; Rogers W; De Rosa S; Dalal B; Azad A; Pothen A; Brandes A; Bretschneider H; Bruggner R; Finck R; Jia R; Zimmerman N; Linderman M; Dill D; Nolan G; Chan C; El Khettabi F; O'Neill K; Chikina M; Ge Y; Sealfon S; Sugár I; Gupta A; Shooshtari P; Zare H; De Jager PL; Jiang M; Keilwagen J; Maisog JM; Luta G; Barbo AA; Májek P; Vilček J; Mannin

Nature Methods Volume 10, Issue 3, Pages 228–238

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Traditional methods for flow cytometry (FCM) data processing rely on subjective manual gating. Recently, several groups have developed computational methods for identifying cell populations in multidimensional FCM data. The Flow Cytometry: Critical Assessment of Population Identification Methods (FlowCAP) challenges were established to compare the performance of these methods on two tasks: (i) mammalian cell population identification, to determine whether automated algorithms can reproduce expert manual gating and (ii) sample classification, to determine whether analysis pipelines can identify characteristics that correlate with external variables (such as clinical outcome). This analysis presents the results of the first FlowCAP challenges. Several methods performed well as compared to manual gating or external variables using statistical performance measures, which suggests that automated methods have reached a sufficient level of maturity and accuracy for reliable use in FCM data analysis.

#34 HRS/EHRA/APHRS Expert Consensus Statement on the Diagnosis and Management of Patients with Inherited Primary Arrhythmia Syndromes Open access logo Link logo PDF logo

Priori, Silvia G.; Wilde, Arthur A.; Horie, Minoru; Cho, Yongkeun; Behr, Elijah R.; Berul, Charles; Blom, Nico; Brugada, Josep; Chiang, Chern-En; Huikuri, Heikki; Kannankeril, Prince; Krahn, Andrew; Leenhardt, Antoine; Moss, Arthur; Schwartz, Peter J.; Sh

Heart Rhythm

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#35 Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer Open access logo Link logo

Bojesen, Stig E.; Pooley, Karen A.; Johnatty, Sharon E.; Beesley, Jonathan; Michailidou, Kyriaki; Tyrer, Jonathan P.; Edwards, Stacey L.; Pickett, Hilda A.; Shen, Howard C.; Smart, Chanel E.; Hillman, Kristine M.; Mai, Phuong L.; Lawrenson, Kate; Stutz, M

Nature Genetics Volume 45, Issue 4, Pages 371–384

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TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed ∼480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 × 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 × 10(-8)) and BRCA1 mutation carrier (P = 1.1 × 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 × 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 × 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 × 10(-12)) and BRCA1 mutation carrier (P = 1.6 × 10(-14)) breast and invasive ovarian (P = 1.3 × 10(-11)) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant.

#36 2013 WSES guidelines for management of intra-abdominal infections Open access logo Link logo PDF logo

Sartelli, Massimo; Viale, Pierluigi; Catena, Fausto; Ansaloni, Luca; Moore, Ernest; Malangoni, Mark; Moore, Frederick A.; Velmahos, George; Coimbra, Raul; Ivatury, Rao; Peitzman, Andrew; Koike, Kaoru; Leppäniemi, Ari; Biffl, Walter; Burlew, Clay Cothren;

World Journal of Emergency Surgery Volume 8, Issue 1

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Despite advances in diagnosis, surgery, and antimicrobial therapy, mortality rates associated with complicated intra-abdominal infections remain exceedingly high.The 2013 update of the World Society of Emergency Surgery (WSES) guidelines for the management of intra-abdominal infections contains evidence-based recommendations for management of patients with intra-abdominal infections.

#37 Gene-pair expression signatures reveal lineage control Open access logo

Heinäniemi Merja; Nykter Matti; Kramer Roger; Wienecke-Baldacchino Anke; Sinkkonen Lasse; Zhou Joseph Xu; Kreisberg Richard; Kauffman Stuart A; Huang Sui; Shmulevich Ilya

Nature Methods

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The distinct cell types of multicellular organisms arise owing to constraints imposed by gene regulatory networks on the collective change of gene expression across the genome, creating self-stabilizing expression states, or attractors. We curated human expression data comprising 166 cell types and 2,602 transcription-regulating genes and developed a data-driven method for identifying putative determinants of cell fate built around the concept of expression reversal of gene pairs, such as those participating in toggle-switch circuits. This approach allows us to organize the cell types into their ontogenic lineage relationships. Our method identifies genes in regulatory circuits that control neuronal fate, pluripotency and blood cell differentiation, and it may be useful for prioritizing candidate factors for direct conversion of cell fate.

#38 Diagnostic Cancer Genome Sequencing and the Contribution of Germline Variants Open access logo Link logo PDF logo

Kilpivaara, O.; Aaltonen, L. A.


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Whole-genome sequencing (WGS) is revolutionizing medical research and has the potential to serve as a powerful and cost-effective diagnostic tool in the management of cancer. We review the progress to date in the use of WGS to reveal how germline variants and mutations may be associated with cancer. We use colorectal cancer as an example of how the current level of knowledge can be translated into predictions of predisposition. We also address challenges in the clinical implementation of the variants in germline DNA identified through cancer genome sequencing. We call for the international development of standards to facilitate the clinical use of germline information arising from diagnostic cancer genome sequencing.

#39 Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts Open access logo Link logo PDF logo

Vasen, Hans F. A.; Blanco, Ignacio; Aktan-Collan, Katja; Gopie, Jessica P.; Alonso, Angel; Aretz, Stefan; Bernstein, Inge; Bertario, Lucio; Burn, John; Capella, Gabriel; Colas, Chrystelle; Engel, Christoph; Frayling, Ian M.; Genuardi, Maurizio; Heinimann,

Gut Volume 62, Issue 6, Pages 812–823

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Lynch syndrome (LS) is characterised by the development of colorectal cancer, endometrial cancer and various other cancers, and is caused by a mutation in one of the mismatch repair genes: MLH1, MSH2, MSH6 or PMS2. In 2007, a group of European experts (the Mallorca group) published guidelines for the clinical management of LS. Since then substantial new information has become available necessitating an update of the guidelines. In 2011 and 2012 workshops were organised in Palma de Mallorca. A total of 35 specialists from 13 countries participated in the meetings. The first step was to formulate important clinical questions. Then a systematic literature search was performed using the Pubmed database and manual searches of relevant articles. During the workshops the outcome of the literature search was discussed in detail. The guidelines described in this paper may be helpful for the appropriate management of families with LS. Prospective controlled studies should be undertaken to improve further the care of these families.

#40 Forefoot Strikers Exhibit Lower Running-Induced Knee Loading than Rearfoot Strikers Open access logo Link logo PDF logo

Kulmala, Juha-Pekka;Avela, Janne;Pasanen, Kati;Parkkari, Jari

Medicine & Science in Sports & Exercise Volume Publish Ahead of Print, Issue 12

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Knee pain and Achilles tendinopathies are the most common complaints among runners. The differences in the running mechanics may play an important role in the pathogenesis of lower limb overuse injuries. However, the effect of a runner's foot strike pattern on the ankle and especially on the knee loading is poorly understood. The purpose of this study was to examine whether runners using a forefoot strike pattern exhibit a different lower limb loading profile than runners who use rearfoot strike pattern.

#41 Integrated genomic characterization of endometrial carcinoma Open access logo

Cancer Genome Atlas Research Network; Kandoth C; Schultz N; Cherniack AD; Akbani R; Liu Y; Shen H; Robertson AG; Pashtan I; Shen R; Benz CC; Yau C; Laird PW; Ding L; Zhang W; Mills GB; Kucherlapati R; Mardis ER; Levine DA

Nature Volume 497, Issue 7447, Pages 67–73

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We performed an integrated genomic, transcriptomic and proteomic characterization of 373 endometrial carcinomas using array- and sequencing-based technologies. Uterine serous tumours and ∼25% of high-grade endometrioid tumours had extensive copy number alterations, few DNA methylation changes, low oestrogen receptor/progesterone receptor levels, and frequent TP53 mutations. Most endometrioid tumours had few copy number alterations or TP53 mutations, but frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A and KRAS and novel mutations in the SWI/SNF chromatin remodelling complex gene ARID5B. A subset of endometrioid tumours that we identified had a markedly increased transversion mutation frequency and newly identified hotspot mutations in POLE. Our results classified endometrial cancers into four categories: POLE ultramutated, microsatellite instability hypermutated, copy-number low, and copy-number high. Uterine serous carcinomas share genomic features with ovarian serous and basal-like breast carcinomas. We demonstrated that the genomic features of endometrial carcinomas permit a reclassification that may affect post-surgical adjuvant treatment for women with aggressive tumours.

#42 Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) : study design and progress Open access logo

Kivipelto, Miia; Solomon, Alina; Ahtiluoto, Satu; Ngandu, Tiia; Lehtisalo, Jenni; Antikainen, Riitta; Bäckman, Lars; Hänninen, Tuomo; Jula, Antti; Laatikainen, Tiina; Lindström, Jaana; Mangialasche, Francesca; Nissinen, Aulikki; Paajanen, Teemu; Pajala, S

Alzheimer's & Dementia: the Journal of the Alzheimer's Association Volume 9, Issue 6, Pages 657–665

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Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) is a multi-center, randomized, controlled trial ongoing in Finland.

#43 Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial Open access logo Link logo PDF logo

Bennouna, Jaafar; Sastre, Javier; Arnold, Dirk; Österlund, Pia Johanna; Greil, Richard; Van Cutsem, Eric; von Moos, Roger; Maria Vieitez, Jose; Bouche, Olivier; Borg, Christophe; Steffens, Claus-Christoph; Alonso-Orduna, Vicente; Schlichting, Christoph; R

Lancet Oncology

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Bevacizumab plus fluoropyrimidine-based chemotherapy is standard treatment for first-line and bevacizumab-naive second-line metastatic colorectal cancer. We assessed continued use of bevacizumab plus standard second-line chemotherapy in patients with metastatic colorectal cancer progressing after standard first-line bevacizumab-based treatment.

#44 Maturation of autophagosomes and endosomes: A key role for Rab7 Open access logo

Hyttinen JMT, Niittykoski M, Salminen A, Kaarniranta K

Biochimica et Biophysica Acta (BBA)

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#45 Updated international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation Open access logo Link logo PDF logo

Cotton, C. N.; Kumar, Deepali; Caliendo, Angela M.; Åsberg, Anders; Chou, Sunwen; Danziger-Isakov, Lara; Humar, Atul; , ; Lautenschlager, Irmeli

Transplantation Volume Publish Ahead of Print, Issue 4

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Cytomegalovirus (CMV) continues to be one of the most common infections after solid-organ transplantation, resulting in significant morbidity, graft loss, and adverse outcomes. Management of CMV varies considerably among transplant centers but has been become more standardized by publication of consensus guidelines by the Infectious Diseases Section of The Transplantation Society. An international panel of experts was reconvened in October 2012 to revise and expand evidence and expert opinion-based consensus guidelines on CMV management, including diagnostics, immunology, prevention, treatment, drug resistance, and pediatric issues. The following report summarizes the recommendations.

#46 Bruxism defined and graded: an international consensus Open access logo Link logo PDF logo

Lobbezoo, F.; Ahlberg, J.; Glaros, A. G.; Kato, T.; Koyano, K.; Lavigne, G. J.; De Leeuw, R.; Manfredini, D.; Svensson, P.; Winocur, E.

