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Selected AbstractsChildhood life events and childhood trauma in adult patients with depressive, anxiety and comorbid disorders vs. controlsACTA PSYCHIATRICA SCANDINAVICA, Issue 1 2010J. G. F. M. Hovens Hovens JGFM, Wiersma JE, Giltay EJ, van Oppen P, Spinhoven P, Penninx BWJH, Zitman FG. Childhood life events and childhood trauma in adult patients with depressive, anxiety and comorbid disorders vs. controls. Objective:, To investigate the association between childhood life events, childhood trauma and the presence of anxiety, depressive or comorbid anxiety and depressive disorders in adulthood. Method:, Data are from 1931 adult participants in the Netherlands Study of Depression and Anxiety (NESDA). Childhood life events included divorce of parents, early parental loss and ,placed in care', whereas childhood trauma was assessed as experienced emotional neglect, psychological, physical and sexual abuse prior to age 16. Results:, Childhood life events were not associated with psychopathology, except for ,placed in care' in the comorbid group. All types of childhood trauma were increasingly prevalent in the following order: controls, anxiety, depression, and comorbid group (P < 0.001). The higher the score was on the childhood trauma index, the stronger the association with psychopathology (P < 0.001). Conclusion:, Childhood trauma rather than childhood life events are related to anxiety and depressive disorders. The strong associations with the comorbid group suggest that childhood trauma contributes to the severity of psychopathology. Our study underscores the importance of heightened awareness of the possible presence of childhood trauma, especially in adult patients with comorbid anxiety and depressive disorders. [source] Metabolic syndrome: collapsing under its own weight?DIABETIC MEDICINE, Issue 5 2009D. Preiss Invited counterview to article by Cameron AJ, Zimmet PZ, Shaw JE, Alberti KGMM. The metabolic syndrome: in need of a global mission statement. Diabet Med 2009;26: 306,309 [source] Targeted replacement of rodent CCR2 with the human orthologue CCR2B: A mouse model for in vivo analysis of human target-selective small molecule MCP-1 receptor antagonistsDRUG DEVELOPMENT RESEARCH, Issue 4 2002Haydn M. Prosser Abstract Rodent models for testing the efficacy of lead compounds are often invalidated by species selectivity of the compounds. The advent of mouse embryonic stem cell technology has allowed the development of genetically engineered mouse strains that incorporate a specific human gene in place of the orthologous mouse gene, a so-called knock-in mouse. This study describes the generation and validation of a mutant mouse line that expresses human CCR2B as a functional substitute for murine CCR2. The human CCR2B knock-in mice are viable and appear normal. In vitro assays indicate that the CCR2B knock-in is functionally expressed, giving a macrophage chemotactic profile in response to JE or MCP-1 that is similar to human peripheral blood monocytes rather than that of a murine macrophage cell line. In addition, the human selective CCR2B antagonist, SB-399721, was a more potent inhibitor of CCR2B knock-in macrophages in response to hMCP-1 than JE. The ability of the human CCR2B gene to functionally substitute for the mouse orthologue in vivo is demonstrated by a normal inflammatory response to intraperitoneal thioglycollate injection. Drug Dev. Res. 55:197,209, 2002. © 2002 Wiley-Liss, Inc. [source] Ontogenetic diet shift in the June sucker Chasmistes liorus (Cypriniformes, Catostomidae) in the early juvenile stageECOLOGY OF FRESHWATER FISH, Issue 3 2010J. D. Kreitzer Kreitzer JD, Belk MC, Gonzalez DB, Tuckfield RC, Shiozawa DK, Rasmussen JE. Ontogenetic diet shift in the June sucker Chasmistes liorus (Cypriniformes, Catostomidae) in the early juvenile stage. Ecology of Freshwater Fish 2010: 19: 433,438. © 2010 John Wiley & Sons A/S Abstract,,, Ontogenetic diet shifts are common in fishes and often occur during early life stages. The larval and early juvenile period is critical in the life cycle of the endangered June sucker, Chasmistes liorus (Teleostei: Catostomidae). High larval and juvenile mortality leads to low recruitment to the breeding population and hence a declining natural population. To understand diet composition and dynamics in June sucker at early life stages, diet was quantified and compared to available food items in the natural environment during the early juvenile stage. Rotifers (Brachionus sp.) were the primary diet item at week 10, but by week 12 a small cyclopoid copepod (Microcyclops rubellus) became predominant. Availability of diet items varied little across the experimental period. The increase in size of young suckers may explain this rapid dietary shift, but there are some inconsistencies with the size selection argument. This diet shift represents an important nutritional change that should be considered in development of diets for young June sucker and in assessing suitability of nursery habitats. [source] Cluster headache: the challenge of clinical trials.HEADACHE, Issue 3 2003K Moore Curr Pain Headache. Rep 2002 Feb;6(1):52-56 The design and execution of clinical trials poses special problems for cluster headache. Although there is less inter-individual and intra-individual variability of attacks than seen with migraine, the brevity of attacks, spontaneous remissions unrelated to treatment, and the relative rarity of cluster headaches challenge investigators. The International Headache Society has developed guidelines that represent a compromise between scientific rigor and practicality. Only injectable sumatriptan for acute attacks and verapamil for prophylaxis have demonstrated a robust therapeutic effect in controlled clinical trials. Comment: Kenneth Moore raises important methodological considerations. It is possible to undertake crossover trials comparing different active treatments? He is correct in his assertion that few agents show robust efficacy. A major issue relates to the proportion of patients with episodic versus chronic cluster headache where efficacy of active treatments can vary. For example, oral zolmitriptan was effective against placebo only in those patients with episodic disease (Bahra A, Gawel MJ, Hardebo JE, Millson DS, Breen SA, Goadsby PJ. Oral zolmitriptan is effective in the acute treatment of cluster headache. Neurology. 2000;54:1832-1839). And a set of small studies on melatonin and cluster demonstrate the problems Dr. Moore describes. In one study (Leone M, D'Amico D, Moschiano F, Fraschini F, Busonne G. Metalonin versus placebo in the prophylaxis of cluster headache: a double-blind pilot study with parallel groups. Cephalalgia. 1996;16:494-496), the melatonin worked only in episodic, not chronic cluster patients. In the second study (Prinsheim T, Magnoux E, Dobson CF, Hamel E, Aube M. Melatonin as adjuctive therapy in the prophylaxis of cluster headache: a pilot study. Headache. 2002;42:787-792), melatonin did not work better than placebo in either episodic or chronic cluster patients. Furthermore, the paper abstracted above by Torelli and Manzoni suggests that episodic cluster may progress to chronic cluster as a result of extrinsic factors such as smoking. Finally, there are ethical issues in placebo-controlled cluster studies, given the severity of the pain and the availability of effective acute and chronic treatments. As noted above, Dr. Peter Goadsby points out the need to persevere with these studies to find nonvasoactive treatments for patients with cluster headache. DSM and SJT [source] Role of chemokine ligand 2 in the protective response to early murine pulmonary tuberculosisIMMUNOLOGY, Issue 4 2003Andre Kipnis Summary Chemokines play an important role in the development of immunity to tuberculosis. Chemokine ligand 2 (CCL2, JE, monocyte chemoattractant protein-1) is thought to be primarily responsible for recruiting monocytes, dendritic cells, natural killer cells and activated T cells, all of which play critical roles in the effective control of tuberculosis infection in mice. We show here that in mice in which the CCL2 gene was disrupted, low-dose aerosol infection with Mycobacterium tuberculosis resulted in fewer macrophages entering the lungs, but only a minor and transient increase in bacterial load in the lungs; these mice were still able to establish a state of chronic disease. Such animals showed similar numbers of activated T cells as wild-type mice, as determined by their expression of the CD44hi CD62lo phenotype, but a transient reduction in cells secreting interferon-,. These data indicate that the primary deficiency in mice unable to produce CCL2 is a transient failure to focus antigen-specific T lymphocytes into the infected lung, whereas other elements of the acquired host response are compensated for by different ligands interacting with the chemokine receptor CCR2. [source] An early report from newly established laboratory-based influenza surveillance in Lao PDRINFLUENZA AND OTHER RESPIRATORY VIRUSES, Issue 2 2010Phengta Vongphrachanh Please cite this paper as: Vongphrachanh P, Simmerman JM, Phonekeo D, Pansayavong V, Sisouk T, Ongkhamme S, Bryce GT, Corwin A, Bryant JE. An early report from newly established laboratory-based influenza surveillance in Lao PDR. Influenza and Other Respiratory Viruses 4(2), 47,52. Background, Prior to 2007, little information was available about the burden of influenza in Laos. We report data from the first laboratory-based influenza surveillance system established in the Lao People's Democratic Republic. Methods, Three hospitals in the capital city of Vientiane began surveillance for influenza-like illness (ILI) in outpatients in 2007 and expanded to include hospitalized pneumonia patients in 2008. Nasal/throat swab specimens were collected and tested for influenza and other respiratory viruses by multiplex ID-TagTM respiratory viral panel (RVP) assay on a Luminex® 100× MAP IS instrument (Qiagen, Singapore). Results, During January 2007 to December 2008, 287 of 526 (54·6%) outpatients with ILI were positive for at least one respiratory virus. Influenza was most commonly identified, with 63 (12·0%) influenza A and 92 (17·5%) influenza B positive patients identified. In 2008, six of 79 (7·6%) hospitalized pneumonia patients were positive for influenza A and four (5·1%) were positive for influenza B. Children <5 years represented 19% of viral infections in outpatients and 38% of pneumonia inpatients. Conclusion, Our results provide the first documentation of influenza burden among patients with febrile respiratory illness and pneumonia requiring hospitalization in Laos. Implementing laboratory-based influenza surveillance requires substantial investments in infrastructure and training. However, continuing outbreaks of avian influenza A/H5N1 in poultry and emergence of the 2009 influenza A(H1N1) pandemic strain further underscore the importance of establishing and maintaining influenza surveillance in developing countries. [source] Effect of systemic parathyroid hormone (1,34) and a , -tricalcium phosphate biomaterial on local bone formation in a critical-size rat calvarial defect modelJOURNAL OF CLINICAL PERIODONTOLOGY, Issue 5 2010Jonathan I. Yun Yun JI, Wikesjö UME, Borke JL, Bisch FC, Lewis JE, Herold RW, Swiec GD, Wood JC, McPherson III JC. Effect of systemic parathyroid hormone (1,34) and a ,-tricalcium phosphate biomaterial on local bone formation in a critical-size rat calvarial defect model. J Clin Periodontol 2010; 37: 419,426 doi: 10.1111/j.1600-051X.2010.01547.x Abstract Objective: The objective of this study was to evaluate local bone formation following systemic administration of parathyroid hormone (1,34) (PTH), a surgically implanted synthetic , -tricalcium phosphate (, -TCP) bone biomaterial serving as a matrix to support new bone formation. Materials and Methods: Critical-size, 8 mm, calvarial through-and-through osteotomy defects were surgically created in 100 adult male Sprague,Dawley rats. The animals were randomized into five groups of 20 animals each to receive one of the following treatments: PTH (15 ,g PTH/kg/day; subcutaneously), PTH/, -TCP, , -TCP, or particulate human demineralized freeze-dried bone (DFDB), and sham-surgery controls. Ten animals/group were euthanized at 4 and 8 weeks post-surgery for radiographic and histometric analysis. Results: The histometric analysis showed that systemic PTH significantly enhanced local bone formation, bone fill averaging (±SE) 32.2±4.0% compared with PTH/, -TCP (15.7±2.4%), , -TCP (12.5±2.3%), DFDB (14.5±2.3%), and sham-surgery control (10.0±1.5%) at 4 weeks (p<0.014). Systemic PTH showed significantly enhanced bone formation (41.5±4.0%) compared with PTH/, -TCP (22.4±3.0%), , -TCP (21.3±4.4%), and with the sham-surgery control (23.8±4.2%) at 8 weeks (p<0.025). The DFDB group showed significantly increased bone formation from 4 (14.5±2.3%) to 8 weeks (32.0±3.2%) (p<0.006). The PTH/, -TCP and , -TCP groups both showed limited biomaterials resorption. The radiographic analysis was not diagnostic to distinguish local bone formation from the radiopaque , -TCP biomaterial. Conclusions: Systemic administration of PTH significantly stimulates local bone formation. Bone formation was significantly limited by the , -TCP biomaterial. [source] Recurrent erythema multiforme triggered by progesterone sensitivityJOURNAL OF CUTANEOUS PATHOLOGY, Issue 11 2010Teresa J. Nasabzadeh Determining the underlying etiology of recurrent erythema multiforme (EM) can be a difficult endeavor. Although infection with herpes simplex virus (HSV) has been implicated in some cases, the precise trigger of a given patient's recurrent EM often remains elusive. We discuss the case of a woman with a recurrent blistering eruption that was clinically and histopathologically consistent with EM. An investigation into the etiology of the patient's EM suggested that HSV was not the causative factor but instead pointed toward a hormonal influence that we interpret as autoimmune progesterone dermatitis (APD). This case is presented to highlight the importance of considering hormonal triggers in women with recurrent EM that consistently flares during the luteal phase of the menstrual cycle, the point at which serum progesterone levels peak. A brief review of the literature regarding the diagnosis, histopathology, etiology and treatment of APD is further provided. Nasabzadeh TJ, Stefanato CM, Doole JE, Radfar A, Bhawan J, Venna S. Recurrent erythema multiforme triggered by progesterone sensitivity. [source] Fibrillar IgA deposition in dermatitis herpetiformis , an underreported pattern with potential clinical significanceJOURNAL OF CUTANEOUS PATHOLOGY, Issue 4 2010Christine J. Ko Dermatitis herpetiformis has characteristic clinical and histopathologic findings. A fibrillar pattern of IgA deposition on direct immunofluorescence in dermatitis herpetiformis is underreported. Here, we describe three patients with the fibrillar pattern of IgA deposition on direct immunofluorescence examination that initially misled diagnosis in one of the three. Interestingly, two of the three patients lacked anti-transglutaminase and anti-endomysial antibodies but had a clinical course typical of dermatitis herpetiformis. Dermatitis herpetiformis may have a fibrillar