bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeting oncogenic serine/threonine-protein kinase BRAF in cancer cells inhibits angiogenesis and abrogates hypoxia
Authors: Bottos Alessia , Martini Miriam , Di Nicolantonio Federica , Comunanza Valentina , Maione Federica , Minassi Alberto , Appendino Giovanni , Bussolino Federico , Bardelli Alberto
Published: December 2011

Carcinomas are comprised of transformed epithelial cells that are supported in their growth by a dedicated neovasculature. How the genetic milieu of the epithelial compartment influences tumor angiogenesis is largely unexplored. Drugs targeted to mutant cancer genes may act not only on tumor cells but also, directly or indirectly, on the surrounding stroma. We investigated the role of the BRAF
V600E
oncogene in tumor/vessel crosstalk and analyzed the effect of the BRAF inhibitor PLX4720 on tumor angiogenesis. Knock-in of the BRAF
V600E
allele into the genome of human epithelial cells triggered their angiogenic response. In cancer cells harboring oncogenic BRAF, the inhibitor PLX4720 switches off the ERK pathway and inhibits the expression of proangiogenic molecules. In tumor xenografts harboring the BRAF
V600E
, PLX4720 extensively modifies the vascular network causing abrogation of hypoxia. Overall, our results provide a functional link between oncogenic BRAF and angiogenesis. Furthermore, they indicate how the tumor vasculature can be “indirectly” besieged through targeting of a genetic lesion to which the cancer cells are addicted.
High-resolution dose–response screening using droplet-based microfluidics
Authors: Miller Oliver J. , Harrak Abdeslam El , Mangeat Thomas , Baret Jean-Christophe , Frenz Lucas , Debs Bachir El , Mayot Estelle , Samuels Michael L. , Rooney Eamonn K. , Dieu Pierre , Galvan Martin , Link Darren R. , Griffiths Andrew D.
Published: December 2011

A critical early step in drug discovery is the screening of a chemical library. Typically, promising compounds are identified in a primary screen and then more fully characterized in a dose–response analysis with 7–10 data points per compound. Here, we describe a robust microfluidic approach that increases the number of data points to approximately 10,000 per compound. The system exploits Taylor–Aris dispersion to create concentration gradients, which are then segmented into picoliter microreactors by droplet-based microfluidics. The large number of data points results in IC50values that are highly precise (± 2.40% at 95% confidence) and highly reproducible (CV = 2.45%,n = 16). In addition, the high resolution of the data reveals complex dose–response relationships unambiguously. We used this system to screen a chemical library of 704 compounds against protein tyrosine phosphatase 1B, a diabetes, obesity, and cancer target. We identified a number of novel inhibitors, the most potent being sodium cefsulodine, which has an IC50of 27 ± 0.83 μM.
Alpha-1-antitrypsin monotherapy reduces graft-versus-host disease after experimental allogeneic bone marrow transplantation
Authors: Tawara Isao , Sun Yaping , Lewis Eli C. , Toubai Tomomi , Evers Rebecca , Nieves Evelyn , Azam Tania , Dinarello Charles A. , Reddy Pavan
Published: December 2011

Acute graft-versus-host disease (GvHD) is a major complication that prevents successful outcomes after allogeneic bone marrow transplantation (BMT), an effective therapy for hematological malignancies. Several studies demonstrate that donor T cells and host antigen-presenting cells along with several proinflammatory cytokines are required for the induction of GvHD and contribute to its severity. Increasing evidence demonstrates that human serum-derived αalpha-1- anti-trypsin (AAT) reduces production of proinflammatory cytokines, induces anti-inflammatory cytokines, and interferes with maturation of dendritic cells. Using well-characterized mouse models of BMT, we have studied the effects of AAT on GvHD severity. Administration of AAT early after BMT decreased mortality in three models of GvHD and reduced serum levels of proinflammatory cytokines in the allogeneic recipients compared with vehicle (albumin) treated animals. AAT treatment reduced the expansion of alloreactive T effector cells but enhanced the recovery of T regulatory T cells, (Tregs) thus altering the ratio of donor T effector to T regulatory cells in favor of reducing the pathological process. However, despite altering the ratio in vivo, AAT had no direct effects on either the donor T effector cells or T regulatory cells Tregs in vitro. In contrast, AAT suppressed LPS-induced in vitro secretion of proinflammatory cytokines such as TNF-α and IL-1β, enhanced the production of the anti-inflammatory cytokine IL-10, and impaired NF-κB translocation in the host dendritic cells. In light of its long history of safety in humans, these findings suggest that administration of AAT represents a novel unique and viable strategy to mitigate clinical GvHD.
Thrombocytopenia and erythrocytosis in mice with a mutation in the gene encoding the hemoglobin β minor chain
Authors: Kauppi Maria , Hilton Adrienne A. , Metcalf Donald , Ng Ashley P. , Hyland Craig D. , Collinge Janelle E. , Kile Benjamin T. , Hilton Douglas J. , Alexander Warren S.
Published: December 2011

