bluuebunny/crossref_metadata_2025 huggingface dataset:
Dendritic cells treated with resveratrol during differentiation from monocytes gain substantial tolerogenic properties upon activation
Authors: Švajger Urban , Obermajer Nataša , Jeras Matjaž
Published: November 2009

Resveratrol is a polyphenol that acts on multiple molecular targets important for cell differentiation and activation. Dendritic cells (DCs) are a functionally diverse cell type and represent the most potent antigen‐presenting cells of the immune system. In this study, we investigated resveratrol‐induced effects on DCs during their differentiation and maturation. Our results show that resveratrol induces DC‐associated tolerance, particularly when applied during DC differentiation. Costimulatory molecules CD40, CD80 and CD86 were down‐regulated, as was the expression of major histocompatibility complex (MHC) class II molecules. Surface expression of inhibitory immunoglobulin‐like transcript 3 (ILT3) and ILT4 molecules was induced, while human leucocyte antigen (HLA)‐G expression was not affected. Resveratrol‐treated DCs lost the ability to produce interleukin (IL)‐12p70 after activation, but had an increased ability to produce IL‐10. Such DCs were poor stimulators of allogeneic T cells and had lowered ability to induce CD4+ T‐cell migration. Furthermore, treated cells were able to generate allogeneic IL‐10‐secreting T cells, but were not competent in inducing FoxP3 expression These tolerogenic effects are probably associated with the effect of resveratrol on multiple molecular targets through which it interferes with DC differentiation and nuclear factor (NF)‐κB translocation. Our data provide new insights into the molecular and functional mechanisms of the tolerogenic effects that resveratrol exerts on DCs.
Phenotypic correlates of hybridisation between red and sika deer (genus Cervus)
Authors: Senn Helen V. , Swanson Graeme M. , Goodman Simon J. , Barton Nicholas H. , Pemberton Josephine M.
Published: November 2009

1. Hybridisation with an invasive species has the potential to alter the phenotype and hence the ecology of a native counterpart.

2. Here data from populations of native red deer Cervus elaphus and invasive sika deer Cervus nippon in Scotland is used to assess the extent to which hybridisation between them is causing phenotypic change. This is done by regression of phenotypic traits against genetic hybrid scores.

3. Hybridisation is causing increases in the body weight of sika‐like deer and decreases in the body weight of red‐like females. Hybridisation is causing increases in jaw length and increases in incisor arcade breadth in sika‐like females. Hybridisation is also causing decreases in incisor arcade breadth in red‐like females.

4. There is currently no evidence that hybridisation is causing changes in the kidney fat weight or pregnancy rates of either population.

5. Increased phenotypic similarity between the two species is likely to lead to further hybridisation. The ecological consequences of this are difficult to predict.
Worse blood pressure control in patients with cerebrovascular or peripheral arterial disease compared with coronary artery disease
Authors: Mechtouff L. , Touzé E. , Steg P. G. , Ohman E. M. , Goto S. , Hirsch A. T. , Röther J. , Aichner F. T. , Weimar C. , Bhatt D. L. , Alberts M. J. , Mas J.‐L. ,   on behalf of the REACH Registry Investigators
Published: November 2009

Abstract.  Mechtouff L, Touzé E, Steg PG, Ohman EM, Goto S, Hirsch AT, Röther J, Aichner FT, Weimar C, Bhatt DL, Alberts MJ, Mas J‐L, on behalf of the REACH Registry Investigators (Paris‐Descartes University; Université Paris 7; Paris, France, Duke University, Durham NC, USA, Tokai University, Isehara, Japan, University of Minnesota, Minneapolis, MN, USA, Academic Teaching Hospital Hannover Medical School, Minden, Germany, Academic Teaching Hospital Wagner‐Jauregg, Linz, Austria, University of Duisburg‐Essen, Essen, Germany, VA Boston Healthcare System, and Brigham and Women’s Hospital, Boston, MA; and Northwestern University Medical School, Chicago, IL; USA). Worse blood pressure control in patients with cerebrovascular or peripheral arterial disease compared with coronary artery disease. J Intern Med 2010; 267:621–633.

Objectives.  Poor blood pressure (BP) control is common amongst patients with symptomatic atherothrombotic disease. It is unclear whether BP control and management differ across atherothrombotic disease subtypes.

Methods.  We analysed the baseline data of 44 984 patients with documented coronary artery disease (CAD) only (n = 30 414), cerebrovascular disease (CVD) only (n = 11 359) and peripheral arterial disease (PAD) only (n = 3211) from the international REduction of Atherothrombosis for Continued Health Registry and investigated the impact of atherothrombotic disease subtype on BP control and use of antihypertensive drugs.

Results.  The proportion of patients with BP controlled (<140/90 mmHg) was higher in CAD (58.1%) than in CVD (44.8%) or PAD (38.9%) patients (P < 0.001). Amongst patients with treated hypertension, CAD patients were more likely to have BP controlled than were CVD patients [odds ratio (OR) = 1.67; 95% confidence interval (CI) = 1.59–1.75] or PAD (OR = 2.30; 95% CI = 2.10–2.52). These differences were smaller in women than in men and decreased with age. Amongst treated patients, CAD patients were more likely to receive ≥3‐drug combination therapies than were CVD (OR = 1.73; 95% CI = 1.64–1.83) or PAD (OR = 1.64; 95% CI = 1.49–1.80) patients. Adjustment for age, gender, waist obesity, diabetes, education level and world region did not alter the results.