rather than granular pattern of IgA deposition on direct immunofluorescent microscopy, and patients with this pattern of immunoglobulin deposition may lack circulating autoantibodies. Ko CJ, Colegio OR, Moss JE, McNiff JM. Fibrillar IgA deposition in dermatitis herpetiformis,an underreported pattern with potential clinical significance. [source] Adverse endothelial function and the insulin resistance syndromeJOURNAL OF INTERNAL MEDICINE, Issue 4 2000J. E. Tooke Abstract. Tooke JE, Hannemann MM (School of Postgraduate Medicine and Vascular Health Sciences, University of Exeter, Devon). Adverse endothelial function and the insulin resistance syndrome (Review). J Intern Med 2000; 247: 425,431. Type 2 diabetes is characterized by impaired endothelial dependent vasodilatation which may contribute to the high prevalence of vascular disease in such patients. Although hyperglycaemia, dyslipidaemia and hypertension can all independently cause a similar defect, recent data suggest that endothelial dysfunction may be intrinsic to the insulin resistance syndrome that commonly precedes type 2 diabetes. Such abnormalities in endothelial function could represent the impact of subclinical disturbance of metabolism or alternatively the presence of a common cellular defect that influences both nitric oxide bioavailability and insulin mediated glucose disposal. Resolution of this puzzle is likely to lead to important advances in our knowledge and ultimately treatment of vascular disease. [source] A multiplex immunoassay demonstrates reductions in gingival crevicular fluid cytokines following initial periodontal therapyJOURNAL OF PERIODONTAL RESEARCH, Issue 1 2010D. H. Thunell Thunell DH, Tymkiw KD, Johnson GK, Joly S, Burnell KK, Cavanaugh JE, Brogden KA, Guthmiller JM. A multiplex immunoassay demonstrates reductions in gingival crevicular fluid cytokines following initial periodontal therapy. J Periodont Res 2009; doi: 10.1111/j.1600-0765.2009.01204.x. © 2009 John Wiley & Sons A/S Background and Objective:, Cytokines and chemokines play an important role in the pathogenesis of periodontal diseases. The objective of this study was to quantitatively assess the effect of initial periodontal therapy on gingival crevicular fluid levels of a comprehensive panel of cytokines and chemokines, including several less extensively studied mediators. Material and Methods:, Clinical examinations were performed and gingival crevicular fluid samples obtained from six subjects with generalized severe chronic periodontitis prior to initial periodontal therapy and at re-evaluation (6,8 weeks). Four diseased and two healthy sites were sampled in each subject. Twenty-two gingival crevicular fluid mediators were examined using a multiplex antibody capture and detection platform. Statistical analyses were performed by fitting mixed effects linear models to log-transformed gingival crevicular fluid values. Results:, Gingival crevicular fluid interleukin (IL)-1, and IL-1, were the only cytokines to differ in initially diseased vs. initially healthy sites. Following initial therapy, 13 of the 16 detectable cytokines and chemokines decreased significantly in diseased sites, including IL-1,, IL-1,, IL-2, IL-3, IL-6, IL-7, IL-8, IL-12 (p40), CCL5/regulated on activation, normally T cell expressed and secreted (RANTES), eotaxin, macrophage chemotactic protein-1, macrophage inflammatory protein-1, and interferon-,. At healthy sites, only three of the 16 mediators were significantly altered following therapy. Conclusion:, This is the first study, to our knowledge, to evaluate such an extensive panel of gingival crevicular fluid mediators within the same sample prior to and following initial therapy. The results confirm that periodontal therapy effectively reduces pro-inflammatory cytokines and chemokines, including less well-described mediators that may be important in initiation and progression of periodontitis. The multiplex assay will prove useful for future gingival crevicular fluid studies. [source] Localized antimicrobial peptide expression in human gingivaJOURNAL OF PERIODONTAL RESEARCH, Issue 5 2001Beverly A. Dale The stratified epithelia of the oral cavity are continually exposed to bacterial challenge that is initially resisted by innate epithelial factors and by the recruitment of neutrophils. Antimicrobial peptides from phagocytes and epithelia contribute to this antimicrobial barrier. Using antibodies and in situ hybridization, we explored antimicrobial peptide expression in the varied epithelia of the periodontium and in cultured gingival epithelial cells. In gingival tissue, mRNA for the ,-defensins, human beta-defensin 1 (hBD-1) and human beta-defensin 2 (hBD-2) was predominately localized in suprabasal stratified epithelium and the peptides were detected in upper epithelial layers consistent with the formation of the stratified epithelial barrier. In cultured epithelial cells, both hBD-1 and -2 peptides were detected only in differentiating, involucrin-positive epithelial cells, although hBD-2 required stimulation by proinflammatory mediators or bacterial products for expression. ,-defensins were not detected in junctional epithelium (JE) that serves as the attachment to the tooth surface. In contrast, ,-defensins and cathelicidin family member LL-37 were detected in polymorphonuclear neutrophils (PMNs) that migrate through the JE, a localization that persists during inflammation, when the JE and surrounding tissue are highly infiltrated with PMNs. Thus, the undifferentiated JE contains exogenously expressed ,-defensins and LL-37, and the stratified epithelium contains endogenously expressed ,-defensins. These findings show that defensins and other antimicrobial peptides are localized in specific sites in the gingiva, are synthesized in different cell types, and are likely to serve different roles in various regions of the periodontium. [source] Vicenza deciphered: modeling the von Willebrand disease enigma: commentary on accelerated clearance alone explains ultralarge multimers in VWD VicenzaJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 6 2010A. C. GOODEVE See also Gézsi A, Budde U, Deák I, Nagy E, Mohl A, Schlammadinger Á, Boda Z, Masszi T, Sadler JE, Bodó I. Accelerated clearance alone explains ultra-large multimers in von Willebrand disease Vicenza. This issue, pp 1273,80. [source] Enamel matrix proteins; old molecules for new applicationsORTHODONTICS & CRANIOFACIAL RESEARCH, Issue 3 2009SP Lyngstadaas Structured Abstract Authors,,, Lyngstadaas SP, Wohlfahrt JC, Brookes SJ, Paine ML, Snead ML, Reseland JE Emdogain® (enamel matrix derivative, EMD) is well recognized in periodontology, where it is used as a local adjunct to periodontal surgery to stimulate regeneration of periodontal tissues lost to periodontal disease. The biological effect of EMD is through stimulation of local growth factor secretion and cytokine expression in the treated tissues, inducing a regenerative process that mimics odontogenesis. The major (>95%) component of EMD is Amelogenins (Amel). No other active components have so far been isolated from EMD, and several studies have shown that purified amelogenins can induce the same effect as the complete EMD. Amelogenins comprise a family of highly conserved extracellular matrix proteins derived from one gene. Amelogenin structure and function is evolutionary well conserved, suggesting a profound role in biomineralization and hard tissue formation. A special feature of amelogenins is that under physiological conditions the proteins self-assembles into nanospheres that constitute an extracellular matrix. In the body, this matrix is slowly digested by specific extracellular proteolytic enzymes (matrix metalloproteinase) in a controlled process, releasing bioactive peptides to the surrounding tissues for weeks after application. Based on clinical and experimental observations in periodontology indicating that amelogenins can have a significant positive influence on wound healing, bone formation and root resorption, several new applications for amelogenins have been suggested. New experiments now confirm that amelogenins have potential for being used also in the fields of endodontics, bone regeneration, implantology, traumatology, and wound care. [source] The relationships among immunoglobulin levels, allergic sensitization, and viral respiratory illnesses in early childhoodPEDIATRIC ALLERGY AND IMMUNOLOGY, Issue 6 2010Michael E. Possin Possin ME, Morgan S, DaSilva DF, Tisler C, Pappas TE, Roberg KA, Anderson E, Evans MD, Gangnon R, Lemanske RF, Gern JE. The relationships among immunoglobulin levels, allergic sensitization, and viral respiratory illnesses in early childhood. Pediatr Allergy Immunol 2010: 21: 990,996. © 2010 John Wiley & Sons A/S IgE plays an essential role in type I allergy, however, there is less information about the relationship between other immunoglobulins (IgA and IgG) and atopic phenotypes in early childhood. We hypothesized that levels of circulating IgA in early childhood would be inversely related to the number of respiratory infections and the risk of becoming sensitized to allergens. Immunoglobulin levels were analyzed (ELISA) in plasma samples (IgG, IgA), and in nasal secretions (IgA) from children participating in a high-risk birth cohort study. Samples were available from 264 children at age 2 yr and 257 children at age 4 yr, and results were compared to rates of respiratory illnesses, allergic sensitization, atopic dermatitis (AD), and asthma. Children who were sensitized to allergens had higher rather than lower levels of circulating IgA. A subgroup analysis showed that IgA levels were increased in relationship to foods sensitization (58 vs. 50 mg/dl, p = 0.003) but not aeroallergen sensitization (52 vs. 53 mg/dl, p = 0.11). IgA levels in the plasma correlated with levels of IgE levels (rs =0.19, p = 0.003). Levels of IgE, but not IgG or IgA, were positively correlated with rates of respiratory illnesses, AD, and the risk of developing asthma. Finally, there were no significant relationships between IgA in nasal secretions and infectious outcomes. In conclusion, low-normal concentrations of plasma IgA are associated with a reduced prevalence of allergic sensitization in infancy. Further, levels of IgA and IgG in plasma within the range of normal, and IgA in nasal secretions, do not appear to influence the risk of subsequent respiratory illnesses. Further studies to define relationships between IgA and allergic sensitization are likely to provide new insights into the pathogenesis of allergic diseases in infancy. [source] The challenges and opportunities for transitional care researchPEDIATRIC TRANSPLANTATION, Issue 6 2010J. E. McDonagh McDonagh JE, Kelly DA. The challenges and opportunities for transitional care research. Pediatr Transplantation 2010: 14:688,700. © 2010 John Wiley & Sons A/S. Abstract:, The provision of healthcare for young people with solid organ transplants as they move into adult-centered services has received increasing attention over recent years particularly as non-adherence and graft loss increase after transfer. Despite medical advances and that transitional care is now well established on national and international health agendas, progress in the research arena has unfortunately been slow. The aims of this paper are to consider why this is and discuss the particular challenges facing clinical researchers working within the area. [source] Study of Japanese encephalitis and other viral encephalitis in Nepali childrenPEDIATRICS INTERNATIONAL, Issue 6 2007AJIT RAYAMAJHI Abstract Background: A hospital-based prospective cross-sectional study was conducted in children aged 1 month,14 years to identify the proportion of viral encephalitis due to Japanese encephalitis (JE) and compare the clinico-laboratory profile and outcome of JE with that of other viral encephalitis (non-JE). Methods: All probable cases of viral encephalitis on clinical and laboratory evaluation were confirmed as JE on anti-JE IgM in cerebrospinal fluid (CSF) and/or serum. Patients not having anti-JE IgM in CSF and/or serum were diagnosed as having non-JE. Results: Of 94 cases, 58 were JE and 36 non-JE. Although practice of rearing pigs at home was associated with JE (P = 0.0001), significantly higher serum creatinine, protein, aspartate aminotransferase and CSF protein levels were observed in non-JE. Longer duration of fever was associated with complete recovery in JE whereas shorter duration of fever was associated with recovery in non-JE. Risk of neurological sequelae (P = 0.01), especially hemiparesis (P = 0.03) was significantly more in JE. Sequelae were observed at 6 weeks follow up in 18.8% of JE and 13.9% of non-JE. Conclusion: JE was the most common cause of viral encephalitis in eastern Nepal and should be suspected in encephalitic patients having pig rearing at home and neurological sequelae. Although duration of hospitalization and complication were higher in JE, final outcome was similar to non-JE. Longer duration of fever in JE and shorter duration of fever in non-JE correlated with recovery, while altered sensorium and focal neurological deficit were independent predictors of sequelae at 6 weeks only in JE and not in non-JE. [source] REVIEW ARTICLE: Interleukin-10: A Multi-Faceted Agent of PregnancyAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 6 2010Jessica E. Thaxton Citation Thaxton JE, Sharma S. Interleukin-10: a multi-faceted agent of pregnancy. Am J Reprod Immunol 2010 It is widely accepted that pregnancy constitutes a unique developmental event. Unprecedented intrauterine actions of angiogenesis, immunity, and neuroendocrine regulation are juxtaposed to mechanisms of senescence that enable fetal growth and protection. The suppressive and regulatory factors that facilitate healthy pregnancy are under investigation. In non-pregnant systems of infection and inflammation, the cytokine interleukin-10 (IL-10) has been widely investigated because of its potential as a key immunosuppressant in response to a multitude of inflammatory events. In the context of pregnancy, IL-10 levels increase markedly in women during early pregnancy and remain elevated well into the third trimester immediately prior to onset of labor. The role of IL-10 during pregnancy as a suppressor of active maternal immunity to allow acceptance of the fetal allograft has been a point of study. Moreover, secretion of IL-10 by a diverse set of maternal and fetal cells has proven to aid in the orchestration of normal processes of pregnancy. Interestingly, some of the more profound findings regarding the actions of IL-10 during pregnancy have manifested from research that focuses on aberrant pregnancy outcomes as a result of inflammation, hormonal imbalances, or gene,environment interactions. This review focuses on the role of IL-10 as a facilitator of successful pregnancy both as an immune suppressive agent and a mediator of cross talk between the placenta and the decidua. Importantly, we discuss investigations on adverse pregnancy conditions to further elucidate the multifarious role of IL-10 at the maternal,fetal interface. [source] ORIGINAL RESEARCH,BASIC SCIENCE: Effects of ACE Inhibition and Beta-Blockade on Female Genital Structures in Spontaneously Hypertensive RatsTHE JOURNAL OF SEXUAL MEDICINE, Issue 6 2007Jorge E. Toblli MD