Diverse mutations in the genes encoding hemoglobin (Hb) have been characterized in human disease. We describe here a mutation in the mouseHbb-b2gene, denotedPlt12, that precisely mimics the human hemoglobin Hotel Dieu variant. The mutation results in increased affinity of Hb for oxygen andPlt12mutant mice exhibited reduced partial pressure of O2in the blood, accompanied by erythrocytosis characterized by elevated erythropoietin levels and splenomegaly with excess erythropoiesis. Most homozygousHbb-b2Plt12/Plt12mice succumbed to early lethality associated with emphysema, cardiac abnormalities, and liver degeneration. Survivors displayed a marked thrombocytopenia without significant deficiencies in the numbers of megakaryocytes or megakaryocyte progenitor cells. The lifespan of platelets in the circulation ofHbb-b2Plt12/Plt12mice was normal, and splenectomy did not correct the thrombocytopenia, suggesting that increased sequestration was unlikely to be a major contributor. These data, together with the observation that megakaryocytes inHbb-b2Plt12/Plt12mice appeared smaller and deficient in cytoplasm, support a model in which hypoxia causes thrombocytopenia as a consequence of an inability of megakaryocytes, once formed, to properly mature and produce sufficient platelets. ThePlt12mouse is a model of high O2-affinity hemoglobinopathy and provides insights into hematopoiesis under conditions of chronic hypoxia.
Secreted Wingless-interacting molecule (Swim) promotes long-range signaling by maintaining Wingless solubility
Authors: Mulligan Kimberly A. , Fuerer Christophe , Ching Wendy , Fish Matt , Willert Karl , Nusse Roeland
Published: December 2011

Lipid-modified Wnt/Wingless (Wg) proteins can signal to their target cells in a short- or long-range manner. How these hydrophobic proteins travel through the extracellular environment remains an outstanding question. Here, we report on a Wg binding protein, Secreted Wg-interacting molecule (Swim), that facilitates Wg diffusion through the extracellular matrix. Swim, a putative member of the Lipocalin family of extracellular transport proteins, binds to Wg with nanomolar affinity in a lipid-dependent manner. In quantitative signaling assays, Swim is sufficient to maintain the solubility and activity of purified Wg. In
Drosophila
,
swim
RNAi phenotypes resemble
wg
loss-of-function phenotypes in long-range signaling. We propose that Swim is a cofactor that promotes long-range Wg signaling in vivo by maintaining the solubility of Wg.
TANK-binding kinase 1 (TBK1) controls cell survival through PAI-2/serpinB2 and transglutaminase 2
Authors: Delhase Mireille , Kim Soo-Youl , Lee Ho , Naiki-Ito Aya , Chen Yi , Ahn Eu-Ree , Murata Kazuhiro , Kim Se-Jin , Lautsch Norman , Kobayashi Koichi S. , Shirai Tomoyuki , Karin Michael , Nakanishi Makoto
Published: December 2011

The decision between survival and death in cells exposed to TNF relies on a highly regulated equilibrium between proapoptotic and antiapoptotic factors. The TNF-activated antiapoptotic response depends on several transcription factors, including NF-κB and its RelA/p65 subunit, that are activated through phosphorylation-mediated degradation of IκB inhibitors, a process controlled by the IκB kinase complex. Genetic studies in mice have identified the IκB kinase-related kinase TANK-binding kinase 1 (TBK1; also called NAK or T2K) as an additional regulatory molecule that promotes survival downstream of TNF, but the mechanism through which TBK1 exerts its survival function has remained elusive. Here we show that TBK1 triggers an antiapoptotic response by controlling a specific RelA/p65 phosphorylation event. TBK1-induced RelA phosphorylation results in inducible expression of plasminogen activator inhibitor-2 (PAI-2), a member of the serpin family with known antiapoptotic activity. PAI-2 limits caspase-3 activation through stabilization of transglutaminase 2 (TG2), which cross-links and inactivates procaspase-3. Importantly,
Tg2
−/−
mice were found to be more susceptible to apoptotic cell death in two models of TNF-dependent acute liver injury. Our results establish PAI-2 and TG2 as downstream mediators in the antiapoptotic response triggered upon TBK1 activation.
Identification of PlantRAD52Homologs and Characterization of theArabidopsis thaliana RAD52-Like Genes
Authors: Samach Aviva , Melamed-Bessudo Cathy , Avivi-Ragolski Naomi , Pietrokovski Shmuel , Levy Avraham A.
Published: December 2011

RADiation sensitive52 (RAD52) mediates RAD51 loading onto single-stranded DNA ends, thereby initiating homologous recombination and catalyzing DNA annealing. RAD52 is highly conserved among eukaryotes, including animals and fungi. This article reports that RAD52 homologs are present in all plants whose genomes have undergone extensive sequencing. Computational analyses suggest a very early RAD52 gene duplication, followed by later lineage-specific duplications, during the evolution of higher plants. Plant RAD52 proteins have high sequence similarity to the oligomerization and DNA binding N-terminal domain of RAD52 proteins. Remarkably, the two identified Arabidopsis thaliana  RAD52 genes encode four open reading frames (ORFs) through differential splicing, each of which specifically localized to the nucleus, mitochondria, or chloroplast. The A. thaliana RAD52-1A ORF provided partial complementation to the yeast rad52 mutant. A. thaliana mutants and RNA interference lines defective in the expression of RAD52-1 or RAD52-2 showed reduced fertility, sensitivity to mitomycin C, and decreased levels of intrachromosomal recombination compared with the wild type. In summary, computational and experimental analyses provide clear evidence for the presence of functional RAD52 DNA-repair homologs in plants.
Increased exhaled nitric oxide predicts new‐onset rhinitis and persistent rhinitis in adolescents without allergic symptoms
Authors: Malinovschi A. , Alving K. , Kalm‐Stephens P. , Janson C. , Nordvall L.
Published: December 2011

Background

The fraction of nitric oxide in exhaled air (FENO) is increased in rhinitis and asthma. We have previously suggested that elevated FENO levels in the absence of asthma symptoms may be a sign of ‘early asthma’. In the present study, we hypothesize that elevated exhaled NO levels may also precede rhinitis symptoms.