Conclusions.  Coronary artery disease patients are more likely than CVD or PAD patients to have BP controlled and to receive antihypertensive drugs, particularly combination therapies. Promotion of more effective BP control through combination antihypertensive therapies could improve secondary prevention and therefore prevent complications in CVD and PAD patients.
Neuroimaging in acute ischaemic stroke: insights into unanswered questions of pathophysiology
Authors: Wardlaw J. M.
Published: November 2009

Wardlaw JM (Western General Hospital, Edinburgh, UK). Neuroimaging in acute ischaemic stroke: insights into unanswered questions of pathophysiology (Review). J Intern Med 2010; 267: 172–190.

Abstract.  The treatment of acute ischaemic stroke is based on the principle that there is ischaemic but still potentially salvageable tissue that could be rescued if blood flow could be restored quickly. It is assumed that salvage might only be possible in the first few hours, and that infarct expansion is a direct result of failed recanalization of the main artery. This concept arose from experimental work in the 1970s, supported more recently by studies using imaging to identify penumbral tissue. However, although magnetic resonance diffusion and perfusion imaging is a way of imaging penumbral tissue and has been around for over a decade, it is not an easy technique to apply in practice and its use has produced conflicting results. Computed tomography perfusion, and any other tissue perfusion imaging technique, is likely to encounter the same difficulties. Indeed many factors, other than the presence of a diffusion‐perfusion mismatch acutely, may determine or influence ultimate tissue fate even days after the stroke, and in turn, clinical outcome. Many of these potential influences are beginning to emerge from studies using different forms of imaging at later times after stroke. This review will explore the information now emerging from imaging studies in large artery ischaemic stroke to summarize knowledge to date and indicate unresolved issues for the future.
Electron microscopy investigations of V defects in multiple InGaN/GaN quantum wells and InGaN quantum dots
Authors: YANG J.R. , LI W.C. , TSAI H.L. , HSU J.T. , SHIOJIRI M.
Published: November 2009

The mechanism of high emission of InGaN‐based multiple quantum wells, which exhibit exceptionally high light emission efficiency despite their high defect density, is still not fully understood. Here, we deal with this problem, showing the details of structure and formation of V defects in the multiple quantum wells and reviewing interpretations proposed so far. Then, we show a structural investigation of three‐dimensional high‐density quantum dots, fabricated instead of quantum wells in the active layer. The shape and size of the InGaN quantum dots and the SiNx masks for the growth of the dots have been revealed using high‐angle annular dark field scanning transmission electron microscopy, energy dispersive X‐ray spectroscopy nanoanalysis and high‐resolution transmission electron microscopy.
Three‐dimensional analysis of intermediate filament networks using SEM tomography
Authors: LÜCK S. , SAILER M. , SCHMIDT V. , WALTHER P.
Published: November 2009

We identified tomographic reconstruction of a scanning electron microscopy tilt series recording the secondary electron signal as a well‐suited method to generate high‐contrast three‐dimensional data of intermediate filament (IF) networks in pancreatic cancer cells. Although the tilt series does not strictly conform to the projection requirement of tomographic reconstruction, this approach is possible due to specific properties of the detergent‐extracted samples. We introduce an algorithm to extract the graph structure of the IF networks from the tomograms based on image analysis tools. This allows a high‐resolution analysis of network morphology, which is known to control the mechanical response of the cells to large‐scale deformations. Statistical analysis of the extracted network graphs is used to investigate principles of structural network organization which can be linked to the regulation of cell elasticity.
The role of Bacillus anthracis germinant receptors in germination and virulence
Authors: Carr Katherine A. , Lybarger Suzanne R. , Anderson Erica C. , Janes Brian K. , Hanna Philip C.
Published: November 2009

Nutrient‐dependent germination of Bacillus anthracis spores is stimulated when receptors located in the inner membrane detect combinations of amino acid and purine nucleoside germinants. B. anthracis produces five distinct germinant receptors, GerH, GerK, GerL, GerS and GerX. Otherwise isogenic mutant strains expressing only one of these receptors were created and tested for germination and virulence. The GerH receptor was necessary and sufficient for wild‐type levels of germination with inosine‐containing germinants in the absence of other receptors. GerK and GerL were sufficient for germination in 50 mM L‐alanine. When mutants were inoculated intratracheally, any receptor, except for GerX, was sufficient to allow for a fully virulent infection. In contrast, when inoculated subcutaneously only the GerH receptor was able to facilitate a fully virulent infection. These results suggest that route of infection determines germinant receptor requirements. A mutant lacking all five germinant receptors was also attenuated and exhibited a severe germination defect in vitro. Together, these data give us a greater understanding of the earliest moments of germination, and provide a more detailed picture of the signals required to stimulate this process.
Autonomous plasmid‐like replication of Bacillus ICEBs1: a general feature of integrative conjugative elements?
Authors: Grohmann Elisabeth
Published: November 2009