ABSTRACT Introduction and Aim., This study evaluated the possible differences between an angiotensin converting enzyme (ACE) inhibitor and a beta-blocker concerning their potential protective role on female external genitalia in spontaneously hypertensive rats (SHR). Main Outcome Measures., Morphological changes in the clitoris after antihypertensive treatments. Methods., For 6 months, SHR received no treatment; SHR + ramipril (RAM), SHR + atenolol (AT), and control Wistar Kyoto (WKY) rats received no treatment. Clitorises were processed for immunohistochemistry using anti-,-smooth muscle actin (,-SMA), anti-collagen I and III, anti-transforming growth factor ,1 (TGF,1), and anti-endothelial nitric oxide synthase (eNOS) antibodies. Results., SHR + RAM and SHR + AT presented significantly lower blood pressure in both groups vs. untreated SHR. Compared with WKY, ,-SMA was increased in the arteries and in the cavernous spaces of the clitoris together with a marked increase in wall/lumen ratio in clitoral vessels in untreated SHR. All these alterations were diminished in SHR + AT (P < 0.01). SHR + RAM presented differences with respect to SHR + AT in the reduction of these variables. TGF,1 expression in the vessel wall from the clitoris and collagen I and III deposition in the interstitium from the clitoris in untreated SHR were significantly more (P < 0.01) than in WKY. While SHR + AT showed a mild decrease in these variables, SHR + RAM presented a significant reduction (P < 0.01) in TGF,1 expression interstitial fibrosis and in both types of collagens. Positive immunostaining of eNOS in the sinusoidal endothelium from the clitoris was less (P < 0.01) in untreated SHR (3.4 ± 1.3%) and SHR + AT (5.1 ± 1.2%) than in SHR + RAM (17.2 ± 1.6%) and WKY (15.9 ± 1.7%). Untreated SHR and SHR + AT presented more surrounding connective tissue at the perineurium in the clitoris (P < 0.01) than SHR + RAM. Conclusion., ACE inhibition provided a considerable protective role on the female external genitalia structures in SHR by a mechanism that may be, at least in part, independent of the degree of blood pressure lowering. Toblli JE, Cao G, Casabé AR, and Bechara AJ. Effects of ACE inhibition and beta-blockade on female genital structures in spontaneously hypertensive rats. J Sex Med 2007;4:1593,1603. [source] European Mathematical Genetics Meeting, Heidelberg, Germany, 12th,13th April 2007ANNALS OF HUMAN GENETICS, Issue 4 2007Article first published online: 28 MAY 200 Saurabh Ghosh 11 Indian Statistical Institute, Kolkata, India High correlations between two quantitative traits may be either due to common genetic factors or common environmental factors or a combination of both. In this study, we develop statistical methods to extract the contribution of a common QTL to the total correlation between the components of a bivariate phenotype. Using data on bivariate phenotypes and marker genotypes for sib-pairs, we propose a test for linkage between a common QTL and a marker locus based on the conditional cross-sib trait correlations (trait 1 of sib 1 , trait 2 of sib 2 and conversely) given the identity-by-descent sharing at the marker locus. The null hypothesis cannot be rejected unless there exists a common QTL. We use Monte-Carlo simulations to evaluate the performance of the proposed test under different trait parameters and quantitative trait distributions. An application of the method is illustrated using data on two alcohol-related phenotypes from the Collaborative Study On The Genetics Of Alcoholism project. Rémi Kazma 1 , Catherine Bonaïti-Pellié 1 , Emmanuelle Génin 12 INSERM UMR-S535 and Université Paris Sud, Villejuif, 94817, France Keywords: Gene-environment interaction, sibling recurrence risk, exposure correlation Gene-environment interactions may play important roles in complex disease susceptibility but their detection is often difficult. Here we show how gene-environment interactions can be detected by investigating the degree of familial aggregation according to the exposure of the probands. In case of gene-environment interaction, the distribution of genotypes of affected individuals, and consequently the risk in relatives, depends on their exposure. We developed a test comparing the risks in sibs according to the proband exposure. To evaluate the properties of this new test, we derived the formulas for calculating the expected risks in sibs according to the exposure of probands for various values of exposure frequency, relative risk due to exposure alone, frequencies of latent susceptibility genotypes, genetic relative risks and interaction coefficients. We find that the ratio of risks when the proband is exposed and not exposed is a good indicator of the interaction effect. We evaluate the power of the test for various sample sizes of affected individuals. We conclude that this test is valuable for diseases with moderate familial aggregation, only when the role of the exposure has been clearly evidenced. Since a correlation for exposure among sibs might lead to a difference in risks among sibs in the different proband exposure strata, we also add an exposure correlation coefficient in the model. Interestingly, we find that when this correlation is correctly accounted for, the power of the test is not decreased and might even be significantly increased. Andrea Callegaro 1 , Hans J.C. Van Houwelingen 1 , Jeanine Houwing-Duistermaat 13 Dept. of Medical Statistics and Bioinformatics, Leiden University Medical Center, The Netherlands Keywords: Survival analysis, age at onset, score test, linkage analysis Non parametric linkage (NPL) analysis compares the identical by descent (IBD) sharing in sibling pairs to the expected IBD sharing under the hypothesis of no linkage. Often information is available on the marginal cumulative hazards (for example breast cancer incidence curves). Our aim is to extend the NPL methods by taking into account the age at onset of selected sibling pairs using these known marginal hazards. Li and Zhong (2002) proposed a (retrospective) likelihood ratio test based on an additive frailty model for genetic linkage analysis. From their model we derive a score statistic for selected samples which turns out to be a weighed NPL method. The weights depend on the marginal cumulative hazards and on the frailty parameter. A second approach is based on a simple gamma shared frailty model. Here, we simply test whether the score function of the frailty parameter depends on the excess IBD. We compare the performance of these methods using simulated data. Céline Bellenguez 1 , Carole Ober 2 , Catherine Bourgain 14 INSERM U535 and University Paris Sud, Villejuif, France 5 Department of Human Genetics, The University of Chicago, USA Keywords: Linkage analysis, linkage disequilibrium, high density SNP data Compared with microsatellite markers, high density SNP maps should be more informative for linkage analyses. However, because they are much closer, SNPs present important linkage disequilibrium (LD), which biases classical nonparametric multipoint analyses. This problem is even stronger in population isolates where LD extends over larger regions with a more stochastic pattern. We investigate the issue of linkage analysis with a 500K SNP map in a large and inbred 1840-member Hutterite pedigree, phenotyped for asthma. Using an efficient pedigree breaking strategy, we first identified linked regions with a 5cM microsatellite map, on which we focused to evaluate the SNP map. The only method that models LD in the NPL analysis is limited in both the pedigree size and the number of markers (Abecasis and Wigginton, 2005) and therefore could not be used. Instead, we studied methods that identify sets of SNPs with maximum linkage information content in our pedigree and no LD-driven bias. Both algorithms that directly remove pairs of SNPs in high LD and clustering methods were evaluated. Null simulations were performed to control that Zlr calculated with the SNP sets were not falsely inflated. Preliminary results suggest that although LD is strong in such populations, linkage information content slightly better than that of microsatellite maps can be extracted from dense SNP maps, provided that a careful marker selection is conducted. In particular, we show that the specific LD pattern requires considering LD between a wide range of marker pairs rather than only in predefined blocks. Peter Van Loo 1,2,3 , Stein Aerts 1,2 , Diether Lambrechts 4,5 , Bernard Thienpont 2 , Sunit Maity 4,5 , Bert Coessens 3 , Frederik De Smet 4,5 , Leon-Charles Tranchevent 3 , Bart De Moor 2 , Koen Devriendt 3 , Peter Marynen 1,2 , Bassem Hassan 1,2 , Peter Carmeliet 4,5 , Yves Moreau 36 Department of Molecular and Developmental Genetics, VIB, Belgium 7 Department of Human Genetics, University of Leuven, Belgium 8 Bioinformatics group, Department of Electrical Engineering, University of Leuven, Belgium 9 Department of Transgene Technology and Gene Therapy, VIB, Belgium 10 Center for Transgene Technology and Gene Therapy, University of Leuven, Belgium Keywords: Bioinformatics, gene prioritization, data fusion The identification of genes involved in health and disease remains a formidable challenge. Here, we describe a novel bioinformatics method to prioritize candidate genes underlying pathways or diseases, based on their similarity to genes known to be involved in these processes. It is freely accessible as an interactive software tool, ENDEAVOUR, at http://www.esat.kuleuven.be/endeavour. Unlike previous methods, ENDEAVOUR generates distinct prioritizations from multiple heterogeneous data sources, which are then integrated, or fused, into one global ranking using order statistics. ENDEAVOUR prioritizes candidate genes in a three-step process. First, information about a disease or pathway is gathered from a set of known "training" genes by consulting multiple data sources. Next, the candidate genes are ranked based on similarity with the training properties obtained in the first step, resulting in one prioritized list for each data source. Finally, ENDEAVOUR fuses each of these rankings into a single global ranking, providing an overall prioritization of the candidate genes. Validation of ENDEAVOUR revealed it was able to efficiently prioritize 627 genes in disease data sets and 76 genes in biological pathway sets, identify candidates of 16 mono- or polygenic diseases, and discover regulatory genes of myeloid differentiation. Furthermore, the approach identified YPEL1 as a novel gene involved in craniofacial development from a 2-Mb chromosomal region, deleted in some patients with DiGeorge-like birth defects. Finally, we are currently evaluating a pipeline combining array-CGH, ENDEAVOUR and in vivo validation in zebrafish to identify novel genes involved in congenital heart defects. Mark Broom 1 , Graeme Ruxton 2 , Rebecca Kilner 311 Mathematics Dept., University of Sussex, UK 12 Division of Environmental and Evolutionary Biology, University of Glasgow, UK 13 Department of Zoology, University of Cambridge, UK Keywords: Evolutionarily stable strategy, parasitism, asymmetric game Brood parasites chicks vary in the harm that they do to their companions in the nest. In this presentation we use game-theoretic methods to model this variation. Our model considers hosts which potentially abandon single nestlings and instead choose to re-allocate their reproductive effort to future breeding, irrespective of whether the abandoned chick is the host's young or a brood parasite's. The parasite chick must decide whether or not to kill host young by balancing the benefits from reduced competition in the nest against the risk of desertion by host parents. The model predicts that three different types of evolutionarily stable strategies can exist. (1) Hosts routinely rear depleted broods, the brood parasite always kills host young and the host never then abandons the nest. (2) When adult survival after deserting single offspring is very high, hosts always abandon broods of a single nestling and the parasite never kills host offspring, effectively holding them as hostages to prevent nest desertion. (3) Intermediate strategies, in which parasites sometimes kill their nest-mates and host parents sometimes desert nests that contain only a single chick, can also be evolutionarily stable. We provide quantitative descriptions of how the values given to ecological and behavioral parameters of the host-parasite system influence the likelihood of each strategy and compare our results with real host-brood parasite associations in nature. Martin Harrison 114 Mathematics Dept, University of Sussex, UK Keywords: Brood parasitism, games, host, parasite The interaction between hosts and parasites in bird populations has been studied extensively. Game theoretical methods have been used to model this interaction previously, but this has not been studied extensively taking into account the sequential nature of this game. We consider a model allowing the host and parasite to make a number of decisions, which depend on a number of natural factors. The host lays an egg, a parasite bird will arrive at the nest with a certain probability and then chooses to destroy a number of the host eggs and lay one of it's own. With some destruction occurring, either natural or through the actions of the parasite, the host chooses to continue, eject an egg (hoping to eject the parasite) or abandon the nest. Once the eggs have hatched the game then falls to the parasite chick versus the host. The chick chooses to destroy or eject a number of eggs. The final decision is made by the host, choosing whether to raise or abandon the chicks that are in the nest. We consider various natural parameters and probabilities which influence these decisions. We then use this model to look at real-world situations of the interactions of the Reed Warbler and two different parasites, the Common Cuckoo and the Brown-Headed Cowbird. These two parasites have different methods in the way that they parasitize the nests of their hosts. The hosts in turn have a different reaction to these parasites. Arne Jochens 1 , Amke Caliebe 2 , Uwe Roesler 1 , Michael Krawczak 215 Mathematical Seminar, University of Kiel, Germany 16 Institute of Medical Informatics and Statistics, University of Kiel, Germany Keywords: Stepwise mutation model, microsatellite, recursion equation, temporal behaviour We consider the stepwise mutation model which occurs, e.g., in microsatellite loci. Let X(t,i) denote the allelic state of individual i at time t. We compute expectation, variance and covariance of X(t,i), i=1,,,N, and provide a recursion equation for P(X(t,i)=z). Because the variance of X(t,i) goes to infinity as t grows, for the description of the temporal behaviour, we regard the scaled process X(t,i)-X(t,1). The results furnish a better understanding of the behaviour of the stepwise mutation model and may in future be used to derive tests for neutrality under this model. Paul O'Reilly 1 , Ewan Birney 2 , David Balding 117 Statistical Genetics, Department of Epidemiology and Public Health, Imperial, College London, UK 18 European Bioinformatics Institute, EMBL, Cambridge, UK Keywords: Positive selection, Recombination rate, LD, Genome-wide, Natural Selection In recent years efforts to develop population genetics methods that estimate rates of recombination and levels of