Objective

To investigate in a cohort of adolescents whether or not increased exhaled NO levels at the age of 13–14 years predicted new‐onset or persistent rhinitis within a 4‐year period.

Methods

A total of 959 randomly selected adolescents (13–14 years) completed a questionnaire on respiratory symptoms at baseline and follow‐up, 4 years later. Exhaled NO was measured at baseline. After exclusion of subjects with asthma diagnosis or asthma symptoms at baseline, 657 participants were eligible for the present study.

Results

Higher FENO levels at baseline were associated with increased risk for new‐onset (P = 0.009) and persistent rhinitis (P = 0.03) within a 4‐year period. The risk of new‐onset rhinitis was 2.32 (1.23, 4.37) [OR (95% CI)] times higher if FENO > 90th percentile of the group without rhinitis at baseline. This increased risk for new‐onset rhinitis was significant [2.49 (1.24, 5.01)] after excluding subjects with allergic symptoms. The risk of persistent rhinitis was 5.11 (1.34, 19.57) times higher if FENO > 90th percentile of the group without rhinitis at baseline.

Conclusion

Elevated exhaled nitric oxide levels predicted incident and persistent rhinitis in this population‐based study of adolescents. Moreover, these findings were consistent after excluding subjects with allergic symptoms. Thus, it appears that elevation of exhaled NO precedes airway symptoms and predicts development of rhinitis in subjects without allergic symptoms or family history of allergic disease.
Anaphylaxis and reactions to foods in children – a population‐based case study of emergency department visits
Authors: Vetander M. , Helander D. , Flodström C. , Östblom E. , Alfvén T. , Ly D. H. , Hedlin G. , Lilja G. , Nilsson C. , Wickman M.
Published: December 2011

Background

Information about acute reactions to foods among children is limited.

Objective

To describe the overall incidence of anaphylaxis in a paediatric emergency department (ED) setting and to describe reactions to foods in relation to sex and age, clinical characteristics and management.

Methods

In a review of medical records, children with ED visits at any of three paediatric hospitals in Stockholm County during 2007 were targeted. Inclusion criteria were any adverse reaction to foods or anaphylaxis.

Results

383 children fulfilled the inclusion criteria of which 371 had had reactions to foods. The incidence of anaphylaxis was 32 per 100 000 person years irrespective of cause and food was involved in 92%. Tree nuts, particular cashew, and peanut were the most common eliciting foods, and in children under 3 years, reactions to these two food allergens were as common as reactions to milk and egg. Pollen‐allergic children seemed to be admitted due to food‐induced anaphylaxis more often during the deciduous tree pollen season compared with the rest of the year (P = 0.015). Symptoms from the lower airways occurred in 49% of children with anaphylaxis but without underlying asthma compared with 72% of children with anaphylaxis and asthma, P < 0.01.

Conclusions and Clinical Relevance

Reactions to peanut and tree nuts are as common as reactions to milk and egg in early life. Concomitant exposure to airborne allergens seems to increase the risk of anaphylaxis to foods. Among children with anaphylaxis, wheeze is prevalent even in children without asthma diagnosis.
Immunology in the clinic review series; focus on type 1 diabetes and viruses: the enterovirus link to type 1 diabetes: critical review of human studies
Authors: Stene L C , Rewers M
Published: December 2011

OTHER THEMES PUBLISHED IN THIS IMMUNOLOGY IN THE CLINIC REVIEW SERIES

Metabolic diseases, host responses, cancer, autoinflammatory diseases, allergy.

The hypothesis that under some circumstances enteroviral infections can lead to type 1 diabetes (T1D) was proposed several decades ago, based initially on evidence from animal studies and sero-epidemiology. Subsequently, enterovirus RNA has been detected more frequently in serum of patients than in control subjects, but such studies are susceptible to selection bias and reverse causality. Here, we review critically recent evidence from human studies, focusing on longitudinal studies with potential to demonstrate temporal association. Among seven longitudinal birth cohort studies, the evidence that enterovirus infections predict islet autoimmunity is quite inconsistent in our interpretation, due partially, perhaps, to heterogeneity in study design and a limited number of subjects studied. An association between enterovirus and rapid progression from autoimmunity to T1D was reported by one longitudinal study, but although consistent with evidence from animal models, this novel observation awaits replication. It is possible that a potential association with initiation and/or progression of islet autoimmunity can be ascribed to a subgroup of the many enterovirus serotypes, but this has still not been investigated properly. There is a need for larger studies with frequent sample intervals and collection of specimens of sufficient quality and quantity for detailed characterization of enterovirus. More research into the molecular epidemiology of enteroviruses and enterovirus immunity in human populations is also warranted. Ultimately, this knowledge may be used to devise strategies to reduce the risk of T1D in humans.
The association between neutrophil gelatinase‐associated lipocalin and clinical outcome in chronic heart failure: results from CORONA*
Authors: Nymo S. H. , Ueland T. , Askevold E. T. , Flo T. H. , Kjekshus J. , Hulthe J. , Wikstrand J. , McMurray J. , Van Veldhuisen D. J. , Gullestad L. , Aukrust P. , Yndestad A.
Published: December 2011

Abstract.  Nymo SH, Ueland T, Askevold ET, Flo TH, Kjekshus J, Hulthe J, Wikstrand J, McMurray J, Van Veldhuisen DJ, Gullestad L, Aukrust P, Yndestad A (Oslo University Hospital Rikshospitalet; University of Oslo; Oslo; Norwegian University of Technology and Science, Trondheim, Norway; Gothenburg University, Gothenburg; AstraZeneca, Mölndal, Sweden; University of Glasgow, UK; and University Medical Center Groningen, University of Groningen, The Netherlands). The association between neutrophil gelatinase‐associated lipocalin and clinical outcome in chronic heart failure: results from CORONA. J Intern Med 2012; 271: 436–443.