Journal of Oral Rehabilitation Volume 40, Issue 1, Pages 2–4

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#47 The Actin and Tetraspanin Networks Organize Receptor Nanoclusters to Regulate B Cell Receptor-Mediated Signaling Open access logo PDF logo

Mattila PK, Feest C, Depoil D, Treanor B, Montaner B, Otipoby KL, Carter R, Justement LB, Bruckbauer A, Batista FD


  • 3 tweets
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A key role is emerging for the cytoskeleton in coordinating receptor signaling, although the underlying molecular requirements remain unclear. Here we show that cytoskeleton disruption triggered signaling requiring not only the B cell receptor (BCR), but also the coreceptor CD19 and tetraspanin CD81, thus providing a mechanism for signal amplification upon surface-bound antigen stimulation. By using superresolution microscopy, we demonstrated that endogenous IgM, IgD, and CD19 exhibited distinct nanoscale organization within the plasma membrane of primary B cells. Upon stimulation, we detect a local convergence of receptors, although their global organization was not dramatically altered. Thus, we postulate that cytoskeleton reorganization releases BCR nanoclusters, which can interact with CD19 held in place by the tetraspanin network. These results not only suggest that receptor compartmentalization regulates antigen-induced activation but also imply a potential role for CD19 in mediating ligand-independent "tonic" BCR signaling necessary for B cell survival.

#48 Exome array analysis identifies new loci and low-frequency variants influencing insulin processing and secretion Open access logo

Huyghe JR, Jackson AU, Fogarty MP, Buchkovich ML, Stancáková A, Stringham HM, Sim X, Yang L, Fuchsberger C, Cederberg H, Chines PS, Teslovich TM, Romm JM, Ling H, McMullen I, Ingersoll R, Pugh EW, Doheny KF, Neale BM, Daly MJ, et al (including J Kuusisto,

Nature Genetics

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Insulin secretion has a crucial role in glucose homeostasis, and failure to secrete sufficient insulin is a hallmark of type 2 diabetes. Genome-wide association studies (GWAS) have identified loci contributing to insulin processing and secretion; however, a substantial fraction of the genetic contribution remains undefined. To examine low-frequency (minor allele frequency (MAF) 0.5-5%) and rare (MAF < 0.5%) nonsynonymous variants, we analyzed exome array data in 8,229 nondiabetic Finnish males using the Illumina HumanExome Beadchip. We identified low-frequency coding variants associated with fasting proinsulin concentrations at the SGSM2 and MADD GWAS loci and three new genes with low-frequency variants associated with fasting proinsulin or insulinogenic index: TBC1D30, KANK1 and PAM. We also show that the interpretation of single-variant and gene-based tests needs to consider the effects of noncoding SNPs both nearby and megabases away. This study demonstrates that exome array genotyping is a valuable approach to identify low-frequency variants that contribute to complex traits.

#49 Uncovering the mysteries of hantavirus infections Open access logo Link logo

Vaheri, Antti; Strandin, Tomas; Hepojoki, Jussi; Sironen, Tarja; Henttonen, Heikki; Makela, Satu; Mustonen, Jukka

Nature Reviews Microbiology

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#50 The skin prick test - European standards Open access logo Link logo PDF logo

Heinzerling, L.; Mari, A.; Bergmann, K. C.; Bresciani, M.; Burbach, G.; Darsow, U.; Durham, S.; Fokkens, W.; Gjomarkaj, M.; Haahtela, T.; Bom, A. T.; Wohrl, S.; Maibach, H.; Lockey, R.

Clinical and Translational Allergy Volume 3, Issue 1

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Skin prick testing is an essential test procedure to confirm sensitization in IgE-mediated allergic disease in subjects with rhinoconjunctivitis, asthma, urticaria, anapylaxis, atopic eczema and food and drug allergy. This manuscript reviews the available evidence including Medline and Embase searches, abstracts of international allergy meetings and position papers from the world allergy literature. The recommended method of prick testing includes the appropriate use of specific allergen extracts, positive and negative controls, interpretation of the tests after 15 - 20 minutes of application, with a positive result defined as a wheal ≥3 mm diameter. A standard prick test panel for Europe for inhalants is proposed and includes hazel (Corylus avellana), alder (Alnus incana), birch (Betula alba), plane (Platanus vulgaris), cypress (Cupressus sempervirens), grass mix (Poa pratensis, Dactilis glomerata, Lolium perenne, Phleum pratense, Festuca pratensis, Helictotrichon pretense), Olive (Olea europaea), mugwort (Artemisia vulgaris), ragweed (Ambrosia artemisiifolia), Alternaria alternata (tenuis), Cladosporium herbarum, Aspergillus fumigatus, Parietaria, cat, dog, Dermatophagoides pteronyssinus, Dermatophagoides farinae, and cockroach (Blatella germanica). Standardization of the skin test procedures and standard panels for different geographic locations are encouraged worldwide to permit better comparisons for diagnostic, clinical and research purposes.

#51 Evaluation of methods for modeling transcription factor sequence specificity Open access logo

Weirauch MT; Cote A; Norel R; Annala M; Zhao Y; Riley TR; Saez-Rodriguez J; Cokelaer T; Vedenko A; Talukder S; Agius P; Arvey A; Bucher P; Callan CG Jr; Chang CW; Chen CY; Chen YS; Chu YW; Grau J; Grosse I; Jagannathan V; Keilwagen J; Kiełbasa SM; Kinney JB; Klein H; Kursa MB; Lähdesmäki H; Laurila K; Lei C; Leslie C; Linhart C; Murugan A; Myšicková A; Noble WS; Nykter M; Orenstein Y; Posch S; Ruan J; Rudnicki WR; Schmid CD; Shamir R; Sung WK; Vingron M; Zhang Z; Bussemaker HJ; Morris QD; Bulyk ML; St

Nature Biotechnology Volume 31, Issue 2, Pages 126–134

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Genomic analyses often involve scanning for potential transcription factor (TF) binding sites using models of the sequence specificity of DNA binding proteins. Many approaches have been developed to model and learn a protein's DNA-binding specificity, but these methods have not been systematically compared. Here we applied 26 such approaches to in vitro protein binding microarray data for 66 mouse TFs belonging to various families. For nine TFs, we also scored the resulting motif models on in vivo data, and found that the best in vitro-derived motifs performed similarly to motifs derived from the in vivo data. Our results indicate that simple models based on mononucleotide position weight matrices trained by the best methods perform similarly to more complex models for most TFs examined, but fall short in specific cases (<10% of the TFs examined here). In addition, the best-performing motifs typically have relatively low information content, consistent with widespread degeneracy in eukaryotic TF sequence preferences.

#52 Oxygen consumption and usage during physical exercise: the balance between oxidative stress and ROS-dependent adaptive signaling Open access logo

Radak Z, Zhao Z, Koltai E, Ohno H, Atalay M

Antioxidants & Redox Signaling Volume 18, Issue 10

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The complexity of human DNA has been affected by aerobic metabolism, including endurance exercise and oxygen toxicity. Aerobic endurance exercise could play an important role in the evolution of Homo sapiens, and oxygen was not important just for survival, but it was crucial to redox-mediated adaptation. The metabolic challenge during physical exercise results in an elevated generation of reactive oxygen species (ROS) that are important modulators of muscle contraction, antioxidant protection, and oxidative damage repair, which at moderate levels generate physiological responses. Several factors of mitochondrial biogenesis, such as peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), mitogen-activated protein kinase, and SIRT1, are modulated by exercise-associated changes in the redox milieu. PGC-1α activation could result in decreased oxidative challenge, either by upregulation of antioxidant enzymes and/or by an increased number of mitochondria that allows lower levels of respiratory activity for the same degree of ATP generation. Endogenous thiol antioxidants glutathione and thioredoxin are modulated with high oxygen consumption and ROS generation during physical exercise, controlling cellular function through redox-sensitive signaling and protein-protein interactions. Endurance exercise-related angiogenesis, up to a significant degree, is regulated by ROS-mediated activation of hypoxia-inducible factor 1α. Moreover, the exercise-associated ROS production could be important to DNA methylation and post-translation modifications of histone residues, which create heritable adaptive conditions based on epigenetic features of chromosomes. Accumulating data indicate that exercise with moderate intensity has systemic and complex health-promoting effects, which undoubtedly involve regulation of redox homeostasis and signaling.

#53 A Senescence-Inflammatory Switch from Cancer-Inhibitory to Cancer-Promoting Mechanism Open access logo Link logo PDF logo

Pribluda, Ariel; Elyada, Ela; Wiener, Zoltan; Hamza, Haya; Goldstein, Robert E.; Biton, Moshe; Burstain, Ido; Morgenstern, Yael; Brachya, Guy; Billauer, Hana; Biton, Sharon; Snir-Alkalay, Irit; Vucic, Domagoj; Schlereth, Katharina; Mernberger, Marco; Stie

Cancer Cell

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Senescence, perceived as a cancer barrier, is paradoxically associated with inflammation, which promotes tumorigenesis. Here, we characterize a distinct low-grade inflammatory process in stressed epithelium that is related to para-inflammation; this process either represses or promotes tumorigenesis, depending on p53 activity. Csnk1a1 (CKIα) downregulation induces a senescence-associated inflammatory response (SIR) with growth arrest in colorectal tumors, which loses its growth control capacity in the absence of p53 and instead, accelerates growth and invasiveness. Corresponding processes occur in CKIα-deleted intestinal organoids, assuming tumorigenic transformation properties ex vivo, upon p53 loss. Treatment of organoids and mice with anti-inflammatory agents suppresses the SIR and prevents p53-deficient organoid transformation and mouse carcinogenesis. SIR/para-inflammation suppression may therefore constitute a key mechanism in the anticarcinogenic effects of nonsteroidal anti-inflammatory drugs.

#54 Hexokinase 2 is required for tumor initiation and maintenance and its systemic deletion is therapeutic in mouse models of cancer Open access logo PDF logo

Patra KC, Wang Q, Bhaskar PT, Miller L, Wang Z, Wheaton W, Chandel N, Laakso M, Muller WJ, Allen EL, Jha AK, Smolen GA, Clasquin MF, Robey RB, Hay N

Cancer Cell Volume 24, Issue 2

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Accelerated glucose metabolism is a common feature of cancer cells. Hexokinases catalyze the first committed step of glucose metabolism. Hexokinase 2 (HK2) is expressed at high level in cancer cells, but only in a limited number of normal adult tissues. Using Hk2 conditional knockout mice, we showed that HK2 is required for tumor initiation and maintenance in mouse models of KRas-driven lung cancer, and ErbB2-driven breast cancer, despite continued HK1 expression. Similarly, HK2 ablation inhibits the neoplastic phenotype of human lung and breast cancer cells in vitro and in vivo. Systemic Hk2 deletion is therapeutic in mice bearing lung tumors without adverse physiological consequences. Hk2 deletion in lung cancer cells suppressed glucose-derived ribonucleotides and impaired glutamine-derived carbon utilization in anaplerosis.