Integrative conjugative elements (ICEs) occur frequently in Gram‐positive and Gram‐negative bacteria. In contrast to plasmids, they are stably integrated in the bacterial genome, often inserted in a tRNA gene. They are excised from the host chromosome upon induction in order to be transferred to a recipient cell. When conjugative transfer is completed, they stably reintegrate in the chromosome. It is generally thought that ICEs are incapable of autonomous replication, instead relying on replication and segregation along with the host chromosome. In this issue of Molecular Microbiology Lee and co‐workers demonstrate that ICEBs1 from Bacillus subtilis is capable of autonomous plasmid‐like replication in its circular form after excision. The authors show that ICEBs1 replication is unidirectional; it initiates at oriTICEBs1 and requires the ICEBs1‐encoded conjugative relaxase NicK. Replication also requires the catalytic subunit of the host DNA polymerase PolC, the host processivity clamp DnaN and the host‐encoded alternative helicase PcrA. Autonomous replication of ICEBs1 appears to be important for its stable maintenance, but not for horizontal transfer of the element. Lee and co‐workers argue that plasmid‐like replication is likely a common property of ICEs, probably contributing to stability and maintenance of ICEs in bacterial populations. I discuss these findings in context with data on other ICEs from Gram‐positive and Gram‐negative bacteria and with respect to possible consequences of the findings for basic research on mobile genetic elements from Gram‐positive bacteria and their applications in biotechnology.
Candida albicans Cyr1, Cap1 and G‐actin form a sensor/effector apparatus for activating cAMP synthesis in hyphal growth
Authors: Zou Hao , Fang Hao‐Ming , Zhu Yong , Wang Yue
Published: November 2009

A key virulence trait of Candida albicans is its ability to undergo the yeast‐to‐hyphal growth transition in response to environmental signals. This transition critically requires a rapid activation of the adenylyl cyclase Cyr1 to generate a cAMP spike. However, the identity of the signal sensors and mechanisms of signal processing and integration remain largely unclear. Recent evidence suggests that some sensors are embedded in Cyr1 itself. To test this hypothesis, we asked whether purified Cyr1 can respond to hyphal induction. Here, we report that Cyr1 co‐purifies with Cap1 and G‐actin as a tripartite complex which can increase cAMP synthesis in response to hyphal inducing signals in an actin‐dependent manner. Cap1 binds Cyr1 and G‐actin through its N‐ and C‐terminus respectively. Deleting the G‐actin binding sites or treating the complex with the actin toxin latrunculin A or cytochalasin A inhibits the activation of cAMP synthesis. Strains expressing Cap1 mutants lacking the G‐actin binding site are impaired in both cAMP synthesis and hyphal morphogenesis. Thus, our findings reveal an essentially intact sensor/effector apparatus composed of Cyr1, Cap1 and G‐actin. Furthermore, G‐actin's regulatory role in this apparatus may prove to be the missing link whereby cellular actin status knowingly influences cAMP‐mediated cellular processes.
Genetics of the glutamate‐mediated methylamine utilization pathway in the facultative methylotrophic beta‐proteobacterium Methyloversatilis universalis FAM5
Authors: Latypova Ekaterina , Yang Song , Wang Yi‐Shun , Wang Tiansong , Chavkin Theodore A. , Hackett Murray , Schäfer Hendrik , Kalyuzhnaya Marina G.
Published: November 2009

The ability of some microbial species to oxidize monomethylamine via glutamate‐mediated pathways was proposed in the 1960s; however, genetic determinants of the pathways have never been described. In the present study we describe a gene cluster essential for operation of the N‐methylglutamate pathway in the methylotrophic beta‐proteobacterium Methyloversatilis universalis FAM5. Four major polypeptides from protein fractions displaying high activities of N‐methylglutamate synthetase, N‐methylglutamate dehydrogenase and γ‐glutamylmethylamide synthetase were selected for mass spectrometry‐based identification. The activities of enzymes were associated with the presence of peptides identified as ferredoxin‐dependent glutamate synthase (GltB2), large subunit of putative heterotetrameric sarcosine oxidase (SoxA) and glutamine synthetase type III (GSIII) respectively. A gene cluster (8.3 kb) harbouring gltB2, soxA and gsIII‐like genes was amplified from M. universalis FAM5, sequenced and assembled. Two partial and six complete open reading frames arranged in the order soxBDAG‐gsIII‐gltB132 were identified and subjected to mutational analysis, functional and metabolic profiling. We demonstrated that gltB‐like and sox‐like genes play a key role in methylamine utilization and encode N‐methylglutamate synthetase and N‐methylglutamate dehydrogenase respectively. Metabolic, enzymatic and mutational analyses showed that the gsIII‐like gene encodes γ‐glutamylmethylamide synthetase; however, this enzyme is not essential for oxidation of methylamine.
Immunohistological intensity measurements as a tool to assess sarcolemma‐associated protein expression
Authors: Arechavala‐Gomeza V. , Kinali M. , Feng L. , Brown S. C. , Sewry C. , Morgan J. E. , Muntoni F.
Published: November 2009

V. Arechavala‐Gomeza, M. Kinali, L. Feng, S. C. Brown, C. Sewry, J. E. Morgan and F. Muntoni (2010) Neuropathology and Applied Neurobiology36, 265–274 Immunohistological intensity measurements as a tool to assess sarcolemma‐associated protein expression

Aims: The quantification of protein levels in muscle biopsies is of particular relevance in the diagnostic process of neuromuscular diseases, but is difficult to assess in cases of partial protein deficiency, particularly when information on protein localization is required. The combination of immunohistochemistry and Western blotting is often used in these cases, but is not always possible if the sample is scarce. We therefore sought to develop a method to quantify relative levels of sarcolemma‐associated proteins using digitally captured images of immunolabelled sections of skeletal muscle. Methods: To validate our relative quantification method, we labelled dystrophin and other sarcolemmal proteins in transverse sections of muscle biopsies taken from Duchenne muscular dystrophy and Becker muscular dystrophy patients, a manifesting carrier of Duchenne muscular dystrophy and normal controls. Results: Using this method to quantify relative sarcolemmal protein abundance, we were able to accurately distinguish between the different patients on the basis of the relative amount of dystrophin present. Conclusions: This comparative method adds value to techniques that are already part of the diagnostic process and can be used with minimal variation of the standardized protocols, without using extra amounts of valuable biopsy samples. Comparative quantification of sarcolemmal proteins on immunostained muscle sections will be of use to establish both the abundance and localization of the protein. Moreover, it can be applied to assess the efficacy of experimental therapies where only partial restoration or upregulation of the protein may occur.
Control of leaf growth by abscisic acid: hydraulic or non‐hydraulic processes?
Authors: TARDIEU FRANÇOIS , PARENT BORIS , SIMONNEAU THIERRY
Published: November 2009