Objective.  To study the prognostic value of neutrophil gelatinase‐associated lipocalin (NGAL) in chronic heart failure (HF) of ischaemic aetiology.

Background.  Neutrophil gelatinase‐associated lipocalin is a marker of kidney injury as well as matrix degradation and inflammation and has previously been shown to be increased in HF. We investigated whether serum NGAL levels could provide prognostic information in chronic HF.

Methods.  We assessed NGAL as a predictor of primary outcomes (cardiovascular death, nonfatal stroke and nonfatal myocardial infarction, n = 307) and all‐cause mortality (n = 321), cardiovascular mortality (n = 259) and hospitalization (n = 647) as well as the number of hospitalizations during follow‐up for all (n = 1934) and CV causes (n = 1204) in 1415 patients with chronic HF (≥60 years, New York Heart Association class II–IV, ischaemic systolic HF) in the CORONA population, randomly assigned to 10 mg rosuvastatin or placebo.

Results.  Multivariate analysis revealed that NGAL added significant information when adjusting for clinical variables, but was no longer significant when further adjusting for apolipoprotein A‐1 (ApoA‐1), glomerular filtration rate (GFR), C‐reactive protein (CRP) and N‐terminal pro‐brain natriuretic peptide (NT‐proBNP). However, belonging to the highest NGAL tertile was associated with more frequent hospitalization, even after adjusting for clinical variables, GFR and ApoA‐1, but not after adjusting for CRP and NT‐proBNP. There was no interaction between rosuvastatin treatment and NGAL.

Conclusion.  Neutrophil gelatinase‐associated lipocalin added no significant information to NT‐proBNP and GFR in a multivariate model for primary and secondary end‐points.
Mutational dissection of the S/T‐kinase StkP reveals crucial roles in cell division of Streptococcus pneumoniae
Authors: Fleurie Aurore , Cluzel Caroline , Guiral Sébastien , Freton Céline , Galisson Frédéric , Zanella‐Cleon Isabelle , Di Guilmi Anne‐Marie , Grangeasse Christophe
Published: December 2011

Eukaryotic‐like serine/threonine‐kinases are involved in the regulation of a variety of physiological processes in bacteria. In Streptococcus pneumoniae, deletion of the single serine/threonine‐kinase gene stkP results in an aberrant cell morphology suggesting that StkP participates in pneumococcus cell division. To understand the function of StkP, we have engineered various pneumococcus strains expressing truncated or kinase‐dead forms of StkP. We show that StkP kinase activity, but also its extracellular and cytoplasmic domains per se, are required for pneumococcus cell division. Indeed, we observe that mutant cells show round or elongated shapes with non‐functional septa and a chain phenotype, delocalized sites of peptidoglycan synthesis and diffused membrane StkP localization. To gain understanding of the underlying StkP‐mediated regulatory mechanism, we show that StkP specifically phosphorylates in vivo the cell division protein DivIVA on threonine 201. Pneumococcus cells expressing non‐phosphorylatable DivIVA‐T201A possess an elongated shape with a polar bulge and aberrant spatial organization of nascent peptidoglycan. This brings the first evidence of the importance of StkP in relationship to the phosphorylation of one of its substrates in cell division. It is concluded that StkP is a multifunctional protein that plays crucial functions in pneumococcus cell shape and division.
The GtaR protein negatively regulates transcription of the gtaRI operon and modulates gene transfer agent (RcGTA) expression in Rhodobacter capsulatus
Authors: Leung Molly M. , Brimacombe Cedric A. , Spiegelman G. B. , Beatty J. Thomas
Published: December 2011

The gtaI gene of Rhodobacter capsulatus encodes an N‐acyl‐homoserine lactone (acyl‐HSL) synthase. Immediately 5′ of the gtaI gene is ORF rcc00328 that encodes a potential acyl‐HSL receptor protein. A combination of genetic and biochemical approaches showed that rcc00328 (renamed gtaR) modulates the production of a genetic exchange element called the gene transfer agent (RcGTA), and regulates the transcription of gtaI. Although gtaI mutants exhibited decreased levels of RcGTA production, mutagenesis of gtaR did not, whereas a gtaR/gtaI double mutant produced wild‐type levels of RcGTA. Because mutagenesis of gtaR suppressed the effect of the gtaI mutation, we suggest that the GtaR protein is a negative transcriptional regulator of RcGTA gene expression. We discovered that the gtaR and gtaI genes are co‐transcribed, and also negatively regulated by the GtaR protein in the absence of acyl‐HSL. A His‐tagged GtaR protein was purified, and DNA‐binding experiments revealed a binding site in the promoter region of the gtaRI operon. This GtaR protein did not bind to the RcGTA promoter region, and therefore modulation of RcGTA production appears to require at least one additional factor. We found that RcGTA production was stimulated by spent media from other species, and identified exogenous acyl‐HSLs that induce RcGTA.
The plastid redox insensitive 2 mutant of Arabidopsis is impaired in PEP activity and high light‐dependent plastid redox signalling to the nucleus
Authors: Kindgren Peter , Kremnev Dmitry , Blanco Nicolás E. , de Dios Barajas López Juan , Fernández Aurora Piñas , Tellgren‐Roth Christian , Small Ian , Strand Åsa
Published: December 2011