#55 GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer Open access logo Link logo

Pharoah, Paul D. P.; Tsai, Ya-Yu; Ramus, Susan J.; Phelan, Catherine M.; Goode, Ellen L.; Lawrenson, Kate; Buckley, Melissa; Fridley, Brooke L.; Tyrer, Jonathan P.; Shen, Howard; Weber, Rachel; Karevan, Rod; Larson, Melissa C.; Song, Honglin; Tessier, Dan

Nature Genetics Volume 45, Issue 4, Pages 362–370

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Genome-wide association studies (GWAS) have identified four susceptibility loci for epithelial ovarian cancer (EOC), with another two suggestive loci reaching near genome-wide significance. We pooled data from a GWAS conducted in North America with another GWAS from the UK. We selected the top 24,551 SNPs for inclusion on the iCOGS custom genotyping array. We performed follow-up genotyping in 18,174 individuals with EOC (cases) and 26,134 controls from 43 studies from the Ovarian Cancer Association Consortium. We validated the two loci at 3q25 and 17q21 that were previously found to have associations close to genome-wide significance and identified three loci newly associated with risk: two loci associated with all EOC subtypes at 8q21 (rs11782652, P = 5.5 × 10(-9)) and 10p12 (rs1243180, P = 1.8 × 10(-8)) and another locus specific to the serous subtype at 17q12 (rs757210, P = 8.1 × 10(-10)). An integrated molecular analysis of genes and regulatory regions at these loci provided evidence for functional mechanisms underlying susceptibility and implicated CHMP4C in the pathogenesis of ovarian cancer.

#56 Accuracy of medical models made by additive manufacturing (rapid manufacturing) Open access logo Link logo

Salmi, Mika; Paloheimo, Kaija-Stiina; Tuomi, Jukka; Wolff, Jan; Mäkitie, Antti Aarni

Journal of Cranio-Maxillofacial Surgery

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Additive manufacturing (AM) is being increasingly used for producing medical models. The accuracy of these models varies between different materials, AM technologies and machine runs.

#57 European consensus guidelines on the management of neonatal respiratory distress syndrome in preterm infants - 2013 update Open access logo

Sweet, David G; Carnielli, Virgilio; Greisen, Gorm; Hallman, Mikko; Ozek, Eren; Plavka, Richard; Saugstad, Ola D; Simeoni, Umberto; Speer, Christian P; Vento, Maximo; Halliday, Henry L

Neonatology (16617800) Volume 103, Issue 4

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#58 Therapeutic Potential of Fecal Microbiota Transplantation Open access logo Link logo PDF logo

Smits, Loek P.; Bouter, Kristien E. C.; de Vos, Willem M.; Borody, Thomas J.; Nieuwdorp, Max

Gastroenterology Volume 145, Issue 5

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  • 164 Mendeley readers

There has been growing interest in the use of fecal microbiota for the treatment of patients with chronic gastrointestinal infections and inflammatory bowel diseases. Lately, there has also been interest in its therapeutic potential for cardiometabolic, autoimmune, and other extraintestinal conditions that were not previously considered to be associated with the intestinal microbiota. Although it is not clear if changes in the microbiota cause these conditions, we review the most current and best methods for performing fecal microbiota transplantation and summarize clinical observations that have implicated the intestinal microbiota in various diseases. We also discuss case reports of fecal microbiota transplantations for different disorders, including Clostridium difficile infection, irritable bowel syndrome, inflammatory bowel diseases, insulin resistance, multiple sclerosis, and idiopathic thrombocytopenic purpura. There has been increasing focus on the interaction between the intestinal microbiome, obesity, and cardiometabolic diseases, and we explore these relationships and the potential roles of different microbial strains. We might someday be able to mine for intestinal bacterial strains that can be used in the diagnosis or treatment of these diseases.

#59 The MLL recombinome of acute leukemias in 2013 Open access logo

Meyer C, Hofmann J, Burmeister T, Groger D, Park TS, Emerenciano M, de Oliveira MP, Renneville A, Villarese P, Macintyre E, Cave H, Clappier E, Mass-Malo K, Zuna J, Trka J, De Braekeleer E, De Braekeleer M, Oh SH, Tsaur G, Fechina L, van der Velden VHJ, v

Leukemia (08876924) Volume 27, Issue 11, Pages 2165–2176

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Chromosomal rearrangements of the human MLL (mixed lineage leukemia) gene are associated with high-risk infant, pediatric, adult and therapy-induced acute leukemias. We used long-distance inverse-polymerase chain reaction to characterize the chromosomal rearrangement of individual acute leukemia patients. We present data of the molecular characterization of 1590 MLL-rearranged biopsy samples obtained from acute leukemia patients. The precise localization of genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) were determined and novel TPGs identified. All patients were classified according to their gender (852 females and 745 males), age at diagnosis (558 infant, 416 pediatric and 616 adult leukemia patients) and other clinical criteria. Combined data of our study and recently published data revealed a total of 121 different MLL rearrangements, of which 79 TPGs are now characterized at the molecular level. However, only seven rearrangements seem to be predominantly associated with illegitimate recombinations of the MLL gene (≈ 90%): AFF1/AF4, MLLT3/AF9, MLLT1/ENL, MLLT10/AF10, ELL, partial tandem duplications (MLL PTDs) and MLLT4/AF6, respectively. The MLL breakpoint distributions for all clinical relevant subtypes (gender, disease type, age at diagnosis, reciprocal, complex and therapy-induced translocations) are presented. Finally, we present the extending network of reciprocal MLL fusions deriving from complex rearrangements.

#60 Identification of Small Exonic CNV from Whole-Exome Sequence Data and Application to Autism Spectrum Disorder Open access logo Link logo PDF logo

Poultney, Christopher S.; Goldberg, Arthur P.; Drapeau, Elodie; Kou, Yan; Harony-Nicolas, Hala; Kajiwara, Yuji; De Rubeis, Silvia; Durand, Simon; Stevens, Christine; Rehnström, Karola Hannele; Palotie, Aarno; Daly, Mark J.; Ma'ayan, Avi; Fromer, Menachem;

American Journal of Human Genetics Volume 93, Issue 4

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Copy number variation (CNV) is an important determinant of human diversity and plays important roles in susceptibility to disease. Most studies of CNV carried out to date have made use of chromosome microarray and have had a lower size limit for detection of about 30 kilobases (kb). With the emergence of whole-exome sequencing studies, we asked whether such data could be used to reliably call rare exonic CNV in the size range of 1-30 kilobases (kb), making use of the eXome Hidden Markov Model (XHMM) program. By using both transmission information and validation by molecular methods, we confirmed that small CNV encompassing as few as three exons can be reliably called from whole-exome data. We applied this approach to an autism case-control sample (n = 811, mean per-target read depth = 161) and observed a significant increase in the burden of rare (MAF ≤1%) 1-30 kb CNV, 1-30 kb deletions, and 1-10 kb deletions in ASD. CNV in the 1-30 kb range frequently hit just a single gene, and we were therefore able to carry out enrichment and pathway analyses, where we observed enrichment for disruption of genes in cytoskeletal and autophagy pathways in ASD. In summary, our results showed that XHMM provided an effective means to assess small exonic CNV from whole-exome data, indicated that rare 1-30 kb exonic deletions could contribute to risk in up to 7% of individuals with ASD, and implicated a candidate pathway in developmental delay syndromes.

#61 The histaminergic network in the brain: basic organization and role in disease Open access logo Link logo

Panula, Pertti; Nuutinen, Saara

Nature Reviews Neuroscience

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Histamine acts as a modulatory neurotransmitter in the mammalian brain. It has an important role in the maintenance of wakefulness, and dysfunction in the histaminergic system has been linked to narcolepsy. Recent evidence suggests that aberrant histamine signalling in the brain may also be a key factor in Gilles de la Tourette syndrome, Parkinson's disease and addictive behaviours. Furthermore, multiple sclerosis (MS) and experimental autoimmune encephalitis, which is an often-used model for MS, are associated with changes in the histaminergic system. This Review explores the possible roles of brain histamine in the mechanisms underlying these diseases.

#62 Genome-wide meta-analysis identifies new susceptibility loci for migraine Open access logo Link logo

Anttila, Verneri; Winsvold, Bendik S.; Gormley, Padhraig; Kurth, Tobias; Bettella, Francesco; McMahon, George; Kallela, Kaarlo Mikko Juhani; Malik, Rainer; de Vries, Boukje; Terwindt, Gisela; Medland, Sarah E.; Todt, Unda; McArdle, Wendy L.; Quaye, Lydia;

Nature Genetics Volume 45, Issue 8, Pages 912–917

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Migraine is the most common brain disorder, affecting approximately 14% of the adult population, but its molecular mechanisms are poorly understood. We report the results of a meta-analysis across 29 genome-wide association studies, including a total of 23,285 individuals with migraine (cases) and 95,425 population-matched controls. We identified 12 loci associated with migraine susceptibility (P<5×10(-8)). Five loci are new: near AJAP1 at 1p36, near TSPAN2 at 1p13, within FHL5 at 6q16, within C7orf10 at 7p14 and near MMP16 at 8q21. Three of these loci were identified in disease subgroup analyses. Brain tissue expression quantitative trait locus analysis suggests potential functional candidate genes at four loci: APOA1BP, TBC1D7, FUT9, STAT6 and ATP5B.

#63 Diabetes and periodontal diseases : concensus report of the Joint EFP/AAP Workshop on periodontitis and systemic diseases Open access logo Link logo PDF logo

Chapple, Iain L C; Genco, Robert; Berglundh, Tord; Eickholz, Peter; Engebretson, Steven; Graves, Dana; Grossi, Sarah; Hasturk, Hatice; Kocher, Thomas; Lalla, Evanthia; Lamster, Ira; Lang, Niklaus; Mealey, Brian; Meyle, Joerg; Nesse, Willem; Paquette, Davi

Journal of Clinical Periodontology Volume 40, Issue s14, Pages S106–S112

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Diabetes and periodontitis are complex chronic diseases with an established bidirectional relationship. There is long-established evidence that hyperglycaemia in diabetes is associated with adverse periodontal outcomes. However, given the ubiquity of periodontal diseases and the emerging global diabetes epidemic, the complications of which contribute to significant morbidity and premature mortality, it is timely to review the role of periodontitis in diabetes.

#64 The Long-Term Multicenter Observational Study of Dabigatran Treatment in Patients With Atrial Fibrillation (RELY-ABLE) Study Open access logo Link logo PDF logo

Connolly, Stuart J.; Wallentin, Lars; Ezekowitz, Michael D.; Eikelboom, John; Oldgren, Jonas; Reilly, Paul A.; Brueckmann, Martina; Pogue, Janice; Alings, Marco; Amerena, John V.; Avezum, Alvaro; Baumgartner, Iris; Budaj, Andrzej J.; Chen, Jyh-Hong; Dans,

Circulation Volume 128, Issue 3

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During follow-up of between 1 and 3 years in the Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial, 2 doses of dabigatran etexilate were shown to be effective and safe for the prevention of stroke or systemic embolism in patients with atrial fibrillation. There is a need for longer-term follow-up of patients on dabigatran and for further data comparing the 2 dabigatran doses. Patients randomly assigned to dabigatran in RE-LY were eligible for the Long-term Multicenter Extension of Dabigatran Treatment in Patients with Atrial Fibrillation (RELY-ABLE) trial if they had not permanently discontinued study medication at the time of their final RE-LY study visit. Enrolled patients continued to receive the double-blind dabigatran dose received in RE-LY, for up to 28 months of follow up after RE-LY (median follow-up, 2.3 years). There were 5851 patients enrolled, representing 48% of patients originally randomly assigned to receive dabigatran in RE-LY and 86% of RELY-ABLE-eligible patients. Rates of stroke or systemic embolism were 1.46% and 1.60%/y on dabigatran 150 and 110 mg twice daily, respectively (hazard ratio, 0.91; 95% confidence interval, 0.69-1.20). Rates of major hemorrhage were 3.74% and 2.99%/y on dabigatran 150 and 110 mg (hazard ratio, 1.26; 95% confidence interval, 1.04-1.53). Rates of death were 3.02% and 3.10%/y (hazard ratio, 0.97; 95% confidence interval, 0.80-1.19). Rates of hemorrhagic stroke were 0.13% and 0.14%/y. During 2.3 years of continued treatment with dabigatran after RE-LY, there was a higher rate of major bleeding with dabigatran 150 mg twice daily in comparison with 110 mg, and similar rates of stroke and death.