Abscisic acid (ABA) affects plant metabolism and water transfers via multiple mechanisms at cell, organ and whole plant levels. These mechanisms translate into contradictory effects on leaf growth, so the literature reports positive, null or negative effects of ABA on leaf growth upon water deficit. We review evidences based on genetic manipulations of ABA biosynthesis, feeding the plant with artificial ABA or partial root drying and provide elements to avoid confusions of effects. We propose that ABA has mainly three effects on growth. (i) Via its controlling effect on stomatal aperture and transpiration rate, an increased concentration of ABA tends to buffer the day‐night alternations of leaf growth rate and the negative effect of evaporative demand. (ii) ABA tends to improve leaf growth via an increase in the conductance to water transfer in the plant as a result of increased tissue hydraulic conductivity. (iii) ABA has also a modest non‐hydraulic effect which is negative in plants subjected to water deficit, either manipulated for ABA synthesis or fed with artificial ABA, but can be positive in well watered plants deficient of ABA. The overall effect of increasing ABA biosynthesis depends on the relative weight of each of these effects under different environmental scenarios.
Making the most of drought and salinity transcriptomics
Authors: DEYHOLOS MICHAEL K.
Published: November 2009

More than 100 different studies of plant transcriptomic responses to salinity or drought‐related stress have now been published. Most of these use microarrays or related high‐throughput profiling technologies. This compels us to ask three questions in review: (1) what has transcriptomics contributed to our understanding of stress physiology; (2) what limits the ability of transcriptomics to contribute to increases in stress tolerance; and (3) given these limits, what are the most appropriate uses of transcriptomics? We conclude that although microarrays are now a mature technology that accurately describes the transcriptome, the consistently low correlation between transcript abundance and other measures of gene expression imposes an inherent limitation that cannot be ignored. Further limitations on the relevance of transcriptomics arise in some cases from experimental practices related to the treatment regimen and the selection of tissue or germplasm. Nevertheless, there is good evidence to support the continued use of transcriptomics, especially emerging techniques such as RNA‐Seq, as a screening tool for candidate gene discovery. Microarrays can also be valuable in analysing the transcriptome per se (e.g. when describing the phenotype of a transcription factor mutant or discovering non‐coding RNA species), and when integrated with other types of data including metabolomic analyses.
TLR‐related pathway analysis: novel gene–gene interactions in the development of asthma and atopy
Authors: Reijmerink N. E. , Bottema R. W. B. , Kerkhof M. , Gerritsen J. , Stelma F. F. , Thijs C. , Van Schayck C. P. , Smit H. A. , Brunekreef B. , Koppelman G. H. , Postma D. S.
Published: November 2009

To cite this article: Reijmerink NE, Bottema RWB, Kerkhof M, Gerritsen J, Stelma FF, Thijs C, van Schayck CP, Smit HA, Brunekreef B, Koppelman GH, Postma DS. TLR‐related pathway analysis: novel gene–gene interactions in the development of asthma and atopy. Allergy 2010; 65: 199–207.

Background:  The toll‐like receptor (TLR)‐related pathway is important in host defence and may be crucial in the development of asthma and atopy. Numerous studies have shown associations of TLR‐related pathway genes with asthma and atopy phenotypes. So far it has not been investigated whether gene–gene interactions in this pathway contribute to atopy and asthma development.

Methods:  One hundred and sixty‐nine haplotype tagging single nucleotide polymorphisms (SNPs) of 29 genes (i.e. membrane and intracellular receptors, TLR4 or lipopolysaccharide‐binding/facilitating proteins, adaptors, interleukin‐1 receptor associated kinases, kinases, chaperone molecules, transcription factors and inhibitors) were analysed for single‐ and multilocus associations with atopy [total and specific immunglobulin E (IgE) at 1–2 and 6–8 years] and asthma (6–8 years). A total of 3062 Dutch children from the birth cohorts PIAMA, PREVASC and KOALA (Allergenic study) were investigated. Chi‐squared test, logistic regression and the data mining approach multifactor dimensionality reduction method (MDR) were used in analysis.

Results:  Several genes in the TLR‐related pathway were associated with atopy and/or asthma [e.g. IL1RL1, BPI, NOD1, NOD2 and MAP3K7IP1]. Multiple, single associations were found with the phenotypes under study. MDR analysis showed novel, significant gene–gene interactions in association with atopy and asthma phenotypes (e.g. IL1RL1 and TLR4 with sIgE to indoor allergens and IRAK1, NOD1 and MAP3K7IP1 with asthma). Interestingly, gene–gene interactions were identified with SNPs that did not have an effect on their own.

Conclusion:  Our unbiased approach provided suggestive evidence for interaction between several TLR‐related pathway genes important in atopy and/or asthma development and pointed to novel genes.
Opposing roles of IL‐17A and IL‐25 in the regulation of TSLP production in human nasal epithelial cells
Authors: Xu G. , Zhang L. , Wang D. Y. , Xu R. , Liu Z. , Han D. M. , Wang X. D. , Zuo K. J. , Li H. B.
Published: November 2009

To cite this article: Xu G, Zhang L, Wang DY, Xu R, Liu Z, Han DM, Wang XD, Zuo KJ, Li HB. Opposing roles of IL‐17A and IL‐25 in the regulation of TSLP production in human nasal epithelial cells. Allergy 2010; 65: 581–589.