The photosynthetic apparatus is composed of proteins encoded by genes from both the nuclear and the chloroplastic genomes. The activities of the nuclear and chloroplast genomes must therefore be closely coordinated through intracellular signalling. The plastids produce multiple retrograde signals at different times of their development, and in response to changes in the environment. These signals regulate the expression of nuclear‐encoded photosynthesis genes to match the current status of the plastids. Using forward genetics we identified PLASTID REDOX INSENSITIVE 2 (PRIN2), a chloroplast component involved in redox‐mediated retrograde signalling. The allelic mutants prin2‐1 and prin2‐2 demonstrated a misregulation of photosynthesis‐associated nuclear gene expression in response to excess light, and an inhibition of photosynthetic electron transport. As a consequence of the misregulation of LHCB1.1 and LHCB2.4, the prin2 mutants displayed a high irradiance‐sensitive phenotype with significant photoinactivation of photosystem II, indicated by a reduced variable to maximal fluorescence ratio (Fv/Fm). PRIN2 is localized to the nucleoids, and plastid transcriptome analyses demonstrated that PRIN2 is required for full expression of genes transcribed by the plastid‐encoded RNA polymerase (PEP). Similarly to the prin2 mutants, the ys1 mutant with impaired PEP activity also demonstrated a misregulation of LHCB1.1 and LHCB2.4 expression in response to excess light, suggesting a direct role for PEP activity in redox‐mediated retrograde signalling. Taken together, our results indicate that PRIN2 is part of the PEP machinery, and that the PEP complex responds to photosynthetic electron transport and generates a retrograde signal, enabling the plant to synchronize the expression of photosynthetic genes from both the nuclear and plastidic genomes.
Development of genic‐SSRs markers from soybean aphid sequences generated by high‐throughput sequencing of cDNA library
Authors: Jun T.‐H. , Mian M. A. R. , Freewalt K. , Mittapalli O. , Michel A. P.
Published: December 2011

The soybean aphid (Aphis glycines Matsumura) is one of the most important insect pests of soybean [Glycine max (L.) Merr.] in North America, and three biotypes of the aphid have been confirmed. Genetic studies of the soybean aphid are needed to determine genetic diversity, movement pattern, biotype distribution and mapping of virulence genes for efficient control of the pest. Simple sequence repeats (SSR) markers are useful for population and classical genetic studies, but few are currently available for the soybean aphid. In this study, we designed primers for 342 genic‐SSR markers from a dataset of more than 102 024 transcript reads generated by 454 GS FLX sequencing of a cDNA library of the soybean aphid. Two hundred forty‐six markers generated PCR products of expected size and 26 were polymorphic among four pooled aphid DNA samples. An additional five markers that were fixed for two alleles among the pooled samples were found to be polymorphic when tested on 96 individual aphids. Sequencing of the PCR products generated by two polymorphic SSR markers revealed that the polymorphisms were strictly because of variations in the SSR repeats among the aphids tested. The genetic diversity among 96 soybean aphids, 24 each from two field collections (South Dakota and Michigan, biotype unknown) and two laboratory colonies [biotype 1 (B1) and biotype 2 (B2)], was assessed with 29 polymorphic SSR markers. These markers discriminated laboratory colonies from field collections and field collections from different states. The genic‐SSR markers developed and validated in this study will be a significant addition to the limited number of SSR markers, mostly genomic‐SSR, currently available for the soybean aphid. These markers will be useful for genetic studies, including population genetics, genetic and QTL mapping, migration and biotype differentiation of the soybean aphid.
Cannabinoid CB1 receptor mediates glucocorticoid effects on hormone secretion induced by volume and osmotic changes
Authors: Ruginsk SG , Uchoa ET , Elias LLK , Antunes‐Rodrigues J
Published: December 2011

The present study provides the first in vivo evidence that the cannabinoid CB1 receptor mediates the effects of dexamethasone on hormone release induced by changes in circulating volume and osmolality. Male adult rats were administered with the CB1 receptor antagonist rimonabant (10 mg/Kg, p.o.), followed or not in 1 hour by dexamethasone (1 mg/Kg, i.p.). Extracellular volume expansion (EVE, 2 mL/100 g of body weight, i.v.) was performed 2 hours after dexamethasone or vehicle treatment using either isotonic (I‐EVE, 0.15 mol/L) or hypertonic (H‐EVE, 0.30 mol/L) NaCl solution. Five minutes after EVE, animals were decapitated and trunk blood was collected for all plasma measurements.

Rimonabant potentiated oxytocin (OT) secretion induced by H‐EVE and completely reversed the inhibitory effects of dexamethasone in response to the same stimulus. These data suggest that glucocorticoid modulation of OT release is mediated by the CB1 receptor.

Although dexamethasone did not affect vasopressin (AVP) secretion induced by H‐EVE, the administration of rimonabant potentiated AVP release in response to the same stimulus, supporting the hypothesis that the CB1 receptor regulates AVP secretion independently of glucocorticoid‐mediated signalling.

Dexamethasone alone did not affect atrial natriuretic peptide (ANP) release stimulated by I‐EVE or H‐EVE. However, pretreatment with rimonabant potentiated ANP secretion induced by H‐EVE, suggesting a possible role for the CB1 receptor in the control of peripheral factors that modulate cardiovascular function.

Rimonabant also reversed the inhibitory effects of dexamethasone on H‐EVE‐induced corticosterone secretion, reinforcing the hypothesis that the CB1 receptor may be involved in the negative feedback exerted by glucocorticoids on the activity of the hypothalamic–pituitary–adrenal axis.