natural selection in the human genome have intensified. However, since the two processes have an intimately related impact on genetic variation their inference is vulnerable to confounding. Genomic regions subject to recent selection are likely to have a relatively recent common ancestor and consequently less opportunity for historical recombinations that are detectable in contemporary populations. Here we show that selection can reduce the population-based recombination rate estimate substantially. In genome-wide studies for detecting selection we observe a tendency to highlight loci that are subject to low levels of recombination. We find that the outlier approach commonly adopted in such studies may have low power unless variable recombination is accounted for. We introduce a new genome-wide method for detecting selection that exploits the sensitivity to recent selection of methods for estimating recombination rates, while accounting for variable recombination using pedigree data. Through simulations we demonstrate the high power of the Ped/Pop approach to discriminate between neutral and adaptive evolution, particularly in the context of choosing outliers from a genome-wide distribution. Although methods have been developed showing good power to detect selection ,in action', the corresponding window of opportunity is small. In contrast, the power of the Ped/Pop method is maintained for many generations after the fixation of an advantageous variant Sarah Griffiths 1 , Frank Dudbridge 120 MRC Biostatistics Unit, Cambridge, UK Keywords: Genetic association, multimarker tag, haplotype, likelihood analysis In association studies it is generally too expensive to genotype all variants in all subjects. We can exploit linkage disequilibrium between SNPs to select a subset that captures the variation in a training data set obtained either through direct resequencing or a public resource such as the HapMap. These ,tag SNPs' are then genotyped in the whole sample. Multimarker tagging is a more aggressive adaptation of pairwise tagging that allows for combinations of two or more tag SNPs to predict an untyped SNP. Here we describe a new method for directly testing the association of an untyped SNP using a multimarker tag. Previously, other investigators have suggested testing a specific tag haplotype, or performing a weighted analysis using weights derived from the training data. However these approaches do not properly account for the imperfect correlation between the tag haplotype and the untyped SNP. Here we describe a straightforward approach to testing untyped SNPs using a missing-data likelihood analysis, including the tag markers as nuisance parameters. The training data is stacked on top of the main body of genotype data so there is information on how the tag markers predict the genotype of the untyped SNP. The uncertainty in this prediction is automatically taken into account in the likelihood analysis. This approach yields more power and also a more accurate prediction of the odds ratio of the untyped SNP. Anke Schulz 1 , Christine Fischer 2 , Jenny Chang-Claude 1 , Lars Beckmann 121 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ) Heidelberg, Germany 22 Institute of Human Genetics, University of Heidelberg, Germany Keywords: Haplotype, haplotype sharing, entropy, Mantel statistics, marker selection We previously introduced a new method to map genes involved in complex diseases, using haplotype sharing-based Mantel statistics to correlate genetic and phenotypic similarity. Although the Mantel statistic is powerful in narrowing down candidate regions, the precise localization of a gene is hampered in genomic regions where linkage disequilibrium is so high that neighboring markers are found to be significant at similar magnitude and we are not able to discriminate between them. Here, we present a new approach to localize susceptibility genes by combining haplotype sharing-based Mantel statistics with an iterative entropy-based marker selection algorithm. For each marker at which the Mantel statistic is evaluated, the algorithm selects a subset of surrounding markers. The subset is chosen to maximize multilocus linkage disequilibrium, which is measured by the normalized entropy difference introduced by Nothnagel et al. (2002). We evaluated the algorithm with respect to type I error and power. Its ability to localize the disease variant was compared to the localization (i) without marker selection and (ii) considering haplotype block structure. Case-control samples were simulated from a set of 18 haplotypes, consisting of 15 SNPs in two haplotype blocks. The new algorithm gave correct type I error and yielded similar power to detect the disease locus compared to the alternative approaches. The neighboring markers were clearly less often significant than the causal locus, and also less often significant compared to the alternative approaches. Thus the new algorithm improved the precision of the localization of susceptibility genes. Mark M. Iles 123 Section of Epidemiology and Biostatistics, LIMM, University of Leeds, UK Keywords: tSNP, tagging, association, HapMap Tagging SNPs (tSNPs) are commonly used to capture genetic diversity cost-effectively. However, it is important that the efficacy of tSNPs is correctly estimated, otherwise coverage may be insufficient. If the pilot sample from which tSNPs are chosen is too small or the initial marker map too sparse, tSNP efficacy may be overestimated. An existing estimation method based on bootstrapping goes some way to correct for insufficient sample size and overfitting, but does not completely solve the problem. We describe a novel method, based on exclusion of haplotypes, that improves on the bootstrap approach. Using simulated data, the extent of the sample size problem is investigated and the performance of the bootstrap and the novel method are compared. We incorporate an existing method adjusting for marker density by ,SNP-dropping'. We find that insufficient sample size can cause large overestimates in tSNP efficacy, even with as many as 100 individuals, and the problem worsens as the region studied increases in size. Both the bootstrap and novel method correct much of this overestimate, with our novel method consistently outperforming the bootstrap method. We conclude that a combination of insufficient sample size and overfitting may lead to overestimation of tSNP efficacy and underpowering of studies based on tSNPs. Our novel approach corrects for much of this bias and is superior to the previous method. Sample sizes larger than previously suggested may still be required for accurate estimation of tSNP efficacy. This has obvious ramifications for the selection of tSNPs from HapMap data. Claudio Verzilli 1 , Juliet Chapman 1 , Aroon Hingorani 2 , Juan Pablo-Casas 1 , Tina Shah 2 , Liam Smeeth 1 , John Whittaker 124 Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, UK 25 Division of Medicine, University College London, UK Keywords: Meta-analysis, Genetic association studies We present a Bayesian hierarchical model for the meta-analysis of candidate gene studies with a continuous outcome. Such studies often report results from association tests for different, possibly study-specific and non-overlapping markers (typically SNPs) in the same genetic region. Meta analyses of the results at each marker in isolation are seldom appropriate as they ignore the correlation that may exist between markers due to linkage disequlibrium (LD) and cannot assess the relative importance of variants at each marker. Also such marker-wise meta analyses are restricted to only those studies that have typed the marker in question, with a potential loss of power. A better strategy is one which incorporates information about the LD between markers so that any combined estimate of the effect of each variant is corrected for the effect of other variants, as in multiple regression. Here we develop a Bayesian hierarchical linear regression that models the observed genotype group means and uses pairwise LD measurements between markers as prior information to make posterior inference on adjusted effects. The approach is applied to the meta analysis of 24 studies assessing the effect of 7 variants in the C-reactive protein (CRP) gene region on plasma CRP levels, an inflammatory biomarker shown in observational studies to be positively associated with cardiovascular disease. Cathryn M. Lewis 1 , Christopher G. Mathew 1 , Theresa M. Marteau 226 Dept. of Medical and Molecular Genetics, King's College London, UK 27 Department of Psychology, King's College London, UK Keywords: Risk, genetics, CARD15, smoking, model Recently progress has been made in identifying mutations that confer susceptibility to complex diseases, with the potential to use these mutations in determining disease risk. We developed methods to estimate disease risk based on genotype relative risks (for a gene G), exposure to an environmental factor (E), and family history (with recurrence risk ,R for a relative of type R). ,R must be partitioned into the risk due to G (which is modelled independently) and the residual risk. The risk model was then applied to Crohn's disease (CD), a severe gastrointestinal disease for which smoking increases disease risk approximately 2-fold, and mutations in CARD15 confer increased risks of 2.25 (for carriers of a single mutation) and 9.3 (for carriers of two mutations). CARD15 accounts for only a small proportion of the genetic component of CD, with a gene-specific ,S, CARD15 of 1.16, from a total sibling relative risk of ,S= 27. CD risks were estimated for high-risk individuals who are siblings of a CD case, and who also smoke. The CD risk to such individuals who carry two CARD15 mutations is approximately 0.34, and for those carrying a single CARD15 mutation the risk is 0.08, compared to a population prevalence of approximately 0.001. These results imply that complex disease genes may be valuable in estimating with greater precision than has hitherto been possible disease risks in specific, easily identified subgroups of the population with a view to prevention. Yurii Aulchenko 128 Department of Epidemiology & Biostatistics, Erasmus Medical Centre Rotterdam, The Netherlands Keywords: Compression, information, bzip2, genome-wide SNP data, statistical genetics With advances in molecular technology, studies accessing millions of genetic polymorphisms in thousands of study subjects will soon become common. Such studies generate large amounts of data, whose effective storage and management is a challenge to the modern statistical genetics. Standard file compression utilities, such as Zip, Gzip and Bzip2, may be helpful to minimise the storage requirements. Less obvious is the fact that the data compression techniques may be also used in the analysis of genetic data. It is known that the efficiency of a particular compression algorithm depends on the probability structure of the data. In this work, we compared different standard and customised tools using the data from human HapMap project. Secondly, we investigate the potential uses of data compression techniques for the analysis of linkage, association and linkage disequilibrium Suzanne Leal 1 , Bingshan Li 129 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, USA Keywords: Consanguineous pedigrees, missing genotype data Missing genotype data can increase false-positive evidence for linkage when either parametric or nonparametric analysis is carried out ignoring intermarker linkage disequilibrium (LD). Previously it was demonstrated by Huang et al (2005) that no bias occurs in this situation for affected sib-pairs with unrelated parents when either both parents are genotyped or genotype data is available for two additional unaffected siblings when parental genotypes are missing. However, this is not the case for consanguineous pedigrees, where missing genotype data for any pedigree member within a consanguinity loop can increase false-positive evidence of linkage. The false-positive evidence for linkage is further increased when cryptic consanguinity is present. The amount of false-positive evidence for linkage is highly dependent on which family members are genotyped. When parental genotype data is available, the false-positive evidence for linkage is usually not as strong as when parental genotype data is unavailable. Which family members will aid in the reduction of false-positive evidence of linkage is highly dependent on which other family members are genotyped. For a pedigree with an affected proband whose first-cousin parents have been genotyped, further reduction in the false-positive evidence of linkage can be obtained by including genotype data from additional affected siblings of the proband or genotype data from the proband's sibling-grandparents. When parental genotypes are not available, false-positive evidence for linkage can be reduced by including in the analysis genotype data from either unaffected siblings of the proband or the proband's married-in-grandparents. Najaf Amin 1 , Yurii Aulchenko 130 Department of Epidemiology & Biostatistics, Erasmus Medical Centre Rotterdam, The Netherlands Keywords: Genomic Control, pedigree structure, quantitative traits The Genomic Control (GC) method was originally developed to control for population stratification and cryptic relatedness in association studies. This method assumes that the effect of population substructure on the test statistics is essentially constant across the genome, and therefore unassociated markers can be used to estimate the effect of confounding onto the test statistic. The properties of GC method were extensively investigated for different stratification scenarios, and compared to alternative methods, such as the transmission-disequilibrium test. The potential of this method to correct not for occasional cryptic relations, but for regular pedigree structure, however, was not investigated before. In this work we investigate the potential of the GC method for pedigree-based association analysis of quantitative traits. The power and type one error of the method was compared to standard methods, such as the measured genotype (MG) approach and quantitative trait transmission-disequilibrium test. In human pedigrees, with trait heritability varying from 30 to 80%, the power of MG and GC approach was always higher than that of TDT. GC had correct type 1 error and its power was close to that of MG under moderate heritability (30%), but decreased with higher heritability. William Astle 1 , Chris Holmes 2 , David Balding 131 Department of Epidemiology and Public Health, Imperial College London, UK 32 Department of Statistics, University of Oxford, UK Keywords: Population structure, association studies, genetic epidemiology, statistical genetics In the analysis of population association studies, Genomic Control (Devlin & Roeder, 1999) (GC) adjusts the Armitage test statistic to correct the type I error for the effects of population substructure, but its power is often sub-optimal. Turbo Genomic Control (TGC) generalises GC to incorporate co-variation of relatedness and phenotype, retaining control over type I error while improving power. TGC is similar to the method of Yu et al. (2006), but we extend it to binary (case-control) in addition to quantitative phenotypes, we implement improved estimation