Background:  The importance of IL‐17A, IL‐17F, and IL‐25 in allergic rhinitis (AR), as well as their possible role in regulation on thymic stromal lymphopoietin (TSLP) production in nasal epithelial cells, is not well understood.

Objective:  To determine the possible regulation of IL‐17A, IL‐17F, and IL‐25 on TSLP production in the initiation of allergic responses.

Methods:  The levels of IL‐17A, IL‐17F, IL‐25, and TSLP in nasal lavages of patients with AR were measured using an enzyme‐linked immunosorbent assay (ELISA) and compared with that in normal controls. Then, primary human nasal epithelial cells (HNECs) were stimulated with dsRNA (0–75 μg/ml), as well as IL‐17A (100 ng/ml), IL‐17F (100 ng/ml), and IL‐25(100 ng/ml). The mRNA expression of IL‐17A, IL‐17F, IL‐25, TSLP, as well as the chemokines CCL20, IL‐8, and eotaxin was analyzed using quantitative real‐time PCR, and their protein levels in the supernatants of cultured HNECs were determined by ELISA.

Results:  Both TSLP and IL‐17 cytokines are significantly elevated in patients with AR. dsRNA was found to increase the production of IL‐17F, IL‐25, TSLP, CCL20, and IL‐8 in HNECs. Furthermore, IL‐25 significantly enhanced dsRNA‐induced TSLP production in primary HNECs and was dominant to the inhibitory effect of IL‐17A on TSLP regulation.

Conclusions:  Our study provides the first evidence that both IL‐17F and IL‐25 can be induced by dsRNA in HNECs. Despite of the opposing effects of IL‐17A and IL‐25 on TSLP regulation in HNECs, IL‐25 was dominant to IL‐17A, providing a plausible explanation for the simultaneous upregulation of IL‐17 cytokines and TSLP in patients with AR.
Gene–gene and gene–environment interactions on IgE production in prenatal stage
Authors: Yang K. D. , Chang J.‐C. , Chuang H. , Liang H.‐M. , Kuo H.‐C. , Lee Y.‐S. , Hsu T.‐Y. , Ou C.‐Y.
Published: November 2009

To cite this article: Yang KD, Chang J‐C, Chuang H, Liang H‐M, Kuo H‐C, Lee Y‐S, Hsu T‐Y, Ou C‐Y. Gene–gene and gene–environment interactions on IgE production in prenatal stage. Allergy 2010; 65: 731–739.

Background:  Prevalence of allergic diseases in children has increased worldwide over the past decades. Allergy sensitization may occur in fetal life. This study investigated whether gene–gene and gene–environment interactions affected cord blood IgE (CBIgE) levels.

Methods:  A total of 575 cord blood DNA samples were subjected to a multiplex microarray for 384 single nucleotide polymorphisms (SNPs) in 159 allergy candidate genes. Genetic association was initially assessed by univariate and multivariate analyses. Multifactor dimensionality reduction (MDR) was used to identify gene–gene and gene–environment interactions. Environmental factors for analysis included maternal atopy, paternal atopy, parental smoking, gender, and prematurity.

Results:  Twenty‐one SNPs in 14 genes were associated with CBIgE elevation (≥0.5 KU/l) in univariate analysis. Multivariate analysis identified eleven genes (IL13, IL17A, IL2RA, CCL17, CXCL1, PDGFRA, FGF1, HAVCR1, GNAQ, C11orf72, and ADAM33) which were significantly associated with CBIgE elevation. MDR analyses of gene–gene interactions identified IL13 interacted with IL17A and/or redox genes on CBIgE elevation with the prediction accuracy of 62.52%. Analyses of gene–environment interactions identified that maternal atopy combined with IL13, rs1800925 and CCL22, rs170359 SNPs had the highest prediction accuracy of 67.15%. All the high and low risk classifications on gene–gene and gene–environment interactions by MDR analyses could be validated by Chi‐square test.

Conclusions:  Gene–gene (e.g. immune and redox genes) and gene–environment (e.g. maternal atopy and FGF1or redox genes) interactions on IgE production begin in prenatal stage, suggesting that prevention of IgE‐mediated diseases may be made possible by control of maternal atopy and redox responses in prenatal stage.
CMS oversight, OPOs and transplant centers and the law of unintended consequences
Authors: Howard Richard J. , Cornell Danielle L. , Schold Jesse D.
Published: November 2009

Abstract:  The Health Resources and Services Administration launched collaboratives with the goals of increasing donation rates, increasing the number of organs transplanted, eliminating deaths on the waiting list and improving outcomes. The Center for Medicare and Medicaid Services (CMS) recently published requirements for organ procurement organizations (OPOs) and transplant centers. Failure to meet CMS performance measures could result in OPOs losing their service area or transplant centers losing their CMS certification. CMS uses analyses by the Scientific Registry of Transplant Recipients (SRTR) to evaluate a transplant center’s performance based on risk‐adjusted outcomes. However, CMS also uses a more liberal (one‐sided) statistical test rendering more centers likely to qualify as low performing. Furthermore, the SRTR model does not incorporate some important patient variables in its statistical model which may result in biased determinations of quality of care. Cumulatively, there is much unexplained variation for transplant outcomes as suggested by the low predictive ability of survival models compared to other disease contexts. OPOs and transplant centers are unlikely to quietly accept their elimination. They may take certain steps that can result in exclusion of candidates who might otherwise benefit from transplantation and/or result in fewer transplants through restricted use of organs thought to carry higher risk of failure. CMS should join with transplant organizations to ensure that the goals of the collaborative are not inhibited by their performance measures.
Proliferative drive and liver carcinogenesis: Too much of a good thing?
Authors: Teoh Narci C
Published: November 2009