#65 Transfusion requirements in septic shock (TRISS) trial - comparing the effects and safety of liberal versus restrictive red blood cell transfusion in septic shock patients in the ICU: protocol for a randomised controlled trial Open access logo Link logo

Holst, Lars B.; Haase, Nicolai; Wetterslev, Jorn; Wernerman, Jan; Aneman, Anders; Guttormsen, Anne B.; Johansson, Par I.; Karlsson, Sari; Klemenzson, Gudmundur; Winding, Robert; Nebrich, Lars; Albeck, Carsten; Vang, Marianne L.; Bulow, Hans-Henrik; Elkjae

Trials Volume 14, Issue 1

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Process evaluations are recommended to open the 'black box' of complex interventions evaluated in trials, but there is limited guidance to help researchers design process evaluations. Much current literature on process evaluations of complex interventions focuses on qualitative methods, with less attention paid to quantitative methods. This discrepancy led us to develop our own framework for designing process evaluations of cluster-randomised controlled trials.

#66 Mouse models for studying angiogenesis and lymphangiogenesis in cancer Open access logo Link logo

Eklund, Lauri; Bry, Maija; Alitalo, Kari

Molecular Oncology

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The formation of new blood vessels (angiogenesis) is required for the growth of most tumors. The tumor microenvironment also induces lymphangiogenic factors that promote metastatic spread. Anti-angiogenic therapy targets the mechanisms behind the growth of the tumor vasculature. During the past two decades, several strategies targeting blood and lymphatic vessels in tumors have been developed. The blocking of vascular endothelial growth factor (VEGF)/VEGF receptor-2 (VEGFR-2) signaling has proven effective for inhibition of tumor angiogenesis and growth, and inhibitors of VEGF-C/VEGFR-3 involved in lymphangiogenesis have recently entered clinical trials. However, thus far anti-angiogenic treatments have been less effective in humans than predicted on the basis of pre-clinical tests in mice. Intrinsic and induced resistance against anti-angiogenesis occurs in patients, and thus far the clinical benefit of the treatments has been limited to modest improvements in overall survival in selected tumor types. Our current knowledge of tumor angiogenesis is based mainly on experiments performed in tumor-transplanted mice, and it has become evident that these models are not representative of human cancer. For an improved understanding, angiogenesis research needs models that better recapitulate the multistep tumorigenesis of human cancers, from the initial genetic insults in single cells to malignant progression in a proper tissue environment. To improve anti-angiogenic therapies in cancer patients, it is necessary to identify additional molecular targets important for tumor angiogenesis, and to get mechanistic insight into their interactions for eventual combinatorial targeting. The recent development of techniques for manipulating the mammalian genome in a precise and predictable manner has opened up new possibilities for the generation of more reliable models of human cancer that are essential for the testing of new therapeutic strategies. In addition, new imaging modalities that permit visualization of the entire mouse tumor vasculature down to the resolution of single capillaries have been developed in pre-clinical models and will likely benefit clinical imaging.

#67 The biodiversity hypothesis and allergic disease: world allergy organization position statement Open access logo Link logo PDF logo

Haahtela, T.; Holgate, S.; Pawankar, R.; Akdis, C. A.; Benjaponpitak, S.; Caraballo, L.; Demain, J.; Portnoy, J.; von Hertzen, Leena; ,

World Allergy Organization Journal Volume 6, Issue 1

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Biodiversity loss and climate change secondary to human activities are now being associated with various adverse health effects. However, less attention is being paid to the effects of biodiversity loss on environmental and commensal (indigenous) microbiotas. Metagenomic and other studies of healthy and diseased individuals reveal that reduced biodiversity and alterations in the composition of the gut and skin microbiota are associated with various inflammatory conditions, including asthma, allergic and inflammatory bowel diseases (IBD), type1 diabetes, and obesity. Altered indigenous microbiota and the general microbial deprivation characterizing the lifestyle of urban people in affluent countries appear to be risk factors for immune dysregulation and impaired tolerance. The risk is further enhanced by physical inactivity and a western diet poor in fresh fruit and vegetables, which may act in synergy with dysbiosis of the gut flora. Studies of immigrants moving from non-affluent to affluent regions indicate that tolerance mechanisms can rapidly become impaired in microbe-poor environments. The data on microbial deprivation and immune dysfunction as they relate to biodiversity loss are evaluated in this Statement of World Allergy Organization (WAO). We propose that biodiversity, the variability among living organisms from all sources are closely related, at both the macro- and micro-levels. Loss of the macrodiversity is associated with shrinking of the microdiversity, which is associated with alterations of the indigenous microbiota. Data on behavioural means to induce tolerance are outlined and a proposal made for a Global Allergy Plan to prevent and reduce the global allergy burden for affected individuals and the societies in which they live.

#68 Heart rate variability in prediction of individual adaptation to endurance training in recreational endurance runners Open access logo Link logo PDF logo

Vesterinen, Ville;Häkkinen, Keijo;Hynynen, Esa;Mikkola, Jussi;Hokka, Laura;Nummela, Ari

Scandinavian Journal of Medicine & Science in Sports Volume 23, Issue 2, Pages 171–180

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The aim of this study was to investigate whether nocturnal heart rate variability (HRV) can be used to predict changes in endurance performance during 28 weeks of endurance training. The training was divided into 14 weeks of basic training (BTP) and 14 weeks of intensive training periods (ITP). Endurance performance characteristics, nocturnal HRV, and serum hormone concentrations were measured before and after both training periods in 28 recreational endurance runners. During the study peak treadmill running speed (Vpeak ) improved by 7.5 ± 4.5%. No changes were observed in HRV indices after BTP, but after ITP, these indices increased significantly (HFP: 1.9%, P=0.026; TP: 1.7%, P=0.007). Significant correlations were observed between the change of Vpeak and HRV indices (TP: r=0.75, P<0.001; HFP: r=0.71, P<0.001; LFP: r=0.69, P=0.01) at baseline during ITP. In order to lead to significant changes in HRV among recreational endurance runners, it seems that moderate- and high-intensity training are needed. This study showed that recreational endurance runners with a high HRV at baseline improved their endurance running performance after ITP more than runners with low baseline HRV.

#69 Effects of targeting higher vs lower arterial oxygen saturations on death or disability in extremely preterm infants : a randommized clinical trial Open access logo

Schmidt, Barbara; Whyte, Robin K; Asztalos, Elizabeth V; Moddemann, Diane; Poets, Christian; Rabi, Yacov; Solimano, Alfonso; Roberts, Robin S; Canadian Oxygen Trial (COT) Group

JAMA: Journal of the American Medical Association Volume 309, Issue 20

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The goal of oxygen therapy is to deliver sufficient oxygen to the tissues while minimizing oxygen toxicity and oxidative stress. It remains uncertain what values of arterial oxygen saturations achieve this balance in preterm infants.

#70 Muscular strength in male adolescents and premature death: cohort study of one million participants Open access logo

Ortega , Francisco ; Silventoinen, Karri; Tynelius , Per ; Rasmussen, Finn

British Medical Journal Volume 345, Issue nov20 3, Pages e7279–e7279

  • 45 tweets
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To explore the extent to which muscular strength in adolescence is associated with all cause and cause specific premature mortality (<55 years).

#71 Effects of Early Prebiotic and Probiotic Supplementation on Development of Gut Microbiota and Fussing and Crying in Preterm Infants: A Randomized, Double-Blind, Placebo-Controlled Trial Open access logo

Partty A, Luoto R, Kalliomaki M, Salminen S, Isolauri E

Journal of Pediatrics

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To evaluate the impact of early prebiotic and probiotic intervention on preterm infants' well-being, crying, growth, and microbiological programming.

#72 Bacterial Diversity in Meconium of Preterm Neonates and Evolution of Their Fecal Microbiota during the First Month of Life Open access logo Link logo PDF logo

Moles, Laura; Gomez, Marta; Heilig, Hans; Bustos, Gerardo; Fuentes, Susana; de Vos, Willem; Fernandez, Leonides; Rodriguez, Juan M.; Jimenez, Esther

PLoS ONE Volume 8, Issue 6

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The establishment and succession of bacterial communities in infants may have a profound impact in their health, but information about the composition of meconium microbiota and its evolution in hospitalized preterm infants is scarce. In this context, the objective of this work was to characterize the microbiota of meconium and fecal samples obtained during the first 3 weeks of life from 14 donors using culture and molecular techniques, including DGGE and the Human Intestinal Tract Chip (HITChip) analysis of 16S rRNA amplicons. Culture techniques offer a quantification of cultivable bacteria and allow further study of the isolate, while molecular techniques provide deeper information on bacterial diversity. Culture and HITChip results were very similar but the former showed lower sensitivity. Inter-individual differences were detected in the microbiota profiles although the meconium microbiota was peculiar and distinct from that of fecal samples. Bacilli and other Firmicutes were the main bacteria groups detected in meconium while Proteobacteria dominated in the fecal samples. Culture technique showed that Staphylococcus predominated in meconium and that Enterococcus, together with Gram-negative bacteria such as Escherichia coli, Escherichia fergusonii, Klebsiella pneumoniae and Serratia marcescens, was more abundant in fecal samples. In addition, HITChip results showed the prevalence of bacteria related to Lactobacillus plantarum and Streptococcus mitis in meconium samples whereas those related to Enterococcus, Escherichia coli, Klebsiella pneumoniae and Yersinia predominated in the 3(rd) week feces. This study highlights that spontaneously-released meconium of preterm neonates contains a specific microbiota that differs from that of feces obtained after the first week of life. Our findings indicate that the presence of Serratia was strongly associated with a higher degree of immaturity and other hospital-related parameters, including antibiotherapy and mechanical ventilation.

#73 The intestinal microbiota and host immune interactions in the critically ill Open access logo Link logo PDF logo

Schuijt, Tim J.; van der Poll, Tom; de Vos, Willem M.; Wiersinga, W. Joost

Trends in Microbiology

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The gastrointestinal tract harbors a complex population of microbes that play a fundamental role in the development of the immune system and human health. Besides an important local contribution in the host defense against infections, it has become increasingly clear that intestinal bacteria also modulate immune responses at systemic sites. These new insights can be of profound clinical relevance especially for intensive care medicine where the majority of patients are treated with antibiotics, which have pervasive and long-term effects on the intestinal microbiota. Moreover, considerable progress has been made in defining the role of the intestinal microbiota in both health and disease. In this review, we highlight these aspects and focus on recent key findings addressing the role of intestinal microbiota in antimicrobial defense mechanisms and its impact on intestinal homeostasis in the critically ill.