of relatedness coefficients, and we derive an explicit statistic that generalizes the Armitage test statistic and is fast to compute. TGC also has similarities to EIGENSTRAT (Price et al., 2006) which is a new method based on principle components analysis. The problems of population structure(Clayton et al., 2005) and cryptic relatedness (Voight & Pritchard, 2005) are essentially the same: if patterns of shared ancestry differ between cases and controls, whether distant (coancestry) or recent (cryptic relatedness), false positives can arise and power can be diminished. With large numbers of widely-spaced genetic markers, coancestry can now be measured accurately for each pair of individuals via patterns of allele-sharing. Instead of modelling subpopulations, we work instead with a coancestry coefficient for each pair of individuals in the study. We explain the relationships between TGC, GC and EIGENSTRAT. We present simulation studies and real data analyses to illustrate the power advantage of TGC in a range of scenarios incorporating both substructure and cryptic relatedness. References Clayton, D. G.et al. (2005) Population structure, differential bias and genomic control in a large-scale case-control association study. Nature Genetics37(11) November 2005. Devlin, B. & Roeder, K. (1999) Genomic control for association studies. Biometics55(4) December 1999. Price, A. L.et al. (2006) Principal components analysis corrects for stratification in genome-wide association studies. Nature Genetics38(8) (August 2006). Voight, B. J. & Pritchard, J. K. (2005) Confounding from cryptic relatedness in case-control association studies. Public Library of Science Genetics1(3) September 2005. Yu, J.et al. (2006) A unified mixed-model method for association mapping that accounts for multiple levels of relatedness. Nature Genetics38(2) February 2006. Hervé Perdry 1 , Marie-Claude Babron 1 , Françoise Clerget-Darpoux 133 INSERM U535 and Univ. Paris Sud, UMR-S 535, Villejuif, France Keywords: Modifier genes, case-parents trios, ordered transmission disequilibrium test A modifying locus is a polymorphic locus, distinct from the disease locus, which leads to differences in the disease phenotype, either by modifying the penetrance of the disease allele, or by modifying the expression of the disease. The effect of such a locus is a clinical heterogeneity that can be reflected by the values of an appropriate covariate, such as the age of onset, or the severity of the disease. We designed the Ordered Transmission Disequilibrium Test (OTDT) to test for a relation between the clinical heterogeneity, expressed by the covariate, and marker genotypes of a candidate gene. The method applies to trio families with one affected child and his parents. Each family member is genotyped at a bi-allelic marker M of a candidate gene. To each of the families is associated a covariate value; the families are ordered on the values of this covariate. As the TDT (Spielman et al. 1993), the OTDT is based on the observation of the transmission rate T of a given allele at M. The OTDT aims to find a critical value of the covariate which separates the sample of families in two subsamples in which the transmission rates are significantly different. We investigate the power of the method by simulations under various genetic models and covariate distributions. Acknowledgments H Perdry is funded by ARSEP. Pascal Croiseau 1 , Heather Cordell 2 , Emmanuelle Génin 134 INSERM U535 and University Paris Sud, UMR-S535, Villejuif, France 35 Institute of Human Genetics, Newcastle University, UK Keywords: Association, missing data, conditionnal logistic regression Missing data is an important problem in association studies. Several methods used to test for association need that individuals be genotyped at the full set of markers. Individuals with missing data need to be excluded from the analysis. This could involve an important decrease in sample size and a loss of information. If the disease susceptibility locus (DSL) is poorly typed, it is also possible that a marker in linkage disequilibrium gives a stronger association signal than the DSL. One may then falsely conclude that the marker is more likely to be the DSL. We recently developed a Multiple Imputation method to infer missing data on case-parent trios Starting from the observed data, a few number of complete data sets are generated by Markov-Chain Monte Carlo approach. These complete datasets are analysed using standard statistical package and the results are combined as described in Little & Rubin (2002). Here we report the results of simulations performed to examine, for different patterns of missing data, how often the true DSL gives the highest association score among different loci in LD. We found that multiple imputation usually correctly detect the DSL site even if the percentage of missing data is high. This is not the case for the naïve approach that consists in discarding trios with missing data. In conclusion, Multiple imputation presents the advantage of being easy to use and flexible and is therefore a promising tool in the search for DSL involved in complex diseases. Salma Kotti 1 , Heike Bickeböller 2 , Françoise Clerget-Darpoux 136 University Paris Sud, UMR-S535, Villejuif, France 37 Department of Genetic Epidemiology, Medical School, University of Göttingen, Germany Keywords: Genotype relative risk, internal controls, Family based analyses Family based analyses using internal controls are very popular both for detecting the effect of a genetic factor and for estimating the relative disease risk on the corresponding genotypes. Two different procedures are often applied to reconstitute internal controls. The first one considers one pseudocontrol genotype formed by the parental non-transmitted alleles called also 1:1 matching of alleles, while the second corresponds to three pseudocontrols corresponding to all genotypes formed by the parental alleles except the one of the case (1:3 matching). Many studies have compared between the two procedures in terms of the power and have concluded that the difference depends on the underlying genetic model and the allele frequencies. However, the estimation of the Genotype Relative Risk (GRR) under the two procedures has not been studied. Based on the fact that on the 1:1 matching, the control group is composed of the alleles untransmitted to the affected child and on the 1:3 matching, the control group is composed amongst alleles already transmitted to the affected child, we expect a difference on the GRR estimation. In fact, we suspect that the second procedure leads to biased estimation of the GRRs. We will analytically derive the GRR estimators for the 1:1 and 1:3 matching and will present the results at the meeting. Family based analyses using internal controls are very popular both for detecting the effect of a genetic factor and for estimating the relative disease risk on the corresponding genotypes. Two different procedures are often applied to reconstitute internal controls. The first one considers one pseudocontrol genotype formed by the parental non-transmitted alleles called also 1:1 matching of alleles, while the second corresponds to three pseudocontrols corresponding to all genotypes formed by the parental alleles except the one of the case (1:3 matching). Many studies have compared between the two procedures in terms of the power and have concluded that the difference depends on the underlying genetic model and the allele frequencies. However, the estimation of the Genotype Relative Risk (GRR) under the two procedures has not been studied. Based on the fact that on the 1:1 matching, the control group is composed of the alleles untransmitted to the affected child and on the 1:3 matching, the control group is composed amongst alleles already transmitted to the affected child, we expect a difference on the GRR estimation. In fact, we suspect that the second procedure leads to biased estimation of the GRR. We will analytically derive the GRR estimator for the 1:1 and 1:3 matching and will present the results at the meeting. Luigi Palla 1 , David Siegmund 239 Department of Mathematics,Free University Amsterdam, The Netherlands 40 Department of Statistics, Stanford University, California, USA Keywords: TDT, assortative mating, inbreeding, statistical power A substantial amount of Assortative Mating (AM) is often recorded on physical and psychological, dichotomous as well as quantitative traits that are supposed to have a multifactorial genetic component. In particular AM has the effect of increasing the genetic variance, even more than inbreeding because it acts across loci beside within loci, when the trait has a multifactorial origin. Under the assumption of a polygenic model for AM dating back to Wright (1921) and refined by Crow and Felsenstein (1968,1982), the effect of assortative mating on the power to detect genetic association in the Transmission Disequilibrium Test (TDT) is explored as parameters, such as the effective number of genes and the allelic frequency vary. The power is reflected by the non centrality parameter of the TDT and is expressed as a function of the number of trios, the relative risk of the heterozygous genotype and the allele frequency (Siegmund and Yakir, 2007). The noncentrality parameter of the relevant score statistic is updated considering the effect of AM which is expressed in terms of an ,effective' inbreeding coefficient. In particular, for dichotomous traits it is apparent that the higher the number of genes involved in the trait, the lower the loss in power due to AM. Finally an attempt is made to extend this relation to the Q-TDT (Rabinowitz, 1997), which involves considering the effect of AM also on the phenotypic variance of the trait of interest, under the assumption that AM affects only its additive genetic component. References Crow, & Felsenstein, (1968). The effect of assortative mating on the genetic composition of a population. Eugen.Quart.15, 87,97. Rabinowitz,, 1997. A Transmission Disequilibrium Test for Quantitative Trait Loci. Human Heredity47, 342,350. Siegmund, & Yakir, (2007) Statistics of gene mapping, Springer. Wright, (1921). System of mating.III. Assortative mating based on somatic resemblance. Genetics6, 144,161. Jérémie Nsengimana 1 , Ben D Brown 2 , Alistair S Hall 2 , Jenny H Barrett 141 Leeds Institute of Molecular Medicine, University of Leeds, UK 42 Leeds Institute for Genetics, Health and Therapeutics, University of Leeds, UK Keywords: Inflammatory genes, haplotype, coronary artery disease Genetic Risk of Acute Coronary Events (GRACE) is an initiative to collect cases of coronary artery disease (CAD) and their unaffected siblings in the UK and to use them to map genetic variants increasing disease risk. The aim of the present study was to test the association between CAD and 51 single nucleotide polymorphisms (SNPs) and their haplotypes from 35 inflammatory genes. Genotype data were available for 1154 persons affected before age 66 (including 48% before age 50) and their 1545 unaffected siblings (891 discordant families). Each SNP was tested for association to CAD, and haplotypes within genes or gene clusters were tested using FBAT (Rabinowitz & Laird, 2000). For the most significant results, genetic effect size was estimated using conditional logistic regression (CLR) within STATA adjusting for other risk factors. Haplotypes were assigned using HAPLORE (Zhang et al., 2005), which considers all parental mating types consistent with offspring genotypes and assigns them a probability of occurence. This probability was used in CLR to weight the haplotypes. In the single SNP analysis, several SNPs showed some evidence for association, including one SNP in the interleukin-1A gene. Analysing haplotypes in the interleukin-1 gene cluster, a common 3-SNP haplotype was found to increase the risk of CAD (P = 0.009). In an additive genetic model adjusting for covariates the odds ratio (OR) for this haplotype is 1.56 (95% CI: 1.16-2.10, p = 0.004) for early-onset CAD (before age 50). This study illustrates the utility of haplotype analysis in family-based association studies to investigate candidate genes. References Rabinowitz, D. & Laird, N. M. (2000) Hum Hered50, 211,223. Zhang, K., Sun, F. & Zhao, H. (2005) Bioinformatics21, 90,103. Andrea Foulkes 1 , Recai Yucel 1 , Xiaohong Li 143 Division of Biostatistics, University of Massachusetts, USA Keywords: Haploytpe, high-dimensional, mixed modeling The explosion of molecular level information coupled with large epidemiological studies presents an exciting opportunity to uncover the genetic underpinnings of complex diseases; however, several analytical challenges remain to be addressed. Characterizing the components to complex diseases inevitably requires consideration of synergies across multiple genetic loci and environmental and demographic factors. In addition, it is critical to capture information on allelic phase, that is whether alleles within a gene are in cis (on the same chromosome) or in trans (on different chromosomes.) In associations studies of unrelated individuals, this alignment of alleles within a chromosomal copy is generally not observed. We address the potential ambiguity in allelic phase in this high dimensional data setting using mixed effects models. Both a semi-parametric and fully likelihood-based approach to estimation are considered to account for missingness in cluster identifiers. In the first case, we apply a multiple imputation procedure coupled with a first stage expectation maximization algorithm for parameter estimation. A bootstrap approach is employed to assess sensitivity to variability induced by parameter estimation. Secondly, a fully likelihood-based approach using an expectation conditional maximization algorithm is described. Notably, these models allow for characterizing high-order gene-gene interactions while providing a flexible statistical framework to account for the confounding or mediating role of person specific covariates. The proposed method is applied to data arising from a cohort of human immunodeficiency virus type-1 (HIV-1) infected individuals at risk for therapy associated dyslipidemia. Simulation studies demonstrate reasonable power and control of family-wise type 1 error rates. Vivien Marquard 1 , Lars Beckmann 1 , Jenny Chang-Claude 144 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ) Heidelberg, Germany Keywords: Genotyping errors, type I error, haplotype-based association methods It has been shown in several simulation studies that genotyping errors may have a great impact on the type I error of statistical methods used in genetic association analysis of complex diseases. Our aim was to investigate type I error rates in a case-control study, when differential and non-differential genotyping errors were introduced in realistic scenarios. We simulated case-control data sets, where individual genotypes were drawn from a haplotype distribution of 18 haplotypes with 15 markers in the APM1 gene. Genotyping errors were introduced following the unrestricted and symmetric with 0 edges error models described by Heid et al. (2006). In six scenarios, errors resulted from changes of one allele to another with predefined probabilities of 1%, 2.5% or 10%, respectively. A multiple number of errors per haplotype was possible and