Collectively, the results of the present study indicate that the CB1 receptor modulates neurohypophyseal hormone secretion and systemic factors, such as corticosterone and ANP, thus participating in homeostatic responses to altered extracellular volume and plasma tonicity.
A limited sampling strategy for the simultaneous estimation of tacrolimus, mycophenolic acid and unbound prednisolone exposure in adult kidney transplant recipients
Authors: BARRACLOUGH KATHERINE A , ISBEL NICOLE M , JOHNSON DAVID W , HAWLEY CARMEL M , LEE KATIE J , MCWHINNEY BRETT C , UNGERER JACOBUS P , CAMPBELL SCOTT B , LEARY DIANA R , STAATZ CHRISTINE E
Published: December 2011

Aim:  The aim of this study was to develop a limited sampling strategy (LSS) for the simultaneous estimation of exposure to tacrolimus, mycophenolic acid and unbound prednisolone in adult kidney transplant recipients.

Methods:  Tacrolimus, mycophenolic acid and unbound prednisolone area under the concentration–time curve profiles from 0 to 12 h post dose (AUC0‐12) were collected from 20 subjects. Multiple linear regression analyses were performed to develop a LSS enabling the simultaneous estimation of exposure to all three drugs. Median percentage prediction error and median absolute percentage prediction error were calculated via jackknife analysis to evaluate bias and imprecision.

Results:  LSS showed superior ability to predict exposure compared with single concentration–time points. A LSS incorporating concentration measurements at 0.5 h (C0.5), 2 h (C2) and 4 h (C4) post dose displayed acceptable predictive ability for all three drugs.

Conclusion:  This LSS may serve as a useful research tool for further investigation of the utility of concentration monitoring of these medications.
Social anxiety score is high in adolescents with chronic migraine
Authors: Masruha Marcelo R. , Lin Jaime , Minett Thais S. C. , Vitalle Maria Sylvia de S. , Fisberg Mauro , Vilanova Luiz Celso P. , Peres Mario F. P.
Published: December 2011

Background:  Social anxiety disorder, also known as social phobia, is a marked and persistent fear of one or more social or performance situations in which the person is exposed to unfamiliar people or to possible scrutiny by others. It usually begins in mid‐adolescence and has a chronic course and interferes in academic, social, family and personal functioning. Recent studies have shown that social anxiety disorder is more prevalent in adults with migraine. Little evidence on this subject is available for the adolescent population.

Methods:  This study was performed between August 2009 and August 2010; all patients were recruited in schools, pediatric or neuropediatric facilities, and were submitted to a detailed headache questionnaire, which consisted of demographic and clinical data. To evaluate social anxiety, the Social Phobia Inventory was used.

Results:  A total of 151 subjects were evaluated: 50 had chronic migraine, 50 had episodic migraine and 51 were control subjects. In the chronic migraine group, the mean score in the Social Phobia Inventory was 18.5 ± 12.4, which was significantly higher than in the episodic migraine group (12.1 ± 8.1) and in the control group (13.8 ± 10.8; F2131= 4.8, P= 0.010). The mean score, however, was not significantly different between the control and episodic migraine groups.

Conclusions:  Chronic migraine is strongly associated with high social anxiety score, regardless of demographic data and pain intensity. The total burden of migraine may be increased with social anxiety disorder comorbidity.
Do drivers intentionally target wildlife on roads?
Authors: BECKMANN CHRISTA , SHINE RICHARD
Published: December 2011

Despite frequent reliance on surveys to document public attitudes towards conservation issues (such as invasive‐species control), only rarely do researchers assess the validity of statements made by the public in response to such surveys. Therefore, how well responses match actual behaviour remains an open question. We conducted a survey asking drivers if they had seen and/or run over (intentionally or not) snakes, native frogs or invasive cane toads (Rhinella marina) on roads in the Northern Territory of Australia. To compare actual driver behaviour to the survey responses, we also carried out field experiments where we quantified the rates at which model snakes, frogs and toads (and controls) were run over on a rural highway. Our results show a discrepancy between survey responses and driver behaviour: for example, 25% of the people we surveyed indicated that they intentionally run over cane toads, yet field experiments showed that model toads were run over no more frequently than expected by chance, or than any other type of model.
CT‐guided percutaneous lung biopsy under general anesthesia: a pediatric case series and literature review
Authors: Naumann Heather , Pittaway Andy , Lynn Anne M. , Vo Nghia J.
Published: December 2011

We describe 14 consecutive children who received computed tomography‐guided percutaneous lung biopsy (CT‐PLB) under general anesthesia over an 18‐month period at our institution. Pulmonary hemorrhage (occurring in 36%) and pneumothorax (29%) were the two most common complications; the overall complication rate was 64%. When complications did occur, immediate airway management was facilitated by the presence of an endotracheal tube (ETT). We conclude as follows: (i) CT‐PLB in our series is associated with a high risk of both overall and severe complications; (ii) risk of complications is increased by both patient and procedure‐related factors; (iii) airway management with ETT may be preferable should a complication arise; (iv) severe complications may necessitate ICU admission, which should be available before proceeding.
Patients with diabetes are not more likely to have atypical symptoms when seeking care of a first myocardial infarction. An analysis of 4028 patients in the Northern Sweden MONICA Study
Authors: Ängerud K. H. , Brulin C. , Näslund U. , Eliasson M.
Published: December 2011

Diabet. Med. 29, e82–e87 (2012)

Aim  To describe symptoms of a first myocardial infarction in men and women with and without diabetes.