#74 A versatile platform for creating a comprehensive UAS-ORFeome library in Drosophila Open access logo Link logo PDF logo

Bischof, Johannes; Björklund, Mikael; Furger, Edy; Schertel, Claus; Taipale, Jussi; Basler, Konrad

Development (09501991) Volume 140, Issue 11

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Overexpression screens are used to explore gene functions in Drosophila, but this strategy suffers from the lack of comprehensive and systematic fly strain collections and efficient methods for generating such collections. Here, we present a strategy that could be used efficiently to generate large numbers of transgenic Drosophila strains, and a collection of 1149 UAS-ORF fly lines that were created with the site-specific ΦC31 integrase method. For this collection, we used a set of 655 genes that were cloned as two variants, either as an open reading frame (ORF) with a native stop codon or with a C-terminal 3xHA tag. To streamline the procedure for transgenic fly generation, we demonstrate the utility of injecting pools of plasmids into embryos, each plasmid containing a randomised sequence (barcode) that serves as a unique identifier for plasmids and, subsequently, fly strains. We also developed a swapping technique that facilitates the rapid exchange of promoters and epitope tags in vivo, expanding the versatility of the ORF collection. The work described here serves as the basis of a systematic library of Gal4/UAS-regulated transgenes.

#75 Network-Based Multiple Sclerosis Pathway Analysis with GWAS Data from 15,000 Cases and 30,000 Controls Open access logo Link logo PDF logo

Baranzini, Sergio E.; Khankhanian, Pouya; Patsopoulos, Nikolaos A.; Li, Michael; Stankovich, Jim; Cotsapas, Chris; Sondergaard, Helle Bach; Ban, Maria; Barizzone, Nadia; Bergamaschi, Laura; Booth, David; Buck, Dorothea; Cavalla, Paola; Celius, Elisabeth G

American Journal of Human Genetics Volume 92, Issue 6, Pages 854–865

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Multiple sclerosis (MS) is an inflammatory CNS disease with a substantial genetic component, originally mapped to only the human leukocyte antigen (HLA) region. In the last 5 years, a total of seven genome-wide association studies and one meta-analysis successfully identified 57 non-HLA susceptibility loci. Here, we merged nominal statistical evidence of association and physical evidence of interaction to conduct a protein-interaction-network-based pathway analysis (PINBPA) on two large genetic MS studies comprising a total of 15,317 cases and 29,529 controls. The distribution of nominally significant loci at the gene level matched the patterns of extended linkage disequilibrium in regions of interest. We found that products of genome-wide significantly associated genes are more likely to interact physically and belong to the same or related pathways. We next searched for subnetworks (modules) of genes (and their encoded proteins) enriched with nominally associated loci within each study and identified those modules in common between the two studies. We demonstrate that these modules are more likely to contain genes with bona fide susceptibility variants and, in addition, identify several high-confidence candidates (including BCL10, CD48, REL, TRAF3, and TEC). PINBPA is a powerful approach to gaining further insights into the biology of associated genes and to prioritizing candidates for subsequent genetic studies of complex traits.

#76 Intracellular Complement Activation Sustains T Cell Homeostasis and Mediates Effector Differentiation Open access logo Link logo PDF logo

Liszewski, M. Kathryn; Kolev, Martin; Le Friec, Gaelle; Leung, Marilyn; Bertram, Paula G.; Fara, Antonella F.; Subias, Marta; Pickering, Matthew C.; Drouet, Christian; Meri, Seppo; Arstila, T. Petteri; Pekkarinen, Pirkka T.; Ma, Margaret; Cope, Andrew; Re

Immunity Volume 39, Issue 6

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Complement is viewed as a critical serum-operative component of innate immunity, with processing of its key component, C3, into activation fragments C3a and C3b confined to the extracellular space. We report here that C3 activation also occurred intracellularly. We found that the T cell-expressed protease cathepsin L (CTSL) processed C3 into biologically active C3a and C3b. Resting T cells contained stores of endosomal and lysosomal C3 and CTSL and substantial amounts of CTSL-generated C3a. While "tonic" intracellular C3a generation was required for homeostatic T cell survival, shuttling of this intracellular C3-activation-system to the cell surface upon T cell stimulation induced autocrine proinflammatory cytokine production. Furthermore, T cells from patients with autoimmune arthritis demonstrated hyperactive intracellular complement activation and interferon-γ production and CTSL inhibition corrected this deregulated phenotype. Importantly, intracellular C3a was observed in all examined cell populations, suggesting that intracellular complement activation might be of broad physiological significance.

#77 Causal Relationship between Obesity and Vitamin D Status: Bi-Directional Mendelian Randomization Analysis of Multiple Cohorts Open access logo Link logo PDF logo

Vimaleswaran, Karani S.; Berry, Diane J.; Lu, Chen; Tikkanen, Emmi; Pilz, Stefan; Hiraki, Linda T.; Cooper, Jason D.; Dastani, Zari; Li, Rui; Houston, Denise K.; Wood, Andrew R.; Michaelsson, Karl; Vandenput, Liesbeth; Zgaga, Lina; Yerges-Armstrong, Laura

PLoS Medicine Volume 10, Issue 2

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Obesity is associated with vitamin D deficiency, and both are areas of active public health concern. We explored the causality and direction of the relationship between body mass index (BMI) and 25-hydroxyvitamin D [25(OH)D] using genetic markers as instrumental variables (IVs) in bi-directional Mendelian randomization (MR) analysis.

#78 High-Throughput 3D Screening Reveals Differences in Drug Sensitivities between Culture Models of JIMT1 Breast Cancer Cells Open access logo Link logo

Hongisto, Vesa; Jernstrom, Sandra; Fey, Vidal; Mpindi, John-Patrick; Sahlberg, Kristine Kleivi; Kallioniemi, Olli; Perala, Merja

PLoS ONE Volume 8, Issue 10

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The traditional method for studying cancer in vitro is to grow immortalized cancer cells in two-dimensional monolayers on plastic. However, many cellular features are impaired in these artificial conditions, and large changes in gene expression compared to tumors have been reported. Three-dimensional cell culture models have become increasingly popular and are suggested to be better models than two-dimensional monolayers due to improved cell-to-cell contact and structures that resemble in vivo architecture. The aim of this study was to develop a simple high-throughput three-dimensional drug screening method and to compare drug responses in JIMT1 breast cancer cells when grown in two dimensions, in poly(2-hydroxyethyl methacrylate) induced anchorage-independent three-dimensional models, and in Matrigel three-dimensional cell culture models. We screened 102 compounds with multiple concentrations and biological replicates for their effects on cell proliferation. The cells were either treated immediately upon plating, or they were allowed to grow in three-dimensional cultures for 4 days before the drug treatment. Large variations in drug responses were observed between the models indicating that comparisons of culture model-influenced drug sensitivities cannot be made based on the effects of a single drug. However, we show with the 63 most prominent drugs that, in general, JIMT1 cells grown on Matrigel were significantly more sensitive to drugs than cells grown in two-dimensional cultures, while the responses of cells grown in poly(2-hydroxyethyl methacrylate) resembled those of the two-dimensional cultures. Furthermore, comparing the gene expression profiles of the cell culture models to xenograft tumors indicated that cells cultured in Matrigel and as xenografts most closely resembled each other. In this study, we also suggest that three-dimensional cultures can provide a platform for systematic experimentation of larger compound collections in a high-throughput mode and be used as alternatives to traditional two-dimensional screens for better comparability to the in vivo state.

#79 Dopamine from the Brain Promotes Spinal Motor Neuron Generation during Development and Adult Regeneration Open access logo Link logo PDF logo

Reimer, Michell M.; Norris, Anneliese; Ohnmacht, Jochen; Patani, Rickie; Zhong, Zhen; Dias, Tatyana B.; Kuscha, Veronika; Scott, Angela L.; Chen, Yu-Chia; Rozov, Stanislav; Frazer, Sarah L.; Wyatt, Cameron; Higashijima, Shin-ichi; Patton, E. Elizabeth; Pa

Developmental Cell Volume 25, Issue 5, Pages 478–491

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Coordinated development of brain stem and spinal target neurons is pivotal for the emergence of a precisely functioning locomotor system. Signals that match the development of these far-apart regions of the central nervous system may be redeployed during spinal cord regeneration. Here we show that descending dopaminergic projections from the brain promote motor neuron generation at the expense of V2 interneurons in the developing zebrafish spinal cord by activating the D4a receptor, which acts on the hedgehog pathway. Inhibiting this essential signal during early neurogenesis leads to a long-lasting reduction of motor neuron numbers and impaired motor responses of free-swimming larvae. Importantly, during successful spinal cord regeneration in adult zebrafish, endogenous dopamine promotes generation of spinal motor neurons, and dopamine agonists augment this process. Hence, we describe a supraspinal control mechanism for the development and regeneration of specific spinal cell types that uses dopamine as a signal.

#80 DNA methylation alterations exhibit intraindividual stability and interindividual heterogeneity in prostate cancer metastases Open access logo PDF logo

Aryee Martin J; Liu Wennuan; Engelmann Julia C; Nuhn Philipp; Gurel Meltem; Haffner Michael C; Esopi David; Irizarry Rafael A; Getzenberg Robert H; Nelson William G; Luo Jun; Xu Jianfeng; Isaacs William B; Bova G S; Yegnasubramanian Srinivasan

Science Translational Medicine Volume 5, Issue 169, Pages 169ra10–169ra10

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Human cancers almost ubiquitously harbor epigenetic alterations. Although such alterations in epigenetic marks, including DNA methylation, are potentially heritable, they can also be dynamically altered. Given this potential for plasticity, the degree to which epigenetic changes can be subject to selection and act as drivers of neoplasia has been questioned. We carried out genome-scale analyses of DNA methylation alterations in lethal metastatic prostate cancer and created DNA methylation "cityscape" plots to visualize these complex data. We show that somatic DNA methylation alterations, despite showing marked interindividual heterogeneity among men with lethal metastatic prostate cancer, were maintained across all metastases within the same individual. The overall extent of maintenance in DNA methylation changes was comparable to that of genetic copy number alterations. Regions that were frequently hypermethylated across individuals were markedly enriched for cancer- and development/differentiation-related genes. Additionally, regions exhibiting high consistency of hypermethylation across metastases within individuals, even if variably hypermethylated across individuals, showed enrichment for cancer-related genes. Whereas some regions showed intraindividual metastatic tumor heterogeneity in promoter methylation, such methylation alterations were generally not correlated with gene expression. This was despite a general tendency for promoter methylation patterns to be strongly correlated with gene expression, particularly at regions that were variably methylated across individuals. These findings suggest that DNA methylation alterations have the potential for producing selectable driver events in carcinogenesis and disease progression and highlight the possibility of targeting such epigenome alterations for development of longitudinal markers and therapeutic strategies.