could vary between 0 and 15, the number of markers investigated. We examined three association methods: Mantel statistics using haplotype-sharing; a haplotype-specific score test; and Armitage trend test for single markers. The type I error rates were not influenced for any of all the three methods for a genotyping error rate of less than 1%. For higher error rates and differential errors, the type I error of the Mantel statistic was only slightly and of the Armitage trend test moderately increased. The type I error rates of the score test were highly increased. The type I error rates were correct for all three methods for non-differential errors. Further investigations will be carried out with different frequencies of differential error rates and focus on power. Arne Neumann 1 , Dörthe Malzahn 1 , Martina Müller 2 , Heike Bickeböller 145 Department of Genetic Epidemiology, Medical School, University of Göttingen, Germany 46 GSF-National Research Center for Environment and Health, Neuherberg & IBE-Institute of Epidemiology, Ludwig-Maximilians University München, Germany Keywords: Interaction, longitudinal, nonparametric Longitudinal data show the time dependent course of phenotypic traits. In this contribution, we consider longitudinal cohort studies and investigate the association between two candidate genes and a dependent quantitative longitudinal phenotype. The set-up defines a factorial design which allows us to test simultaneously for the overall gene effect of the loci as well as for possible gene-gene and gene time interaction. The latter would induce genetically based time-profile differences in the longitudinal phenotype. We adopt a non-parametric statistical test to genetic epidemiological cohort studies and investigate its performance by simulation studies. The statistical test was originally developed for longitudinal clinical studies (Brunner, Munzel, Puri, 1999 J Multivariate Anal 70:286-317). It is non-parametric in the sense that no assumptions are made about the underlying distribution of the quantitative phenotype. Longitudinal observations belonging to the same individual can be arbitrarily dependent on one another for the different time points whereas trait observations of different individuals are independent. The two loci are assumed to be statistically independent. Our simulations show that the nonparametric test is comparable with ANOVA in terms of power of detecting gene-gene and gene-time interaction in an ANOVA favourable setting. Rebecca Hein 1 , Lars Beckmann 1 , Jenny Chang-Claude 147 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ) Heidelberg, Germany Keywords: Indirect association studies, interaction effects, linkage disequilibrium, marker allele frequency Association studies accounting for gene-environment interactions (GxE) may be useful for detecting genetic effects and identifying important environmental effect modifiers. Current technology facilitates very dense marker spacing in genetic association studies; however, the true disease variant(s) may not be genotyped. In this situation, an association between a gene and a phenotype may still be detectable, using genetic markers associated with the true disease variant(s) (indirect association). Zondervan and Cardon [2004] showed that the odds ratios (OR) of markers which are associated with the disease variant depend highly on the linkage disequilibrium (LD) between the variant and the markers, and whether the allele frequencies match and thereby influence the sample size needed to detect genetic association. We examined the influence of LD and allele frequencies on the sample size needed to detect GxE in indirect association studies, and provide tables for sample size estimation. For discordant allele frequencies and incomplete LD, sample sizes can be unfeasibly large. The influence of both factors is stronger for disease loci with small rather than moderate to high disease allele frequencies. A decline in D' of e.g. 5% has less impact on sample size than increasing the difference in allele frequencies by the same percentage. Assuming 80% power, large interaction effects can be detected using smaller sample sizes than those needed for the detection of main effects. The detection of interaction effects involving rare alleles may not be possible. Focussing only on marker density can be a limited strategy in indirect association studies for GxE. Cyril Dalmasso 1 , Emmanuelle Génin 2 , Catherine Bourgain 2 , Philippe Broët 148 JE 2492 , Univ. Paris-Sud, France 49 INSERM UMR-S 535 and University Paris Sud, Villejuif, France Keywords: Linkage analysis, Multiple testing, False Discovery Rate, Mixture model In the context of genome-wide linkage analyses, where a large number of statistical tests are simultaneously performed, the False Discovery Rate (FDR) that is defined as the expected proportion of false discoveries among all discoveries is nowadays widely used for taking into account the multiple testing problem. Other related criteria have been considered such as the local False Discovery Rate (lFDR) that is a variant of the FDR giving to each test its own measure of significance. The lFDR is defined as the posterior probability that a null hypothesis is true. Most of the proposed methods for estimating the lFDR or the FDR rely on distributional assumption under the null hypothesis. However, in observational studies, the empirical null distribution may be very different from the theoretical one. In this work, we propose a mixture model based approach that provides estimates of the lFDR and the FDR in the context of large-scale variance component linkage analyses. In particular, this approach allows estimating the empirical null distribution, this latter being a key quantity for any simultaneous inference procedure. The proposed method is applied on a real dataset. Arief Gusnanto 1 , Frank Dudbridge 150 MRC Biostatistics Unit, Cambridge UK Keywords: Significance, genome-wide, association, permutation, multiplicity Genome-wide association scans have introduced statistical challenges, mainly in the multiplicity of thousands of tests. The question of what constitutes a significant finding remains somewhat unresolved. Permutation testing is very time-consuming, whereas Bayesian arguments struggle to distinguish direct from indirect association. It seems attractive to summarise the multiplicity in a simple form that allows users to avoid time-consuming permutations. A standard significance level would facilitate reporting of results and reduce the need for permutation tests. This is potentially important because current scans do not have full coverage of the whole genome, and yet, the implicit multiplicity is genome-wide. We discuss some proposed summaries, with reference to the empirical null distribution of the multiple tests, approximated through a large number of random permutations. Using genome-wide data from the Wellcome Trust Case-Control Consortium, we use a sub-sampling approach with increasing density to estimate the nominal p-value to obtain family-wise significance of 5%. The results indicate that the significance level is converging to about 1e-7 as the marker spacing becomes infinitely dense. We considered the concept of an effective number of independent tests, and showed that when used in a Bonferroni correction, the number varies with the overall significance level, but is roughly constant in the region of interest. We compared several estimators of the effective number of tests, and showed that in the region of significance of interest, Patterson's eigenvalue based estimator gives approximately the right family-wise error rate. Michael Nothnagel 1 , Amke Caliebe 1 , Michael Krawczak 151 Institute of Medical Informatics and Statistics, University Clinic Schleswig-Holstein, University of Kiel, Germany Keywords: Association scans, Bayesian framework, posterior odds, genetic risk, multiplicative model Whole-genome association scans have been suggested to be a cost-efficient way to survey genetic variation and to map genetic disease factors. We used a Bayesian framework to investigate the posterior odds of a genuine association under multiplicative disease models. We demonstrate that the p value alone is not a sufficient means to evaluate the findings in association studies. We suggest that likelihood ratios should accompany p values in association reports. We argue, that, given the reported results of whole-genome scans, more associations should have been successfully replicated if the consistently made assumptions about considerable genetic risks were correct. We conclude that it is very likely that the vast majority of relative genetic risks are only of the order of 1.2 or lower. Clive Hoggart 1 , Maria De Iorio 1 , John Whittakker 2 , David Balding 152 Department of Epidemiology and Public Health, Imperial College London, UK 53 Department of Epidemiology and Public Health, London School of Hygiene and Tropical Medicine, UK Keywords: Genome-wide association analyses, shrinkage priors, Lasso Testing one SNP at a time does not fully realise the potential of genome-wide association studies to identify multiple causal variants of small effect, which is a plausible scenario for many complex diseases. Moreover, many simulation studies assume a single causal variant and so more complex realities are ignored. Analysing large numbers of variants simultaneously is now becoming feasible, thanks to developments in Bayesian stochastic search methods. We pose the problem of SNP selection as variable selection in a regression model. In contrast to single SNP tests this approach simultaneously models the effect of all SNPs. SNPs are selected by a Bayesian interpretation of the lasso (Tibshirani, 1996); the maximum a posterior (MAP) estimate of the regression coefficients, which have been given independent, double exponential prior distributions. The double exponential distribution is an example of a shrinkage prior, MAP estimates with shrinkage priors can be zero, thus all SNPs with non zero regression coefficients are selected. In addition to the commonly-used double exponential (Laplace) prior, we also implement the normal exponential gamma prior distribution. We show that use of the Laplace prior improves SNP selection in comparison with single -SNP tests, and that the normal exponential gamma prior leads to a further improvement. Our method is fast and can handle very large numbers of SNPs: we demonstrate its performance using both simulated and real genome-wide data sets with 500 K SNPs, which can be analysed in 2 hours on a desktop workstation. Mickael Guedj 1,2 , Jerome Wojcik 2 , Gregory Nuel 154 Laboratoire Statistique et Génome, Université d'Evry, Evry France 55 Serono Pharmaceutical Research Institute, Plan-les-Ouates, Switzerland Keywords: Local Replication, Local Score, Association In gene-mapping, replication of initial findings has been put forwards as the approach of choice for filtering false-positives from true signals for underlying loci. In practice, such replications are however too poorly observed. Besides the statistical and technical-related factors (lack of power, multiple-testing, stratification, quality control,) inconsistent conclusions obtained from independent populations might result from real biological differences. In particular, the high degree of variation in the strength of LD among populations of different origins is a major challenge to the discovery of genes. Seeking for Local Replications (defined as the presence of a signal of association in a same genomic region among populations) instead of strict replications (same locus, same risk allele) may lead to more reliable results. Recently, a multi-markers approach based on the Local Score statistic has been proposed as a simple and efficient way to select candidate genomic regions at the first stage of genome-wide association studies. Here we propose an extension of this approach adapted to replicated association studies. Based on simulations, this method appears promising. In particular it outperforms classical simple-marker strategies to detect modest-effect genes. Additionally it constitutes, to our knowledge, a first framework dedicated to the detection of such Local Replications. Juliet Chapman 1 , Claudio Verzilli 1 , John Whittaker 156 Department of Epidemiology and Public Health, London School of Hygiene and Tropical Medicine, UK Keywords: FDR, Association studies, Bayesian model selection As genomewide association studies become commonplace there is debate as to how such studies might be analysed and what we might hope to gain from the data. It is clear that standard single locus approaches are limited in that they do not adjust for the effects of other loci and problematic since it is not obvious how to adjust for multiple comparisons. False discovery rates have been suggested, but it is unclear how well these will cope with highly correlated genetic data. We consider the validity of standard false discovery rates in large scale association studies. We also show that a Bayesian procedure has advantages in detecting causal loci amongst a large number of dependant SNPs and investigate properties of a Bayesian FDR. Peter Kraft 157 Harvard School of Public Health, Boston USA Keywords: Gene-environment interaction, genome-wide association scans Appropriately analyzed two-stage designs,where a subset of available subjects are genotyped on a genome-wide panel of markers at the first stage and then a much smaller subset of the most promising markers are genotyped on the remaining subjects,can have nearly as much power as a single-stage study where all subjects are genotyped on the genome-wide panel yet can be much less expensive. Typically, the "most promising" markers are selected based on evidence for a marginal association between genotypes and disease. Subsequently, the few markers found to be associated with disease at the end of the second stage are interrogated for evidence of gene-environment interaction, mainly to understand their impact on disease etiology and public health impact. However, this approach may miss variants which have a sizeable effect restricted to one exposure stratum and therefore only a modest marginal effect. We have proposed to use information on the joint effects of genes and a discrete list of environmental exposures at the initial screening stage to select promising markers for the second stage [Kraft et al Hum Hered 2007]. This approach optimizes power to detect variants that have a sizeable marginal effect and variants that have a small marginal effect but a sizeable effect in a stratum defined by an environmental exposure. As an example, I discuss a proposed genome-wide association scan for Type II diabetes susceptibility variants based in several large nested case-control studies. Beate Glaser 1 , Peter Holmans 158 Biostatistics and Bioinformatics Unit, Cardiff University, School of Medicine, Heath Park, Cardiff, UK Keywords: Combined case-control and trios analysis, Power, False-positive rate, Simulation, Association studies The statistical power of genetic association studies can be enhanced by combining the analysis of case-control with parent-offspring trio samples. Various combined analysis techniques have been recently developed; as yet, there have been no comparisons of their power. This work was performed with the aim of