There have been innumerable studies published in the attempt to identify gene expression signatures in hepatocellular carcinoma (HCC). When all the regulators and targets of the differentially expressed genes are analyzed from larger studies, the most striking theme is upregulation of mitosis‐promoting and cell proliferation genes in HCC compared with ‘liver‐specific gene clusters’ in non‐tumorous tissue. A major limitation of expression profiling is that it only provides a ‘snapshot’ of what is an evolving process and thus cannot distinguish the differences in gene expression that are primary effectors of dysregulated growth from those that represent downstream consequences. The development of HCC in a chronically diseased liver, often referred to as hepatocarcinogenesis, is a multistep process characterized by the progressive accumulation and interplay of genetic alterations causing aberrant growth, malignant transformation of liver parenchymal cells, followed by vascular invasion and metastasis. This review will discuss HCC precursor lesions, draw on the ‘proliferation cluster’ genes highlighted from HCC expression profiling studies, relate them to a selection of regulatory networks important in liver regeneration, cell cycle control and their potential significance in the pathogenesis of HCC or primary liver cancer.
Epidemiology of colorectal cancer in Asia
Authors: Yee Yuk Kei , Tan Victoria PY , Chan Pierre , Hung Ivan FN , Pang Roberta , Wong Benjamin CY
Published: November 2009

The prevalence of colorectal cancer is increasing in Asia. However, the age‐standardized rate has reached a plateau in some countries. Some studies have shown a male predominance difference and increasing risk in the elderly, but not in the younger population. ‘Right shifting’ of colorectal cancer, not accountable by difference in age or the indications for endoscopic examination, has also been noted. Westernized diet is associated with colorectal cancer, but controversy remains on how it causes colorectal cancer. Alcohol consumption, obesity, diabetes mellitus, consumption of red and processed meat and cigarette smoking are linked to bowel cancer epidemiologically. Only high dietary calcium has a consistent negative (or ‘protective’) effect. The efficacy of fish oil, vitamin D, soy, phytoestrogens, folate, methionine, riboflavin and vitamin B6 has not been established. Aspirin and non‐steroidal anti‐inflammatory drugs use decrease risk of colorectal cancer after 5–10 years of use. There is no evidence for a detrimental effect of proton pump inhibitors or benefit of statins in colorectal cancer. In conclusion, there is a rising trend and prevalence of colorectal cancer in Asia. Dietary modification or supplementation may not be effective in preventing colorectal cancer. Surveillance of colorectal cancer in high‐risk groups, according to current recommendation, is probably most effective.
Collision of EBV‐associated gastric carcinoma and primary gastric extranodal marginal zone lymphoma of mucosa‐associated lymphoid tissue in the remnant stomach
Authors: Akiba Jun , Nakane Tomoyuki , Arakawa Fumiko , Ohshima Koichi , Yano Hirohisa
Published: November 2009

Reported herein is a case of EBV‐associated gastric carcinoma with primary gastric extranodal marginal zone lymphoma of mucosa‐associated lymphoid tissue (MALT lymphoma). A 69‐year‐old Japanese man was found to have an ulcer lesion in his stomach on endoscopy, and a biopsy indicated malignancy. He underwent gastrectomy. Microscopically the tumor had features typical of lymphoepithelioma‐like carcinoma. The neoplastic epithelial cells proliferated in a trabecular fashion. On in situ hybridization for EBV‐encoded RNA, positive signals were observed in most neoplastic epithelial cells. Numerous lymphocytes surrounded the neoplastic epithelial cells. In the stroma, numerous lymphocytes with mild atypia were positive for CD20 and CD79a. In addition, monoclonal proliferation of B cells was confirmed on polymerase chain reaction for IgH. These findings supported MALT lymphoma. The coexistence of EBV‐associated gastric carcinoma and MALT lymphoma is extremely rare.
Maintenance of the relative proportion of oligodendrocytes to axons even in the absence of BAX and BAK
Authors: Kawai Kumi , Itoh Takayuki , Itoh Aki , Horiuchi Makoto , Wakayama Kouji , Bannerman Peter , Garbern James Y. , Pleasure David , Lindsten Tullia
Published: November 2009

Highly purified oligodendroglial lineage cells from mice lacking functional bax and bak genes were resistant to apoptosis after in‐vitro differentiation, indicating an essential role of the intrinsic apoptotic pathway in apoptosis of oligodendrocytes in the absence of neurons (axons) and other glial cells. These mice therefore provide a valuable tool with which to evaluate the significance of the intrinsic apoptotic pathway in regulating the population sizes of oligodendrocytes and oligodendroglial progenitor cells. Quantitative analysis of the optic nerves and the dorsal columns of the spinal cord revealed that the absolute numbers of mature oligodendrocytes immunolabeled for aspartoacylase and adult glial progenitor cells expressing NG2 chondroitin sulfate proteoglycan were increased in both white matter tracts of adult bax/bak‐deficient mice and, to a lesser extent, bax‐deficient mice, except that there was no increase in NG2‐positive progenitor cells in the dorsal columns of these strains of mutant mice. These increases in mature oligodendrocytes and progenitor cells in bax/bak‐deficient mice were unexpectedly proportional to increases in numbers of axons in these white matter tracts, thus retaining the oligodendroglial lineage to axon ratios of at most 1.3‐fold of the physiological numbers. This is in contrast to the prominent expansion in numbers of neural precursor cells in the subventricular zones of these adult mutant mice. Our study indicates that homeostatic control of cell number is different for progenitors of the oligodendroglial and neuronal lineages. Furthermore, regulatory mechanism(s) operating in addition to apoptotic elimination through the intrinsic pathway, appear to prevent the overproduction of highly mitotic oligodendroglial progenitor cells.
Short‐term synaptic plasticity at the main and vomeronasal olfactory receptor to mitral cell synapse in frog
Authors: Delaney K. R. , Qnais E. Y. , Hardy A. B.
Published: November 2009