#81 Deletion of TOP3 beta, a component of FMRP-containing mRNPs, contributes to neurodevelopmental disorders Open access logo Link logo

Stoll, Georg; Pietiläinen, Olli; Linder, Bastian; Suvisaari, Jaana; Brosi, Cornelia; Hennah, William; Leppä, Virpi Maria; Torniainen, Minna; Ripatti, Samuli; Ala-Mello, Sirpa; Plottner, Oliver; Rehnstrom, Karola; Tuulio-Henriksson, Annamari; Varilo, Teppo

Nature Neuroscience Volume 16, Issue 9, Pages 1228–1237

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Implicating particular genes in the generation of complex brain and behavior phenotypes requires multiple lines of evidence. The rarity of most high-impact genetic variants typically precludes the possibility of accruing statistical evidence that they are associated with a given trait. We found that the enrichment of a rare chromosome 22q11.22 deletion in a recently expanded Northern Finnish sub-isolate enabled the detection of association between TOP3B and both schizophrenia and cognitive impairment. Biochemical analysis of TOP3β revealed that this topoisomerase was a component of cytosolic messenger ribonucleoproteins (mRNPs) and was catalytically active on RNA. The recruitment of TOP3β to mRNPs was independent of RNA cis-elements and was coupled to the co-recruitment of FMRP, the disease gene product in fragile X mental retardation syndrome. Our results indicate a previously unknown role for TOP3β in mRNA metabolism and suggest that it is involved in neurodevelopmental disorders.

#82 How Small-Sided and Conditioned Games Enhance Acquisition of Movement and Decision-Making Skills Link logo

Davids, Keith;Araujo, Duarte;Correia, Vanda;Vilar, Luis

Exercise and Sport Sciences Review Volume 41, Issue 3, Pages 154–161

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This article summarizes research from an ecological dynamics program of work on team sports exemplifying how small-sided and conditioned games (SSCG) can enhance skill acquisition and decision-making processes during training. The data highlighted show how constraints of different SSCG can facilitate emergence of continuous interpersonal coordination tendencies during practice to benefit team game players.

#83 Value of quantitative sensory testing in neurological and pain disorders: NeuPSIG consensus Open access logo Link logo

Backonja, Miroslav ""Misha''; Attal, Nadine; Baron, Ralf; Bouhassira, Didier; Drangholt, Mark; Dyck, Peter J.; Edwards, Robert R.; Freeman, Roy; Gracely, Richard; Haanpää, Maija; Hansson, Per; Hatem, Samar M.; Krumova, Elena K.; Jensen, Troels S.; Maier, C

Pain (03043959)

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Quantitative sensory testing (QST) is a psychophysical method used to quantify somatosensory function in response to controlled stimuli in healthy subjects and patients. Although QST shares similarities with the quantitative assessment of hearing or vision, which is extensively used in clinical practice and research, it has not gained a large acceptance among clinicians for many reasons, and in significant part because of the lack of information about standards for performing QST, its potential utility, and interpretation of results. A consensus meeting was convened by the Neuropathic Pain Special Interest Group of the International Association for the Study of Pain (NeuPSIG) to formulate recommendations for conducting QST in clinical practice and research. Research studies have confirmed the utility of QST for the assessment and monitoring of somatosensory deficits, particularly in diabetic and small fiber neuropathies; the assessment of evoked pains (mechanical and thermal allodynia or hyperalgesia); and the diagnosis of sensory neuropathies. Promising applications include the assessment of evoked pains in large-scale clinical trials and the study of conditioned pain modulation. In clinical practice, we recommend the use QST for screening for small and large fiber neuropathies; monitoring of somatosensory deficits; and monitoring of evoked pains, allodynia, and hyperalgesia. QST is not recommended as a stand-alone test for the diagnosis of neuropathic pain. For the conduct of QST in healthy subjects and in patients, we recommend use of predefined standardized stimuli and instructions, validated algorithms of testing, and reference values corrected for anatomical site, age, and gender. Interpretation of results should always take into account the clinical context, and patients with language and cognitive difficulties, anxiety, or litigation should not be considered eligible for QST. When appropriate standards, as discussed here, are applied, QST can provide important and unique information about the functional status of somatosensory system, which would be complementary to already existing clinical methods.

#84 Cation-chloride cotransporters NKCC1 and KCC2 as potential targets for novel antiepileptic and antiepileptogenic treatments Open access logo Link logo

Loescher, Wolfgang; Puskarjov, Martin; Kaila, Kai


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In cortical and hippocampal neurons, cation-chloride cotransporters (CCCs) control the reversal potential (EGABA) of GABAA receptor-mediated current and voltage responses and, consequently, they modulate the efficacy of GABAergic inhibition. Two members of the CCC family, KCC2 (the major neuron-specific K-Cl cotransporter; KCC isoform 2) and NKCC1 (the Na-K-2Cl cotransporter isoform 1 which is expressed in both neurons and glial cells) have attracted much interest in studies on GABAergic signaling under both normal and pathophysiological conditions, such as epilepsy. There is tentative evidence that loop diuretic compounds such as furosemide and bumetanide may have clinically relevant antiepileptic actions, especially when administered in combination with conventional GABA-mimetic drugs such as phenobarbital. Furosemide is a non-selective inhibitor of CCCs while at low concentrations bumetanide is selective for NKCCs. Search for novel antiepileptic drugs (AEDs) is highly motivated especially for the treatment of neonatal seizures which are often resistant to, or even aggravated by conventional AEDs. This review shows that the antiepileptic effects of loop diuretics described in the pertinent literature are based on widely heterogeneous mechanisms ranging from actions on both neuronal NKCC1 and KCC2 to modulation of the brain extracellular volume fraction. A promising strategy for the development of novel CCC-blocking AEDs is based on prodrugs that are activated following their passage across the blood-brain barrier. This article is part of the Special Issue entitled 'New Targets and Approaches to the Treatment of Epilepsy'.

#85 Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes Open access logo Link logo

Lemke, Johannes R.; Lal, Dennis; Reinthaler, Eva M.; Steiner, Isabelle; Nothnagel, Michael; Alber, Michael; Geider, Kirsten; Laube, Bodo; Schwake, Michael; Finsterwalder, Katrin; Franke, Andre; Schilhabel, Markus; Jaehn, Johanna A.; Muhle, Hiltrud; Boor,

Nature Genetics

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Idiopathic focal epilepsy (IFE) with rolandic spikes is the most common childhood epilepsy, comprising a phenotypic spectrum from rolandic epilepsy (also benign epilepsy with centrotemporal spikes, BECTS) to atypical benign partial epilepsy (ABPE), Landau-Kleffner syndrome (LKS) and epileptic encephalopathy with continuous spike and waves during slow-wave sleep (CSWS). The genetic basis is largely unknown. We detected new heterozygous mutations in GRIN2A in 27 of 359 affected individuals from 2 independent cohorts with IFE (7.5%; P = 4.83 × 10(-18), Fisher's exact test). Mutations occurred significantly more frequently in the more severe phenotypes, with mutation detection rates ranging from 12/245 (4.9%) in individuals with BECTS to 9/51 (17.6%) in individuals with CSWS (P = 0.009, Cochran-Armitage test for trend). In addition, exon-disrupting microdeletions were found in 3 of 286 individuals (1.0%; P = 0.004, Fisher's exact test). These results establish alterations of the gene encoding the NMDA receptor NR2A subunit as a major genetic risk factor for IFE.

#86 Effects of the Finnish Alzheimer Disease Exercise Trial (FINALEX) A Randomized Controlled Trial Open access logo Link logo PDF logo

Pitkälä, Kaisu; Pöysti, Minna M.; Laakkonen, Marja-Liisa; Tilvis, Reijo S.; Savikko, Niina; Kautiainen, Hannu; Strandberg, Timo E.

JAMA Internal Medicine Volume 173, Issue 10

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Few rigorous clinical trials have investigated the effectiveness of exercise on the physical functioning of patients with Alzheimer disease (AD).

#87 Risk of childhood undernutrition related to small-for-gestational age and preterm birth in low- and middle-income countries Open access logo

Christian Parul; Lee Sun Eun; Donahue Angel Moira; Adair Linda S; Arifeen Shams E; Ashorn Per; Barros Fernando C; Fall Caroline HD; Fawzi Wafaie W; Hao Wei; Hu Gang; Humphrey Jean H; Huybregts Lieven; Joglekar Charu V; Kariuki Simon K; Kolsteren Patrick;

International Journal of Epidemiology Volume 42, Issue 5, Pages 1340–1355

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Low- and middle-income countries continue to experience a large burden of stunting; 148 million children were estimated to be stunted, around 30-40% of all children in 2011. In many of these countries, foetal growth restriction (FGR) is common, as is subsequent growth faltering in the first 2 years. Although there is agreement that stunting involves both prenatal and postnatal growth failure, the extent to which FGR contributes to stunting and other indicators of nutritional status is uncertain.

#88 'Treatment of the Sportsman's groin': British Hernia Society's 2014 position statement based on the Manchester Consensus Conference Open access logo Link logo PDF logo

Sheen AJ, Stephenson BM, Lloyd DM, Robinson P, Fevre D, Paajanen H, de Beaux A, Kingsnorth A, Gilmore OJ, Bennett D, Maclennan I, O'Dwyer P, Sanders D, Kurzer M

British Journal of Sports Medicine Volume 48, Issue 14, Pages bjsports-2013-092872–1087

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The aim was to produce a multidisciplinary consensus to determine the current position on the nomenclature, definition, diagnosis, imaging modalities and management of Sportsman's groin (SG).

#89 Antagonistic crosstalk between NF-kappaB and SIRT1 in the regulation of inflammation and metabolic disorders Open access logo Link logo

Kauppinen A, Suuronen T, Ojala J, Kaarniranta K, Salminen A

Cellular Signalling Volume 25, Issue 10

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Recent studies have indicated that the regulation of innate immunity and energy metabolism are connected together through an antagonistic crosstalk between NF-κB and SIRT1 signaling pathways. NF-κB signaling has a major role in innate immunity defense while SIRT1 regulates the oxidative respiration and cellular survival. However, NF-κB signaling can stimulate glycolytic energy flux during acute inflammation, whereas SIRT1 activation inhibits NF-κB signaling and enhances oxidative metabolism and the resolution of inflammation. SIRT1 inhibits NF-κB signaling directly by deacetylating the p65 subunit of NF-κB complex. SIRT1 stimulates oxidative energy production via the activation of AMPK, PPARα and PGC-1α and simultaneously, these factors inhibit NF-κB signaling and suppress inflammation. On the other hand, NF-κB signaling down-regulates SIRT1 activity through the expression of miR-34a, IFNγ, and reactive oxygen species. The inhibition of SIRT1 disrupts oxidative energy metabolism and stimulates the NF-κB-induced inflammatory responses present in many chronic metabolic and age-related diseases. We will examine the molecular mechanisms of the antagonistic signaling between NF-κB and SIRT1 and describe how this crosstalk controls inflammatory process and energy metabolism. In addition, we will discuss how disturbances in this signaling crosstalk induce the appearance of chronic inflammation in metabolic diseases.