Methods  We conducted a population‐based study of 4028 people aged 25–74 years, with first myocardial infarction registered in the Northern Sweden Multinational MONItoring of trends and determinants in CArdiovascular disease (MONICA) myocardial infarction registry between 2000 and 2006. Symptoms were classified as typical or atypical according to the World Health Organization MONICA manual.

Results  Among patients with diabetes, 90.1% reported typical symptoms of myocardial infarction; the corresponding proportion among patients without diabetes was 91.5%. In the diabetes group, 88.8% of women and 90.8% of men had typical symptoms of myocardial infarction. No differences were found in symptoms of myocardial infarction between women with and without diabetes or between men with and without diabetes. Atypical symptoms were more prevalent in the older age groups (> 65 years) than in the younger age groups (< 65 years). The increases were approximately equal among men and women, with and without diabetes. Diabetes was not an independent predictor for having atypical symptoms of myocardial infarction.

Conclusions  Typical symptoms of myocardial infarction were equally prevalent in patients with and without diabetes and there were no sex differences in symptoms among persons with diabetes. Diabetes was not a predictor of atypical symptoms.
Effectiveness of male‐only weight loss and weight loss maintenance interventions: a systematic review with meta‐analysis
Authors: Young M. D. , Morgan P. J. , Plotnikoff R. C. , Callister R. , Collins C. E.
Published: December 2011

The objectives of this systematic review were to investigate the effectiveness of male‐only weight loss and weight loss maintenance interventions and to identify intervention characteristics associated with effectiveness. In May 2011, a systematic literature search with no date restrictions was conducted across eight databases. Twenty‐four articles describing 23 studies met the eligibility criteria. All studies included a weight loss intervention and four studies included an additional weight loss maintenance intervention. Study quality was mostly poor for weight loss studies (median = 3/10, range = 1–9) and weight loss maintenance studies (median = 3.5/10, range = 1–6). Twenty‐three of 31 individual weight loss interventions (74%) from the eligible studies were considered effective. Meta‐analysis revealed a significant difference in weight change favouring weight loss interventions over no‐intervention controls at the last reported assessment (weighted mean difference −5.66 kg [−6.35, −4.97], Z = 16.04 [P < 0.00001]). Characteristics common to effectiveness were younger sample (mean age ≤42.8 years), increased frequency of contact (>2.7 contacts/month), group face‐to‐face contact and inclusion of a prescribed energy restriction. Preliminary evidence suggests men‐only weight loss programmes may effectively engage and assist men with weight loss. However, more high‐quality studies are urgently needed to improve the evidence base, particularly for maintenance studies.
Leveraging micro‐ and macro‐structures of embeddedness in alliance networks for exploratory innovation in biotechnology
Authors: Karamanos Anastasios G.
Published: December 2011

Researchers agree that alliance networks can be an important instrument in a firm's innovation process, but there is limited empirical evidence on actually how they facilitate the creation of new knowledge for exploratory innovation. The research question is what alliance network configuration is optimal for exploratory innovation. The present study investigated the interaction between a firm's alliance portfolio structure (the micro‐level) and the industry alliance network structure (the macro‐level), and it empirically tested how their interaction may be affecting the exploratory innovation outcome of network participating firms in the biotechnology industry. The paper uses data from exploratory patents filed by 455 dedicated biotechnology firms in 1986–1999 and an overall network comprising 2,933 technological alliances over the same period. The results indicate that, in the case of biotechnology, firms with high exploratory innovation output have short path indirect access to many other firms (micro‐level), and operate in dense industry alliance networks centralized around a few key firms (macro‐level), and that these effects are curvilinear.
The Prevalence and Burden of Primary Headaches in China: A Population‐Based Door‐to‐Door Survey
Authors: Yu Shengyuan , Liu Ruozhuo , Zhao Gang , Yang Xiaosu , Qiao Xiangyang , Feng Jiachun , Fang Yannan , Cao Xiutang , He Mianwang , Steiner Timothy
Published: December 2011

Objectives.— In the absence of reliable data on the prevalence and burden of primary headache disorders in the mainland of China, a population‐based survey was initiated by Lifting The Burden: the Global Campaign against Headache.

Methods.— Throughout all regions of China, 5041 non‐related adult respondents aged 18‐65 years were randomly sampled from the general population according to the expanded programme on immunization method established by World Health Organization. They were visited by door‐to‐door calling and surveyed using the structured questionnaire developed by Lifting The Burden, translated into Chinese and adapted to Chinese culture after a pilot study.

Results.— The responder rate was 94.1%. The estimated 1‐year prevalence of primary headache disorders was 23.8% (95% confidence interval 22.6‐25.0%), of migraine 9.3% (95% confidence interval 8.5‐10.1%), of tension‐type headache (TTH) 10.8% (9.9‐11.6%), and of chronic daily headache (CDH) 1.0% (0.7‐1.2%). Of respondents with migraine, TTH, and CDH, moderate or severe impact and therefore high need for effective medical care were reported by 38.0%, 23.1%, and 47.9%, respectively. The World Health Organization quality of life‐8 questionnaire showed that all 3 types of headache reduced life quality. The total estimated annual cost of primary headache disorders, including migraine, TTH, and CDH was CNY 672.7 billion, accounting for 2.24% of gross domestic product (GDP) (direct cost: CNY 108.8 billion, 0.36% of GDP; indirect cost: CNY 563.9 billion, 1.88% of GDP).