identifying the most powerful method among available combined techniques including test statistics developed by Kazeem and Farrall (2005), Nagelkerke and colleagues (2004) and Dudbridge (2006), as well as a simple combination of ,2-statistics from single samples. Simulation studies were performed to investigate their power under different additive, multiplicative, dominant and recessive disease models. False-positive rates were determined by studying the type I error rates under null models including models with unequal allele frequencies between the single case-control and trios samples. We identified three techniques with equivalent power and false-positive rates, which included modifications of the three main approaches: 1) the unmodified combined Odds ratio estimate by Kazeem & Farrall (2005), 2) a modified approach of the combined risk ratio estimate by Nagelkerke & colleagues (2004) and 3) a modified technique for a combined risk ratio estimate by Dudbridge (2006). Our work highlights the importance of studies investigating test performance criteria of novel methods, as they will help users to select the optimal approach within a range of available analysis techniques. David Almorza 1 , M.V. Kandus 2 , Juan Carlos Salerno 2 , Rafael Boggio 359 Facultad de Ciencias del Trabajo, University of Cádiz, Spain 60 Instituto de Genética IGEAF, Buenos Aires, Argentina 61 Universidad Nacional de La Plata, Buenos Aires, Argentina Keywords: Principal component analysis, maize, ear weight, inbred lines The objective of this work was to evaluate the relationship among different traits of the ear of maize inbred lines and to group genotypes according to its performance. Ten inbred lines developed at IGEAF (INTA Castelar) and five public inbred lines as checks were used. A field trial was carried out in Castelar, Buenos Aires (34° 36' S , 58° 39' W) using a complete randomize design with three replications. At harvest, individual weight (P.E.), diameter (D.E.), row number (N.H.) and length (L.E.) of the ear were assessed. A principal component analysis, PCA, (Infostat 2005) was used, and the variability of the data was depicted with a biplot. Principal components 1 and 2 (CP1 and CP2) explained 90% of the data variability. CP1 was correlated with P.E., L.E. and D.E., meanwhile CP2 was correlated with N.H. We found that individual weight (P.E.) was more correlated with diameter of the ear (D.E.) than with length (L.E). Five groups of inbred lines were distinguished: with high P.E. and mean N.H. (04-70, 04-73, 04-101 and MO17), with high P.E. but less N.H. (04-61 and B14), with mean P.E. and N.H. (B73, 04-123 and 04-96), with high N.H. but less P.E. (LP109, 04-8, 04-91 and 04-76) and with low P.E. and low N.H. (LP521 and 04-104). The use of PCA showed which variables had more incidence in ear weight and how is the correlation among them. Moreover, the different groups found with this analysis allow the evaluation of inbred lines by several traits simultaneously. Sven Knüppel 1 , Anja Bauerfeind 1 , Klaus Rohde 162 Department of Bioinformatics, MDC Berlin, Germany Keywords: Haplotypes, association studies, case-control, nuclear families The area of gene chip technology provides a plethora of phase-unknown SNP genotypes in order to find significant association to some genetic trait. To circumvent possibly low information content of a single SNP one groups successive SNPs and estimates haplotypes. Haplotype estimation, however, may reveal ambiguous haplotype pairs and bias the application of statistical methods. Zaykin et al. (Hum Hered, 53:79-91, 2002) proposed the construction of a design matrix to take this ambiguity into account. Here we present a set of functions written for the Statistical package R, which carries out haplotype estimation on the basis of the EM-algorithm for individuals (case-control) or nuclear families. The construction of a design matrix on basis of estimated haplotypes or haplotype pairs allows application of standard methods for association studies (linear, logistic regression), as well as statistical methods as haplotype sharing statistics and TDT-Test. Applications of these methods to genome-wide association screens will be demonstrated. Manuela Zucknick 1 , Chris Holmes 2 , Sylvia Richardson 163 Department of Epidemiology and Public Health, Imperial College London, UK 64 Department of Statistics, Oxford Center for Gene Function, University of Oxford, UK Keywords: Bayesian, variable selection, MCMC, large p, small n, structured dependence In large-scale genomic applications vast numbers of markers or genes are scanned to find a few candidates which are linked to a particular phenotype. Statistically, this is a variable selection problem in the "large p, small n" situation where many more variables than samples are available. An additional feature is the complex dependence structure which is often observed among the markers/genes due to linkage disequilibrium or their joint involvement in biological processes. Bayesian variable selection methods using indicator variables are well suited to the problem. Binary phenotypes like disease status are common and both Bayesian probit and logistic regression can be applied in this context. We argue that logistic regression models are both easier to tune and to interpret than probit models and implement the approach by Holmes & Held (2006). Because the model space is vast, MCMC methods are used as stochastic search algorithms with the aim to quickly find regions of high posterior probability. In a trade-off between fast-updating but slow-moving single-gene Metropolis-Hastings samplers and computationally expensive full Gibbs sampling, we propose to employ the dependence structure among the genes/markers to help decide which variables to update together. Also, parallel tempering methods are used to aid bold moves and help avoid getting trapped in local optima. Mixing and convergence of the resulting Markov chains are evaluated and compared to standard samplers in both a simulation study and in an application to a gene expression data set. Reference Holmes, C. C. & Held, L. (2006) Bayesian auxiliary variable models for binary and multinomial regression. Bayesian Analysis1, 145,168. Dawn Teare 165 MMGE, University of Sheffield, UK Keywords: CNP, family-based analysis, MCMC Evidence is accumulating that segmental copy number polymorphisms (CNPs) may represent a significant portion of human genetic variation. These highly polymorphic systems require handling as phenotypes rather than co-dominant markers, placing new demands on family-based analyses. We present an integrated approach to meet these challenges in the form of a graphical model, where the underlying discrete CNP phenotype is inferred from the (single or replicate) quantitative measure within the analysis, whilst assuming an allele based system segregating through the pedigree. [source] Assessment of RNA amplification by multiplex RT-PCR and IgM detection by indirect and capture ELISAs for the diagnosis of measles and rubellaAPMIS, Issue 3 2010JUAN CARLOS SANZ Sanz JC, Mosquera M, Ramos B, Ramírez R, de Ory F, Echevarria JE. Assessment of RNA amplification by multiplex RT-PCR and IgM detection by indirect and capture ELISAs for the diagnosis of measles and rubella. APMIS 2010; 118: 203,9. The aim of the study was to compare RNA amplification using multiplex RT-PCR and IgM detection by means of indirect and capture ELISAs for the diagnosis of measles and rubella. A total of 229 cases of maculopapular rash with serum and throat swab samples were included. Specific serological IgM to measles and rubella was determined by Enzygnost® (Siemens) and PlateliaTM (Bio-Rad). Both viruses were researched using multiplex RT-PCR performed on throat samples. Criteria for inclusion of measles or rubella cases were a positive RT-PCR result for one virus and negative for the other; and/or a positive IgM result for one virus by both ELISAs and negative RT-PCR for the other virus. A total of 74 cases were classified as measles and 54 as rubella. In measles, sensitivity and specificity were 93.2% and 100% for RT-PCR, 97.3% and 98.1% for Enzygnost®, and 90.5% and 95.5% for PlateliaTM. For rubella, these values were 42.6% and 100% for RT-PCR, 100% and 97.1% for Enzygnost®, and 94.4% and 98.3% for PlateliaTM. Enzygnost® and PlateliaTM are useful techniques for detecting IgM against measles and rubella. RNA amplification by RT-PCR was both sensitive and specific for the diagnosis of measles; however, for rubella, the sensitivity of this technique must be improved. [source] Immunohistochemical analysis of NF-,B signaling proteins IKK,, p50/p105, p52/p100 and RelA in prostate cancersAPMIS, Issue 8 2009SEONG IL SEO Seo SI, Song SY, Kang MR, Kim MS, Oh JE, Kim YR, Lee JY, Yoo NJ, Lee SH. Immunohistochemical analysis of NF-,B signaling proteins IKK,, p50/p105, p52/p100 and RelA in prostate cancers. APMIS 2009; 117:623,8. Activation of nuclear factor-kappa B (NF-,B) signaling is considered an important mechanism in the development of prostate cancers. A recent study revealed that I,B kinase epsilon (IKK,), an activator of NF-,B, was overexpressed in breast cancers and acted as an oncogene. Expression of NF-,B members has been reported in prostate cancer tissues, but expression of IKK, has not yet been studied in prostate cancers. In this study, we attempted to explore as to whether expressions of IKK, and NF-,B members p50/105, p52/p100 and RelA are altered in prostate cancers. We analyzed the expression of IKK,, p50/105, p52/p100 and RelA in 107 prostate adenocarcinoma tissues by immunohistochemistry using a tissue microarray (TMA) method. In the TMA, IKK, is expressed in basal cells, but not in alveolar cells in normal prostate glands. IKK, is expressed in 60.0% of prostate intraepithelial neoplasm (PIN) and 70.1% of the prostate cancers in the cytoplasm. Nuclear immunostainings of NF-,B members p50/105, p52/p100 and RelA, which are considered activation of NF-,B signaling, were observed respectively in 28.0%, 18.7% and 37.4% of the cancers. Nuclear staining was detected neither in normal alveolar cells nor in PIN. However, none of the expression of p50/105 nor p52/p100 nor RelA nor IKK, was associated with pathologic characteristics, including size of the cancers, age, Gleason score and stage. The increased cytoplasmic expression of IKK, as well as the increased nuclear expressions of p50/105, p52/p100 and RelA in the prostate cancers compared to normal alveolar cells suggested that overexpression of these proteins may be related to activation of the NF-,B pathway and might play a role in tumorigenesis of prostate cancers. [source] CSIRO shows macropods unlikely hosts for JEAUSTRALIAN VETERINARY JOURNAL, Issue 2 2001Article first published online: 10 MAR 200 No abstract is available for this article. [source] Optimal microvessel density from composite graft of autogenous maxillary cortical bone and anorganic bovine bone in sinus augmentation: influence of clinical variablesCLINICAL ORAL IMPLANTS RESEARCH, Issue 2 2010Pablo Galindo-Moreno Abstract Objectives: The objectives of this study were to assess the microvessel density (MVD) of intra-sinus grafts after 6 months of wound healing and to study the relationship between revascularization processes and patient clinical variables and habits. Material and methods: We performed 45 maxillary sinus augmentations with different implant placements in 25 consecutive patients, obtaining bone cores of the grafted area for histological, histomorphometric and immunohistochemical study. Biopsies were also taken from pristine bone in the posterior maxilla (control). Results: All implants survived at 24 months. Biopsies of sinus augmentation areas showed significantly greater remodeling activity vs. pristine bone, with significantly more osteoid lines. The morphometry study revealed 34.88±15.2% vital bone, 32.02±15.1% non-mineralized tissue and 33.08±25.4% remnant anorganic bovine bone particles. The number of CD34-positive vessels was 86.28±55.52/mm2 in graft tissue vs. 31.52±13.69/mm2 in native tissue (P=0.002, Mann,Whitney U=46). The larger amount of non-mineralized tissue in grafts was directly correlated with a higher MVD (r=0.482, P=0.0001, Pearson's test). MVD was affected by the presence of periodontitis or tobacco and alcohol consumption. Conclusion: The angiogenesis and revascularization obtained by this type of graft achieve adequate tissue remodeling for osseointegration and are influenced by periodontal disease and tobacco or alcohol consumption. To cite this article: Galindo-Moreno P, Padial-Molina M, Fernández-Barbero JE, Mesa F, Rodríguez-Martínez D, O'Valle F. Optimal microvessel density from composite graft of autogenous maxillary cortical bone and anorganic bovine bone in sinus augmentation: influence of clinical variables. Clin. Oral Impl. Res. 21, 2010; 221,227 doi: 10.1111/j.1600-0501.2009.01827.x [source] « Je ne suis pas donc je cogite » : un face à face Pascal-PerecORBIS LITERARUM, Issue 1 2002Sabine Hillen Pascal et Perec se rapprochent par leur écriture apparemment neutre qui réfute la vision substantialiste du sujet. Au premier abord, les deux auteurs arrivent à maîtriser le mot et à exercer un contrôle sur la naissance de la phrase : Pascal le fait par son ordre rhétorique, Perec par son souci de la contraiente oulipienne. En outre, l'écriture « objectiviste » qu'ils pratiquent, se particularise par « la crainte de livrer l'intime au grand public » (Van den Heuvel). Pascal, quand il accuse Montaigne du sot projet qu'il a de se peindre, préfère se cacher derrière le canevas rigide de ses pensées et restreindre sa présence dans le monde. En même temps, surtout dans les passages où le sujet de l'énonciation apparaît et où la maîtrise est relâchée dans le projet d'écriture, Pascal avoue son impuissance à se connaître : « Je ne sais qui m'a mis au monde, ni ce que c'est le monde, ni que moi-même; je suis dans une ignorance terrible de toutes choses; je ne sais ce que c'est que mon corps, que mes sens, que mon âme et cette partie même de moi qui pense ce que je dis, qui fait réflexion sur tout et sur elle-même, et ne se connaît non plus que tout le reste » (pensée 427). Chez Perec, la maîtrise de l'écriture est moins causée par le refus du public que par un regard aveugle portéà soi-même. Privé de sa possibilitéà dire « je », Perec le réduit à une litanie, dans Je me souviens, à un « tu » dans Un Homme qui dort, à une quasi-absence dans La Vie mode d'emploi. Cependant, par son flirt avec le clinamen, détail faisant dériver la structure, l'intervention personnelle ressurgit comme un acte de résistance au silence imposé par la structure. A la lumière des textes de Pascal et Perec, nous aimerions repenser la notion de sujet telle qu'elle se présente chez les deux auteurs. A cet effet, pour arriver à déterminer la naissance du moi dans la production artistique, il sera nécessaire de repérer les apparitions et dispartitions du sujet de l'énonciation à la première personne ainsi que d'interroger la marque stylistique du fragment. [source] Motivation and Performance Following Failure: The Effortful Pursuit of Self-defining GoalsAPPLIED PSYCHOLOGY, Issue 3 2000Joachim Brunstein In this paper, I summarise theory and research, highlighting the role of self-defining goals in how individuals react to and try to cope