#90 Epilepsy biomarkers Open access logo

Engel J Jr, Pitkänen A, Loeb JA, Dudek FE, Bertram EH 3rd, Cole AJ, Moshé SL, Wiebe S, Jensen FE, Mody I, Nehlig A, Vezzani A

Epilepsia (Series 4)

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A biomarker is defined as an objectively measured characteristic of a normal or pathologic biologic process. Identification and proper validation of biomarkers of epileptogenesis (the development of epilepsy) and ictogenesis (the propensity to generate spontaneous seizures) might predict the development of an epilepsy condition; identify the presence and severity of tissue capable of generating spontaneous seizures; measure progression after the condition is established; and determine pharmacoresistance. Such biomarkers could be used to create animal models for more cost-effective screening of potential antiepileptogenic and antiseizure drugs and devices, and to reduce the cost of clinical trials by enriching the trial population, and acting as surrogate markers to shorten trial duration. The objectives of the biomarker subgroup for the London Workshop were to define approaches for identifying possible biomarkers for these purposes. Research to identify reliable biomarkers may also reveal underlying mechanisms that could serve as therapeutic targets for the development of new antiepileptogenic and antiseizure compounds.

#91 Functional Variants at the 11q13 Risk Locus for Breast Cancer Regulate Cyclin D1 Expression through Long-Range Enhancers Open access logo Link logo PDF logo

French, Juliet D.; Ghoussaini, Maya; Edwards, Stacey L.; Meyer, Kerstin B.; Michailidou, Kyriaki; Ahmed, Shahana; Khan, Sofia; Maranian, Mel J.; O'Reilly, Martin; Hillman, Kristine M.; Betts, Joshua A.; Carro, Thomas; Bailey, Peter J.; Dicks, Ed; Beesley,

American Journal of Human Genetics Volume 92, Issue 4, Pages 489–503

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Analysis of 4,405 variants in 89,050 European subjects from 41 case-control studies identified three independent association signals for estrogen-receptor-positive tumors at 11q13. The strongest signal maps to a transcriptional enhancer element in which the G allele of the best candidate causative variant rs554219 increases risk of breast cancer, reduces both binding of ELK4 transcription factor and luciferase activity in reporter assays, and may be associated with low cyclin D1 protein levels in tumors. Another candidate variant, rs78540526, lies in the same enhancer element. Risk association signal 2, rs75915166, creates a GATA3 binding site within a silencer element. Chromatin conformation studies demonstrate that these enhancer and silencer elements interact with each other and with their likely target gene, CCND1.

#92 Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial Open access logo PDF logo

Cefalu WT, Leiter LA, Yoon KH, Arias P, Niskanen L, Xie J, Balis DA, Canovatchel W, Meininger G

The Lancet Volume 382, Issue 9896

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Sodium-glucose cotransporter 2 (SGLT2) inhibitors improve glycaemia in patients with type 2 diabetes by enhancing urinary glucose excretion. We compared the efficacy and safety of canagliflozin, an SGLT2 inhibitor, with glimepiride in patients with type 2 diabetes inadequately controlled with metformin.

#93 Neuromuscular adaptations during combined strength and endurance training in endurance runners: maximal versus explosive strength training or a mix of both Open access logo Link logo

Taipale, Ritva;Mikkola, Jussi;Vesterinen, Ville;Nummela, Ari;Häkkinen, Keijo

European Journal of Applied Physiology and Occupational Physiology Volume 113, Issue 2, Pages 325–335

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This study compared the effects of mixed maximal strength and explosive strength training with maximal strength training and explosive strength training combined with endurance training over an 8-week training intervention. Male subjects (age 21-45 years) were divided into three strength training groups, maximal (MAX, n = 11), explosive (EXP, 10) and mixed maximal and explosive (MIX, 9), and a circuit training control group, (CON, 7). Strength training one to two times a week was performed concurrently with endurance training three to four times a week. Significant increases in maximal dynamic strength (1RM), countermovement jump (CMJ), maximal muscle activation during 1RM in MAX and during CMJ in EXP, peak running speed (S (peak)) and running speed at respiratory compensation threshold (RCT(speed)) were observed in MAX, EXP and MIX. Maximal isometric strength and muscle activation, rate of force development (RFD), maximal oxygen uptake [Formula: see text] and running economy (RE) at 10 and 12 km hr(-1) did not change significantly. No significant changes were observed in CON in maximal isometric strength, RFD, CMJ or muscle activation, and a significant decrease in 1RM was observed in the final 4 weeks of training. RE in CON did not change significantly, but significant increases were observed in S (peak), RCT(speed) and [Formula: see text] Low volume MAX, EXP and MIX strength training combined with higher volume endurance training over an 8-week intervention produced significant gains in strength, power and endurance performance measures of S (peak) and RCT(speed), but no significant changes were observed between groups.

#94 Fine-Mapping the Genetic Association of the Major Histocompatibility Complex in Multiple Sclerosis:HLA and Non-HLA Effects Open access logo Link logo

Patsopoulos, Nikolaos A.; Barcellos, Lisa F.; Hintzen, Rogier Q.; Schaefer, Catherine; Van Duijn, Cornelia M.; Noble, Janelle A.; Raj, Towfique; Gourraud, Pierre-Antoine; Stranger, Barbara E.; Oksenberg, Jorge; Olsson, Tomas; Taylor, Bruce V.; Sawcer, Ste

PLoS Genetics Volume 9, Issue 11

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The major histocompatibility complex (MHC) region is strongly associated with multiple sclerosis (MS) susceptibility. HLA-DRB1*15:01 has the strongest effect, and several other alleles have been reported at different levels of validation. Using SNP data from genome-wide studies, we imputed and tested classical alleles and amino acid polymorphisms in 8 classical human leukocyte antigen (HLA) genes in 5,091 cases and 9,595 controls. We identified 11 statistically independent effects overall: 6 HLA-DRB1 and one DPB1 alleles in class II, one HLA-A and two B alleles in class I, and one signal in a region spanning from MICB to LST1. This genomic segment does not contain any HLA class I or II genes and provides robust evidence for the involvement of a non-HLA risk allele within the MHC. Interestingly, this region contains the TNF gene, the cognate ligand of the well-validated TNFRSF1A MS susceptibility gene. The classical HLA effects can be explained to some extent by polymorphic amino acid positions in the peptide-binding grooves. This study dissects the independent effects in the MHC, a critical region for MS susceptibility that harbors multiple risk alleles.

#95 Angiopoietin signaling in the vasculature Open access logo Link logo

Eklund, Lauri; Saharinen, Pipsa

Experimental Cell Research

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The angiopoietin (Ang) growth factors and the endothelial Tie receptors regulate blood and lymphatic vessel development, and vascular permeability, inflammation, angiogenic remodeling and tumor vascularization in adult tissues. The angiopoietins activate the Tie receptors in unique in trans complexes at endothelial cell-cell and cell-matrix contacts. In addition, integrins have been implicated in the regulation of Ang-Tie signaling. Recent interest has focused on the function of angiopoietin-2 and its inhibition in the tumor vasculature and also in other pathological conditions associated with endothelial dysfunction. Here we review the current understanding of the signaling functions of the Ang-Tie pathway and its potential for future development of targeted vascular therapeutics.

#96 Longitudinal, genome-scale analysis of DNA methylation in twins from birth to 18 months of age reveals rapid epigenetic change in early life and pair-specific effects of discordance Open access logo Link logo PDF logo

Martino, David; Loke, Yuk Jin; Gordon, Lavinia; Ollikainen, Miina; Cruickshank, Mark N.; Saffery, Richard; Craig, Jeffrey M.

Genome Biology (Online Edition) Volume 14, Issue 5

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The extent to which development- and age-associated epigenetic changes are influenced by genetic, environmental and stochastic factors remains to be discovered. Twins provide an ideal model with which to investigate these influences but previous cross-sectional twin studies provide contradictory evidence of within-pair epigenetic drift over time. Longitudinal twin studies can potentially address this discrepancy.

#97 Target Inhibition Networks: Predicting Selective Combinations of Druggable Targets to Block Cancer Survival Pathways Open access logo Link logo PDF logo

Tang, Jing; Karhinen, Leena; Xu, Tao; Szwajda, Agnieszka; Yadav, Bhagwan; Wennerberg, Krister; Aittokallio, Tero

PLoS Computational Biology Volume 9, Issue 9

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A recent trend in drug development is to identify drug combinations or multi-target agents that effectively modify multiple nodes of disease-associated networks. Such polypharmacological effects may reduce the risk of emerging drug resistance by means of attacking the disease networks through synergistic and synthetic lethal interactions. However, due to the exponentially increasing number of potential drug and target combinations, systematic approaches are needed for prioritizing the most potent multi-target alternatives on a global network level. We took a functional systems pharmacology approach toward the identification of selective target combinations for specific cancer cells by combining large-scale screening data on drug treatment efficacies and drug-target binding affinities. Our model-based prediction approach, named TIMMA, takes advantage of the polypharmacological effects of drugs and infers combinatorial drug efficacies through system-level target inhibition networks. Case studies in MCF-7 and MDA-MB-231 breast cancer and BxPC-3 pancreatic cancer cells demonstrated how the target inhibition modeling allows systematic exploration of functional interactions between drugs and their targets to maximally inhibit multiple survival pathways in a given cancer type. The TIMMA prediction results were experimentally validated by means of systematic siRNA-mediated silencing of the selected targets and their pairwise combinations, showing increased ability to identify not only such druggable kinase targets that are essential for cancer survival either individually or in combination, but also synergistic interactions indicative of non-additive drug efficacies. These system-level analyses were enabled by a novel model construction method utilizing maximization and minimization rules, as well as a model selection algorithm based on sequential forward floating search. Compared with an existing computational solution, TIMMA showed both enhanced prediction accuracies in cross validation as well as significant reduction in computation times. Such cost-effective computational-experimental design strategies have the potential to greatly speed-up the drug testing efforts by prioritizing those interventions and interactions warranting further study in individual cancer cases.

#98 Designing appropriate complementary feeding recommendations : tools for programmatic action Open access logo PDF logo

Daelmans Bernadette; Ferguson Elaine; Lutter Chessa K; Singh Neha; Pachón Helena; Creed-Kanashiro Hilary; Woldt Monica; Mangasaryan Nuné; Cheung Edith; Mir Roger; Pareja Rossina; Briend André

Maternal & Child Nutrition Volume 9, Issue S2, Pages 116–130

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Suboptimal complementary feeding practices contribute to a rapid increase in the prevalence of stunting in young children from age 6 months. The design of effective programmes to improve infant and young child feeding requires a sound understanding of the local situation and a systematic process for prioritizing interventions, integrating them into existing delivery platforms and monitoring their implementation and impact. The identification of adequate food-based feeding recommendations that respect locally available foods and address gaps in nutrient availability is particularly challenging. We describe two tools that are now available to strengthen infant and young child-feeding programming at national and subnational levels. ProPAN is a set of research tools that guide users through a step-by-step process for identifying problems related to young child nutrition; defining the context in which these problems occur; formulating, testing, and selecting behaviour-change recommendations and nutritional recipes; developing the interventions to promote them; and designing a monitoring and evaluation system to measure progress towards intervention goals. Optifood is a computer-based platform based on linear programming analysis to develop nutrient-adequate feeding recommendations at lowest cost, based on locally available foods with the addition of fortified products or supplements when needed, or best recommendations when the latter are not available. The tools complement each other and a case study from Peru illustrates how they have been used. The readiness of both instruments will enable partners to invest in capacity development for their use in countries and strengthen programmes to address infant and young child feeding and prevent malnutrition.