Synaptic responses resulting from stimulation of the main olfactory and vomeronasal (VN) nerves were measured in main and accessory olfactory bulb (AOB) of frog, Rana pipiens, to test the hypothesis that properties of these synapses would reflect the distinct differences in the time course of odour delivery to each of these olfactory structures. Paired‐pulse depression dominated responses to repetitive stimulation of the main olfactory nerve for interstimulus intervals (ISI) up to several seconds. Inhibition of voltage‐gated Ca2+ channels by GABAb receptors contributes significantly to this inhibition of transmitter release, particularly for ISI > 0.5 s. In contrast, the monosynaptic connection between VN sensory neurons and mitral cells in the AOB showed enhancement with pairs or short trains of stimuli for ISI of 0.5 to > 10 s. A small inhibitory effect of GABAb receptors on presynaptic Ca2+ influx and release was only evident when a large proportion of the VN axons were stimulated simultaneously but even with inhibition present an overall enhancement of release was observed. Increasing the number of conditioning stimuli from one to five increased residual [Ca2+] and enhancement but a direct correlation between residual [Ca2+] and either the magnitude or the time course of enhancement was not observed. Enhanced transmitter release from VN afferent terminals results in effective integration of sustained low‐frequency activity, which may play a role in the detection of low‐intensity odourant stimuli by the VN system.
Role of polysialylated neural cell adhesion molecule in rapid eye movement sleep regulation in rats
Authors: Black Michelle A. , Deurveilher Samüel , Seki Tatsunori , Marsh Daniel R. , Rutishauser Urs , Rafuse Victor F. , Semba Kazue
Published: November 2009

Recent evidence suggests that synaptic plasticity occurs during homeostatic processes, including sleep–wakefulness regulation, although the underlying mechanisms are not well understood. Polysialylated neural cell adhesion molecule (PSA NCAM) is a transmembrane protein that has been implicated in various forms of plasticity. To investigate whether PSA NCAM is involved in the neuronal plasticity associated with spontaneous sleep–wakefulness regulation and sleep homeostasis, four studies were conducted using rats. First, we showed that PSA NCAM immunoreactivity is present in close proximity to key neurons in several nuclei of the sleep–wakefulness system, including the tuberomammillary hypothalamic nucleus, dorsal raphe nucleus, and locus coeruleus. Second, using western blot analysis and densitometric image analysis of immunoreactivity, we found that 6 h of sleep deprivation changed neither the levels nor the general location of PSA NCAM in the sleep–wakefulness system. Finally, we injected endoneuraminidase (Endo N) intracerebroventricularly to examine the effects of polysialic acid removal on sleep–wakefulness states and electroencephalogram (EEG) slow waves at both baseline and during recovery from 6 h of sleep deprivation. Endo N‐treated rats showed a small but significant decrease in baseline rapid eye movement (REM) sleep selectively in the late light phase, and a facilitated REM sleep rebound after sleep deprivation, as compared with saline‐injected controls. Non‐REM sleep and wakefulness were unaffected by Endo N. These results suggest that PSA NCAM is not particularly involved in the regulation of wakefulness or non‐REM sleep, but plays a role in the diurnal pattern of REM sleep as well as in some aspects of REM sleep homeostasis.
In vivo voltammetric monitoring of norepinephrine release in the rat ventral bed nucleus of the stria terminalis and anteroventral thalamic nucleus
Authors: Park Jinwoo , Kile Brian M. , Mark Wightman R.
Published: November 2009

The role and contribution of the dense noradrenergic innervation in the ventral bed nucleus of the stria terminalis (vBNST) and anteroventral thalamic nucleus (AV) to biological function and animal behaviors is poorly understood due to the small size of these nuclei. The aim of this study was to compare norepinephrine release and uptake in the vBNST with that in the AV of anesthetized rats. Measurements were made in vivo with fast‐scan cyclic voltammetry following electrical stimulation of noradrenergic projection pathways, either the dorsal noradrenergic bundle (DNB) or the ventral noradrenergic bundle (VNB). The substance detected was identified as norepinephrine based upon voltammetric, anatomical, neurochemical and pharmacological evidence. Fast‐scan cyclic voltammetry enables the selective monitoring of local norepinephrine overflow in the vBNST evoked by the stimulation of either the DNB or the VNB while norepinephrine in the AV was only evoked by DNB stimulation. The α2‐adrenoceptor antagonist yohimbine and the norepinephrine uptake inhibitor desipramine increased norepinephrine overflow and slowed its disappearance in both regions. However, control of extracellular norepinephrine by both autoreceptors and uptake was greater in the AV. The greater control exerted by autoreceptors and uptake in the AV resulted in reduced extracellular concentration compared with the v BNST when large numbers of stimulation pulses were employed. The differences in noradrenergic transmission observed in the terminal fields of the v BNST and the AV may differentially regulate activity in these two regions that both contain high densities of norepinephrine terminals.
Characterization of oculomotor and visual activities in the primate pedunculopontine tegmental nucleus during visually guided saccade tasks
Authors: Okada Ken‐Ichi , Kobayashi Yasushi
Published: November 2009