Conclusion.— The prevalence of primary headaches is high in China and not dissimilar from the world average. These headaches cause disability, impair work, study and daily activities, decrease life quality, and bring about a heavy and hitherto unrecognized socioeconomic burden.
Long‐Term Determinants of Muscle Strength Decline: Prospective Evidence from the 22‐Year Mini‐Finland Follow‐Up Survey
Authors: Stenholm Sari , Tiainen Kristina , Rantanen Taina , Sainio Päivi , Heliövaara Markku , Impivaara Olli , Koskinen Seppo
Published: December 2011

Objectives

To examine long‐term changes in handgrip strength and the factors predicting handgrip strength decline.

Design

Longitudinal cohort study with 22 years of follow‐up.

Setting

Population‐based Mini‐Finland Health Examination Survey in Finland.

Participants

Nine hundred sixty‐three men and women aged 30 to 73 at baseline.

Measurements

Handgrip strength was measured using a handheld dynamometer at baseline and follow‐up. Information on potential risk factors, namely lifestyle and chronic conditions, and their changes throughout the follow‐up were based on health interviews.

Results

Based on linear mixed‐effect models, midlife physically strenuous work, excess body weight, smoking, cardiovascular disease, hypertension, diabetes mellitus, and asthma predicted muscle strength decline over 22 years of follow‐up (P < .05 for all). In addition, pronounced weight loss, becoming physically sedentary, persistent smoking, incident coronary heart disease, other cardiovascular disease, diabetes mellitus, chronic bronchitis, chronic back syndrome, long‐lasting cardiovascular disease, hypertension, and asthma were associated with accelerated handgrip strength decline (P < .05 for all).

Conclusion

Lifestyle and physical health earlier in life determine rate of muscle strength decline in old age. Efforts should be made to recognize persons at risk in a timely manner and target early interventions to middle‐aged persons to slow down muscle strength decline and prevent future functional limitations and disability.
Geritalk: Communication Skills Training for Geriatric and Palliative Medicine Fellows
Authors: Kelley Amy S. , Back Anthony L. , Arnold Robert M. , Goldberg Gabrielle R. , Lim Betty B. , Litrivis Evgenia , Smith Cardinale B. , O'Neill Lynn B.
Published: December 2011

Expert communication is essential to high‐quality care for older patients with serious illness. Although the importance of communication skills is widely recognized, formal curricula for teaching communication skills to geriatric and palliative medicine fellows is often inadequate or unavailable. The current study drew upon the educational principles and format of an evidence‐based, interactive teaching method to develop an intensive communication skills training course designed specifically to address the common communication challenges that geriatric and palliative medicine fellows face. The 2‐day retreat, held away from the hospital environment, included large‐group overview presentations, small‐group communication skills practice, and development of future skills practice commitment. Faculty received in‐depth training in small‐group facilitation techniques before the course. Geriatric and palliative medicine fellows were recruited to participate in the course and 100% (n = 18) enrolled. Overall satisfaction with the course was very high (mean 4.8 on a 5‐point scale). After the course, fellows reported an increase in self‐assessed preparedness for specific communication challenges (mean increase 1.4 on 5‐point scale, P < .001). Two months after the course, fellows reported a high level of sustained skills practice (mean 4.3 on 5‐point scale). In sum, the intensive communication skills program, customized for the specific needs of geriatric and palliative medicine fellows, improved fellows’ self‐assessed preparedness for challenging communication tasks and provided a model for ongoing deliberate practice of communication skills.
Median Tests for Censored Survival Data; a Contingency Table Approach
Authors: Tang Shaowu , Jeong Jong‐Hyeon
Published: December 2011

Summary The median failure time is often utilized to summarize survival data because it has a more straightforward interpretation for investigators in practice than the popular hazard function. However, existing methods for comparing median failure times for censored survival data either require estimation of the probability density function or involve complicated formulas to calculate the variance of the estimates. In this article, we modify a K‐sample median test for censored survival data (Brookmeyer and Crowley, 1982, Journal of the American Statistical Association 77, 433–440) through a simple contingency table approach where each cell counts the number of observations in each sample that are greater than the pooled median or vice versa. Under censoring, this approach would generate noninteger entries for the cells in the contingency table. We propose to construct a weighted asymptotic test statistic that aggregates dependent χ2‐statistics formed at the nearest integer points to the original noninteger entries. We show that this statistic follows approximately a χ2‐distribution with k− 1 degrees of freedom. For a small sample case, we propose a test statistic based on combined p‐values from Fisher’s exact tests, which follows a χ2‐distribution with 2 degrees of freedom. Simulation studies are performed to show that the proposed method provides reasonable type I error probabilities and powers. The proposed method is illustrated with two real datasets from phase III breast cancer clinical trials.
Palatal Rugae Pattern in a Portuguese Population: A Preliminary Analysis
Authors: Santos Carlos , Caldas Inês Morais
Published: December 2011

Abstract:  Palatal rugae have been related with specific racial groups and are said to be useful in sex discrimination. This work aimed to characterize the palatal rugae patterns in a Portuguese population. Fifty plaster casts were examined for first and third rugae shape evaluation; shape, frequency, and association with sex were studied. In females, the most prevalent first rugae were the straight type on the right and the curve type on the left; in males, the straight type was the most prevalent on both sides. The most frequent third rugae type was sinuous on both sides, in both sexes. No significant sexual dimorphism in rugae shape was found (p > 0.05). When comparing these results with those from other investigations, it was clear that a particular rugae pattern could be established for different ethnic groups. However, the small sample size justifies further work in larger samples to validate these findings.