#99 Improved lifestyle and decreased diabetes risk over 13 years: long-term follow-up of the randomised Finnish Diabetes Prevention Study (DPS) Open access logo Link logo PDF logo

Lindstrom, J.; Peltonen, M.; Eriksson, J. G.; Ilanne-Parikka, P.; Aunola, S.; Keinanen-Kiukaanniemi, S.; Uusitupa, M.; Tuomilehto, J.; ,

Diabetologia Volume 56, Issue 2, Pages 284–293

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This study aimed to determine whether lifestyle intervention lasting for 4 years affected diabetes incidence, body weight, glycaemia or lifestyle over 13 years among individuals at high risk of type 2 diabetes.

#100 Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk Open access logo Link logo PDF logo

Couch, Fergus J.; Wang, Xianshu; McGuffog, Lesley; Lee, Andrew; Olswold, Curtis; Kuchenbaecker, Karoline B.; Soucy, Penny; Fredericksen, Zachary; Barrowdale, Daniel; Dennis, Joe; Gaudet, Mia M.; Dicks, Ed; Kosel, Matthew; Healey, Sue; Sinilnikova, Olga M.

PLoS Genetics Volume 9, Issue 3

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BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 × 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 × 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 × 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.

#101 A Kinematic Analysis of Three Best 100 m Performances Ever Open access logo Link logo PDF logo

Mackala, Krzysztof;Mero, Antti

Journal of Human Kinetics Volume 36, Issue 1

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The purpose of this investigation was to compare and determine the relevance of the morphological characteristics and variability of running speed parameters (stride length and stride frequency) between Usain Bolt's three best 100 m performances. Based on this, an attempt was made to define which factors determine the performance of Usain Bolt's sprint and, therefore, distinguish him from other sprinters. We analyzed the previous world record of 9.69 s set in the 2008 Beijing Olympics, the current record of 9.58 s set in the 2009 Berlin World Championships in Athletics and the O lympic record of 9.63 s set in 2012 London Olympics Games by Usain Bolt. The application of VirtualDub Programme allowed the acquisition of basic kinematical variables such as step length and step frequency parameters of 100 m sprint from video footage provided by NBC TV station, BBC TV station. This data was compared with other data available on the web and data published by the Scientific Research Project Office responsible on behalf of IAAF and the German Athletics Association (DVL). The main hypothesis was that the step length is the main factor that determines running speed in the 10 and 20 m sections of the entire 100 m distance. Bolt's anthropometric advantage (body height, leg length and liner body) is not questionable and it is one of the factors that makes him faster than the rest of the finalists from each three competitions. Additionally, Bolt's 20 cm longer stride shows benefit in the latter part of the race. Despite these factors, he is probably able to strike the ground more forcefully than rest of sprinters, relative to their body mass, therefore, he might maximize his time on the ground and to exert the same force over this period of time. This ability, combined with longer stride allows him to create very high running speed - over 12 m/s (12.05 - 12.34 m/s) in some 10 m sections of his three 100 m performances. These assumption confirmed the application of Ballerieich's formula for speed development. In most 10 m sections of the 100 m sprint, the step length was the parameter that significantly determined the increase of maximal running speed, therefore, distinguishing Bolt from the other finalists.

#102 Cardiac Imaging and Stress Testing Asymptomatic Athletes to Identify Those at Risk of Sudden Cardiac Death Open access logo PDF logo

La Gerche A, Baggish AL, Knuuti J, Prior DL, Sharma S, Heidbuchel H, Thompson PD

JACC Cardiovascular Imaging Volume 6, Issue 9, Pages 993–1007

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Sudden cardiac death in young athletes is rare but tragic. The cardiology community is faced with the challenge of providing a sensible strategy for the prevention of SCD while simultaneously reaffirming that the benefits of regular exercise far outweigh potential risks. At present, there is a broad range of screening recommendations dependent upon country, sporting discipline, and competition level. While much recent debate has focused on the efficacy of screening with electrocardiography, a number of sporting bodies also mandate the inclusion of exercise testing and echocardiography in screening protocols. Cardiac magnetic resonance imaging, coronary calcium scoring and computed tomography coronary angiography have also been promoted as potentially valuable screening tools for competitive athletes. This review will examine the controversial topic of utilizing cardiac imaging for athlete pre-participation screening. Specifically, the limitations of screening for relatively rare disorders using imaging tools with uncertain or imperfect accuracy will be addressed. Current evidence suggests that the accuracy of all cardiac imaging modalities is insufficient to justify their use as primary screening modalities in athletes. Atypical findings such as marked cardiac dilation, reduced deformation, or small patches of delayed gadolinium enhancement may be commonly encountered in well-trained athletes, but, at present, the prognostic significance of such findings is unknown. Resulting uncertainty for the clinician and athlete has the potential for psychological stress, further testing, and unnecessary exclusions from competition. However, these concerns must not be confused with the extremely useful applications of cardiac imaging for the assessment of athletes with symptoms, an abnormal electrocardiogram or a positive family history. As modern imaging further enhances our understanding of the spectrum of athlete's heart, its role may expand from the assessment of athletes with suspected disease to being part of comprehensive pre-participation screening in apparently healthy athletes.

#103 GENOMICS A gut prediction Open access logo

de Vos, Willem M.; Nieuwdorp, Max


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#104 Bologna guidelines for diagnosis and management of adhesive small bowel obstruction (ASBO): 2013 update of the evidence-based guidelines from the world society of emergency surgery ASBO working group Open access logo Link logo PDF logo

Di Saverio, Salomone; Coccolini, Federico; Galati, Marica; Smerieri, Nazareno; Biffl, Walter L.; Ansaloni, Luca; Tugnoli, Gregorio; Velmahos, George C.; Sartelli, Massimo; Bendinelli, Cino; Fraga, Gustavo Pereira; Kelly, Michael D.; Moore, Frederick A.; M

World Journal of Emergency Surgery Volume 8, Issue 1

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In 2013 Guidelines on diagnosis and management of ASBO have been revised and updated by the WSES Working Group on ASBO to develop current evidence-based algorithms and focus indications and safety of conservative treatment, timing of surgery and indications for laparoscopy.

#105 Optimizing dentin bond durability: Control of collagen degradation by matrix metalloproteinases and cysteine cathepsins Open access logo Link logo

Tjäderhane, Leo; Nascimento, Fabio D.; Breschi, Lorenzo; Mazzoni, Annalisa; Tersariol, Ivarne L.S.; Geraldeli, Saulo; Tezvergil-Mutluay, Arzu; Carrilho, Marcela R.; Carvalho, Ricardo M.; Tay, Franklin R.; Pashley, David H.

Dental Materials Volume 29, Issue 1, Pages 116–135

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#106 The mutational landscape of prostate cancer Open access logo

Barbieri Christopher E; Bangma Chris H; Bjartell Anders; Catto James W; Culig Zoran; Grönberg Henrik; Luo Jun; Visakorpi Tapio; Rubin MarkA

European Urology Volume 64, Issue 4, Pages 567–576

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#107 Neuronal Network Plasticity and Recovery From Depression Open access logo Link logo PDF logo

Castren, Eero

JAMA Psychiatry Volume 70, Issue 9

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The brain processes sensory information in neuronal networks that are shaped by experience, particularly during early life, to optimally represent the internal and external milieu. Recent surprising findings have revealed that antidepressant drugs reactivate a window of juvenile-like plasticity in the adult cortex. When antidepressant-induced plasticity was combined with appropriate rehabilitation, it brought about a functional recovery of abnormally wired neuronal networks. These observations suggest that antidepressants act permissively to facilitate environmental influence on neuronal network reorganization and so provide a plausible neurobiological explanation for the enhanced effect of combining antidepressant treatment with psychotherapy. The results emphasize that pharmacological and psychological treatments of mood disorders are closely entwined: the effect of antidepressant-induced plasticity is facilitated by rehabilitation, such as psychotherapy, that guides the plastic networks, and psychotherapy benefits from the enhanced plasticity provided by the drug treatment. Optimized combinations of pharmacological and psychological treatments might help make best use of existing antidepressant drugs and reduce the number of treatment-resistant patients. The network hypothesis of antidepressant action presented here proposes that recovery from depression and related mood disorders is a gradual process that develops slowly and is facilitated by structured guidance and rehabilitation.

#108 Modulation of neuronal activity by phosphorylation of the K-CI cotransporter KCC2 Open access logo Link logo

Kahle, Kristopher T.; Deeb, Tarek Z.; Puskarjov, Martin; Silayeva, Liliya; Liang, Bo; Kaila, Kai; Moss, Stephen J.

Trends in Neurosciences

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The K-Cl cotransporter KCC2 establishes the low intraneuronal Cl- levels required for the hyperpolarizing inhibitory postsynaptic potentials mediated by ionotropic γ-aminobutyric acid receptors (GABAARs) and glycine receptors (GlyRs). Decreased KCC2-mediated Cl- extrusion and impaired hyperpolarizing GABAAR- and/or GlyR-mediated currents have been implicated in epilepsy, neuropathic pain, and spasticity. Recent evidence suggests that the intrinsic ion transport rate, cell surface stability, and plasmalemmal trafficking of KCC2 are rapidly and reversibly modulated by the (de)phosphorylation of critical serine, threonine, and tyrosine residues in the C terminus of this protein. Alterations in KCC2 phosphorylation have been associated with impaired KCC2 function in several neurological diseases. Targeting KCC2 phosphorylation directly or indirectly via upstream regulatory kinases might be a novel strategy to modulate GABA- and/or glycinergic signaling for therapeutic benefit.

#109 Gene × Physical Activity Interactions in Obesity: Combined Analysis of 111,421 Individuals of European Ancestry Open access logo PDF logo

Ahmad S, Rukh G, Varga TV, Ali A, Kurbasic A, Shungin D, Ericson U, Koivula RW, Chu AY, Rose LM, Ganna A, Qi Q, Stan?áková A, Sandholt CH, Elks CE, Curhan G, Jensen MK, Tamimi RM, Allin KH, Jørgensen T et al. (including Laakso M)

PLoS Genetics Volume 9, Issue 7

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Numerous obesity loci have been identified using genome-wide association studies. A UK study indicated that physical activity may attenuate the cumulative effect of 12 of these loci, but replication studies are lacking. Therefore, we tested whether the aggregate effect of these loci is diminished in adults of European ancestry reporting high levels of physical activity. Twelve obesity-susceptibility loci were genotyped or imputed in 111,421 participants. A genetic risk score (GRS) was calculated by summing the BMI-associated alleles of each genetic variant. Physical activity was assessed using self-administered questionnaires. Multiplicative interactions between the GRS and physical activity on BMI were tested in linear and logistic regression models in each cohort, with adjustment for age, age(2), sex, study center (for multicenter studies), and the marginal terms for physical activity and the GRS. These results were combined using meta-analysis weighted by cohort sample size. The meta-analysis yielded a statistically significant GRS × physical activity interaction effect estimate (Pinteraction  = 0.015). However, a statistically significant interaction effect was only apparent in North American cohorts (n = 39,810, Pinteraction  = 0.014 vs. n = 71,611, Pinteraction  = 0.275 for Europeans). In secondary analyses, both the FTO rs1121980 (Pinteraction  = 0.003) and the SEC16B rs10913469 (Pinteraction  = 0.025) variants showed evidence of SNP × physical activity interactions. This meta-analysis of 111,421 individuals provides further support for an interaction between physical activity and a GRS in obesity disposition, although these findings hinge on the inclusion of cohorts from North America, indicating that these results are either population-specific or non-causal.

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