The pedunculopontine tegmental nucleus (PPTN) has anatomical connections with numerous visuomotor areas including the basal ganglia, thalamus, superior colliculus and frontal eye field. Although many anatomical and physiological studies suggest a role for the PPTN in the control of conditioned behavior and associative learning, the detailed characteristics of saccade‐ and visual‐related activities of PPTN neurons remain unclear. We recorded the activity of PPTN neurons in monkeys (Macaca fuscata ) during visually guided saccade tasks, and examined the response properties of saccade‐ and visual‐related activities such as time course, direction selectivity and contextual modulation. Saccade‐related activity occurred either during saccade execution or after saccade end. The preferred directions of the neuronal activity were biased toward the contralateral and upward sides. Half of the saccade‐related neurons showed activity modulation only for task saccades and not for spontaneous saccades outside the task. Visually‐responsive neurons responded with short latencies. Some responded to the appearance of the visual stimulus in a directionally selective manner, and others responded to both the appearance and disappearance of the visual stimulus in a directionally non‐selective manner. Many of these neurons exhibited distinct visual responses to the appearance of two different stimuli presented under different stages of the task, whereas a population of the neurons responded equally to the disappearance of the two stimuli. Thus, many PPTN neurons exhibited context‐dependent activity related to the visuomotor events, consistent with a role in controlling conditioned behavior.
The role of the hippocampus in mnemonic integration and retrieval: complementary evidence from lesion and inactivation studies
Authors: Iordanova M. D. , Burnett D. J. , Aggleton J. P. , Good M. , Honey R. C.
Published: November 2009

Two forms of account have been proposed for how animals form integrated memories for patterns of stimulation: the elemental account holds that the elements that make up the pattern become directly linked to one another, whereas the configural account holds that these elements become bound together through their capacity to activate a separate, shared configural memory. The hippocampus and perirhinal cortex have been linked to both elemental and configural processes. Here, we assessed the role of the rat hippocampus and perirhinal cortex in these distinct ways of processing patterns of sensory stimulation involving auditory, visual context and temporal information. Using selective lesions and inactivation techniques we identified a specific role for the hippocampus in the retrieval of configural memories but not of those that could be encoded elementally; we also identified a role for the rat perirhinal cortex in visual contextual learning. These results, using a novel combination of behavioural assays, provide clear support for the view that patterns of stimulation can be encoded either elementally or configurally, and that disruption of hippocampal function leaves rats reliant on elemental processes.
Oral delivery of mouse [d‐Leu‐4]‐OB3, a synthetic peptide amide with leptin‐like activity, in male C57BL/6J wild‐type andob/obmice: effects on energy balance, glycaemic control and serum osteocalcin levels
Authors: Novakovic Z. M. , Leinung M. C. , Lee D. W. , Grasso P.
Published: November 2009

Background:We have recently shown that intranasal administration of mouse [d‐Leu‐4]‐OB3 reconstituted in Intravail®to male Swiss Webster mice resulted in significantly higher bioavailability than commonly used injections methods of delivery. The absorption profile associated with intranasal delivery of mouse [d‐Leu‐4]‐OB3 showed an early peak representing absorption across the nasal mucosa, and a later peak suggesting a gastrointestinal site of uptake.

Aim and Methods:In the present study, we examined the effects of orally administered (by gavage) mouse [d‐Leu‐4]‐OB3 on energy balance, glycaemic control and serum osteocalcin levels in male C57BL/6J wild‐type andob/obmice allowed food and waterad libitumor calorie restricted by 40% of normal intake.

Results:In wild‐type mice fedad libitum, oral delivery of mouse [d‐Leu‐4]‐OB3 reduced body weight gain, food intake and serum glucose, by 4.4, 6.8 and 28.2% respectively. Serum osteocalcin levels and water intake were essentially the same in control and treated wild‐type mice. Inob/obmice fedad libitum, mouse [d‐Leu‐4]‐OB3 reduced body weight gain, food intake, water intake and serum glucose by 11.6, 16.5, 22.4 and 24.4% respectively. Serum osteocalcin inob/obmice treated with mouse [d‐Leu‐4]‐OB3 was elevated by 62% over controls. Calorie restriction alone caused significant weight loss in both wild‐type (9.0%) andob/ob(4.8%) mice, and mouse [d‐Leu‐4]‐OB3 did not further enhance this weight loss. As expected, serum glucose levels in wild‐type andob/obmice were significantly reduced by calorie restriction alone. Mouse [d‐Leu‐4]‐OB3 further reduced serum glucose in wild‐type mice and normalized levels inob/obmice. Calorie restriction alone reduced serum osteocalcin levels by 44.2% in wild‐type mice and by 19.1% inob/obmice. Mouse [d‐Leu‐4]‐OB3 prevented this decrease in groups of mice.

Conclusions:The results of this study suggest that oral delivery of mouse [d‐Leu‐4]‐OB3 in Intravail®is possible and may have potential not only as an alternative therapy in the treatment of human obesity and some of its associated metabolic dysfunctions, but also may help to prevent and/or reverse at least some of the bone loss which accompanies osteoporosis, anorexia nervosa and other wasting diseases.