with failure outcomes. I propose that three factors are fundamental to the understanding of whether failure stimulates or impairs motivated behaviour: the relevance of failure to a self-definition, the substitutability of tasks in the service of striving for a self-definition, and a person's commitment to pursuing the respective self-definition. Focusing on students' occupationally directed self-definitions, I first review research showing how the interplay among these factors is reflected in varied measures of achievement behaviour and then discuss practical implications of the theory. Dans cet article, je re´sume la the´orie et les recherches qui retiennent le roôle de la fixation par soi-même de ses propres objectifs dans la fac¸on de re´agir et d'essayer d'affronter les conse´quences de l'e´chec. Je propose trois facteurs essentiels pour savoir si l'e´chec stimule ou affaiblit la motivation: le rapport de l'e´chec avec l'image de soi, l'interchangeabilite´ des tâches dans l'e´laboration de l'image de soi et l'ardeur a` re´pondre a` cette image. En me centrant sur les repre´sentations professionnelles de soi d'e´tudiants, je passe d'abord en revue des e´tudes e´tablissant que l'interaction entre ces facteurs apparaît dans diverses mesures de l'actualisation de soi, puis je traite des retombe´es pratiques de cette the´orie. [source] Through a Public Darkly: Reconstructing Pragmatist Perspectives in Communication TheoryCOMMUNICATION THEORY, Issue 4 2008Chris Russill This article aims to retrieve the problem-responsive dimension of pragmatist theories in their relevance for the reconceptualization of public participation in communication theory. This dimension is central to pragmatist perspectives on the formation and functioning of publics and I propose that we reconstruct pragmatism as a tradition of communication theory in light of this fact. First, I reexamine the historical emergence of pragmatism in communication theory and I suggest James Carey was unable to challenge positivism or objectivism from within a pragmatist tradition. Second, I retrieve John Dewey's account of inquiry in a manner anticipating its implications for his theory of publics. Third, I resituate the Dewey,Lippmann debate within the context of a pragmatist tradition to demonstrate how deeply their differences turn on problem formulation. In conclusion, I connect the pragmatist tradition to contemporary work on problematization to address the limitations of each perspective. Résumé Dans un public, obscurément : Reconstruire les perspectives pragmatiques des théories de la communication Cet article vise à extraire des théories pragmatistes la dimension adaptée aux problèmes dans leur pertinence pour la reconceptualisation de la participation publique dans les théories de la communication. Cette dimension est centrale aux perspectives pragmatistes dans la formation et le fonctionnement des publics. Je propose que nous reconstruisions le pragmatisme comme tradition des théories communicationnelles en vue de ce fait. D'abord, je réexamine l'émergence historique du pragmatisme dans les théories de la communication et je soumets que James Carey était incapable de contester le positivisme ou l'objectivisme à partir d'une tradition pragmatiste. Ensuite, je récupère l'explication que fait John Dewey de l'interrogation d'une manière qui anticipe ses implications pour sa théorie des publics. Puis, je replace le débat Dewey-Lippman dans le contexte d'une tradition pragmatiste afin de démontrer combien profondes sont leurs différences à propos de la formulation des problèmes. En conclusion, je relie la tradition pragmatiste aux travaux contemporains sur la problématisation afin d'aborder les limites de chaque perspective. Abstract Durch ein öffentliches Dunkel: Die Rekonstruktion von pragmatischen Ansichten in der Kommunikationstheorie Dieser Artikel untersucht die problem-responsive Dimension pragmatischer Theorien hinsichtlich ihrer Relevanz für die Rekonzeptualisierung von öffentlicher Teilhabe in der Kommunikationstheorie. Diese Dimension ist zentral innerhalb pragmatischer Ansichten der Formation und des Funktionierens von Öffentlichkeiten. Im Lichte dieser Tatsache schlage ich deshalb vor, den Pragmatismus als eine Tradition der Kommunikationstheorie zu betrachten. Erstens untersuche ich die historische Entstehung von Pragmatismus in der Kommunikationstheorie und schlage vor, dass James Carey außerstande war, den Positivismus oder Objektivismus aus einer pragmatischen Tradition heraus herauszufordern. Zweitens betrachte ich John Dewey's Herangehensweise auf eine Art, die seine Implikationen für seine Theorie der Öffentlichkeiten antizipiert. Drittens, verorte ich die Dewey-Lippman Debatte neu im Kontext einer pragmatischen Tradition, um zu zeigen wie tief greifend sich ihre Unterschiede auf die Problemformulierung auswirken. Zusammenfassend, verbinde ich die pragmatische Tradition mit aktuellen Arbeiten zur Problematisierung, um die Beschränkungen jeder Perspektive aufzuzeigen. Resumen A Través de un Público Misterioso: Reconstruyendo Perspectivas Pragmáticas de la Teoría de la Comunicación Este artículo tiene por objetivo recuperar la dimensión problema-respuesta de las teorías pragmáticas en su relevancia para la reconceptualización de la participación pública en la teoría de la comunicación. Esta dimensión es central en las perspectivas pragmáticas sobre la formación y el funcionamiento de los públicos, y propongo que reconstruyamos el pragmatismo como una tradición de la teoría de la comunicación en respuesta a ese hecho. Primero, re-examino la emergencia histórica del pragmatismo en la teoría de la comunicación y sugiero que James Carey fue incapaz de desafiar el positivismo u objetivismo dentro de la tradición pragmática. Segundo, recupero la explicación de investigación de John Dewey anticipando sus implicancias en su teoría de los públicos. Tercero, restituyo el debate de Dewey,Lippmann dentro del contexto de la tradición pragmática para demonstrar cómo sus profundas diferencias se convierten en problemas de formulación. En conclusión, conecto la tradición pragmática con el trabajo contemporáneo sobre la problematización para tratar las limitaciones de cada perspectiva. ZhaiYao Yo yak [source] Property as Interorganizational Discourse: Rights in the Politics of Public SpacesCOMMUNICATION THEORY, Issue 2 2008Todd Norton In this article, I extend organization and communication theory to conceptualize property as an interorganizational discourse. As an analytic of discourse's capacity to gain and defend stakeholder rights in the public domain, property discourses provide a rigorous, language-centered approach to organizational conflict over environmental spaces by conceptualizing how material,symbolic tensions play out diachronically. I ground this theoretical terrain through a discourse analysis of a decade-long conflict over public lands in the southern part of the U.S. state of Utah. The case,Grand Staircase-Escalante National Monument,constitutes a significant clash of politics between environmental preservation and extraction and especially what political regime ought to control roads accessing this 1.9-million-acre national monument. The analysis and interpretation indicate that property politics involve a complex interplay of symbolic and material forces among stakeholders. Conceptualized in this way property discourses provide considerable insight as many nations and societies face escalating struggles over increasingly scarce resources. Résumé La propriété comme discours interorganisationnel : les droits dans la politique des espaces publics Dans cet article, j'élargis les théories de l,organisation et de la communication pour conceptualiser la propriété comme un discours interorganisationnel. Comme élément analytique de la capacité du discours de gagner et de défendre les droits des parties prenantes dans le domaine public, les discours de propriété offrent une approche rigoureuse et centrée sur le langage pour l'analyse des conflits organisationnels à propos d,espaces environnementaux. En effet, ils permettent de conceptualiser la manière dont les tensions matérielles-symboliques ont lieu de façon diachronique. Je fonde ce terrain théorique sur l'analyse discursive d,un conflit s'étirant sur une dizaine d'années autour de terres publiques dans la partie australe de l'État américain de l,Utah. Le cas , Grand Staircase-Escalante National Monument (GS-ENM) , consiste en une dispute politique importante autour de la préservation de l'environnement et de l,extraction et, surtout, autour de la question à savoir quel régime politique devrait pouvoir contrôler des routes donnant accès à ce monument national d'une superficie de 1,9 million d,acres. L'analyse et l,interprétation indiquent que les politiques de propriété impliquent une interaction complexe de forces symboliques et matérielles des parties prenantes. Conceptualisés de cette manière, les discours de propriété offrent un aperçu considérable alors que plusieurs nations et sociétés font face à des luttes qui s'intensifient autour de ressources de plus en plus rares. Abstract Eigentum als Diskurs zwischen Organisationen. Rechte in der Politik des öffentlichen Raums In diesem Artikel erweitere ich Organisations- und Kommunikationstheorie, um Eigentum als Diskurs zwischen Organisationen zu konzeptualisieren. Als eine Analyse der Vermögens eines Diskurses, Akteursrechte in der öffentlichen Domäne zu erlangen und zu verteidigen, bieten Diskurse zum Eigentum einen entscheidenden, sprachzentrierten Ansatz zu Organisationskonflikten bezüglich Umwelträumen, indem nämlich konzeptualisiert wird, wie material-symbolische Spannungen im Zeitverlauf zusammenspielen. Die Theorie basiert auf der Diskursanalyse eines Jahrzehnte dauernden Konflikts um öffentliches Land im Süden des US-Bundesstaates Utah. Der Fall - Grand Staircase-Escalante National Monument (GS-ENM) - bildet einen wichtigen Politikkonflikt zwischen Umweltschutz und Förderung ab , insbesondere bezüglich der Frage, welches politische Regime die Zugangsstraßen zu diesem 190 km2 großen nationalen Monuments kontrollieren soll. Die Analyse und Interpretation zeigt, dass Eigentumspolitik ein komplexes Zusammenspiel von symbolischen und materiellen Kräften von Akteuren ist. Auf diese Weise konzeptualisiert, lassen sich vor dem Hintergrund knapper werdender Ressourcen und daraus entstehenden nationalen und gesellschaftlichen Krisen wichtige Einsichten gewinnen. Resumen La Propiedad como Discurso entre las Organizaciones: Los Derechos en la Política de los Espacios Públicos En este artículo extiendo la teoría de la organización y la comunicación para conceptualizar la propiedad como un discurso entre organizaciones. Como un elemento analítico de la capacidad del discurso para ganar y defender los derechos de los interesados en el dominio público, los discursos de la propiedad proveen una aproximación rigurosa y un lenguaje centrado en el conflicto organizacional de los espacios medioambientales a través de una conceptualización de cómo las tensiones entre lo material y lo simbólico juegan un rol diacrónico. Conecto este terreno teórico a través de un análisis de una década de un discurso de conflicto sobre las tierras públicas en la parte sur del estado de Utah. El caso,Grand Staircase-Escalante Monumento Nacional (GS-ENM),constituye un enfrentamiento significativo de las políticos de preservación del medioambiente y la extracción y especialmente qué régimen político debe controlar los caminos de acceso a este monumento nacional de 1.9 millones de acres. El análisis y la interpretación indican que la política de la propiedad incluye la compleja interacción de fuerzas simbólicas y materiales entre los interesados. Conceptualizada de esta manera los discursos de la propiedad proveen de un entendimiento considerable para las muchas naciones y sociedades que enfrentan considerable disputas sobre los crecientes recursos escasos. ZhaiYao Yo yak [source] Association of Sphaeropsis sapinea with insect-damaged red pine shoots and conesFOREST PATHOLOGY, Issue 1 2003E. Feci Summary The association of the shoot blight and canker pathogen Sphaeropsis sapinea with red pine (Pinus resinosa) shoots and cones damaged by insects (especially Dioryctria sp.) was investigated. Samples from a single plantation approximately 35 years old, in Sauk Co., Wisconsin and also from three plantations, between approximately 40 and 50 years old, located in an area of pine shoot moth activity in the preceding year in Adams Co., Wisconsin were visually examined. Samples were arbitrarily collected from trees felled in the first plantation in May. Pycnidia of S. sapinea and insect damage were observed on 56 of 91 (62%) of closed cones and 17 of 165 (7%) of previous year's shoots. In the absence of insect damage, pycnidia of the pathogen were identified only on eight of 91 (9%) closed cones and never on previous year's shoots. In each of the other three plantations, 10 trees were located at intervals along transects in mid-June; one branch from the lower half of the crown per tree was pruned off, and both current and previous year's shoots were examined. Insect damage and S. sapinea pycnidia were too rare on current year's shoots to draw any conclusions. Insect damage occurred on 20,40% of over 2000 previous year's shoots that were examined, but pycnidia of the pathogen were identified on only about 5%. Although infrequent, S. sapinea was identified in association with insect-damaged previous year's shoots from these three plantations three times more frequently than those without insect damage. Random amplified polymorphic DNA (RAPD) markers from eight randomly selected isolates were consistent with the A group of S. sapinea, which can be aggressive on red pine. This ability to exploit insect-damaged shoots may facilitate long-term persistence of S. sapinea at low disease incidence and severity. The potential role of insect wounds as infection courts and insects as vectors of this important pathogen of pines deserves further study. Résumé L'étude a porté sur l'association entre le parasite de pousses et agent de chancre Sphaeropsis sapinea, et les pousses et cônes de Pinus resinosa endommagés par des insectes (surtout Dioryctria sp.). Des échantillons ont été examinés visuellement; ils provenaient d'une plantation d'environ 35 ans à Sauk Co., Wisconsin, et de trois plantations âgées d'environ 40 et 50 ans situées dans une zone où les insectes des pousses avaient été actifs l'année précédente à Adams Co., Wisconsin. Dans la première plantation, les échantillons ont été prélevés arbitrairement sur des arbres abattus en mai. Des pycnides de S. sapinea et des dégâts d'insectes ont été observés sur 56/91 (62%) des cônes fermés et sur 17/165 (7%) des pousses de l'année précédente. En l'absence de dégâts d'insectes, les pycnides n'ont été trouvées que sur 8/91 (9%) des cônes fermés, et jamais sur les pousses de l'année précédente. Dans chacune des trois autres plantations, 10 arbres ont été choisis à la mi-juin le long de transects ; sur chaque arbre une branche a été coupée dans la moitié inférieure de la couronne, et les pousses de l'année en cours et de l'année précédente ont été examinées. Sur les pousses de l'année, les dégâts d'insectes et les pycnides de S. sapineaétaient trop rares pour pouvoir en tirer des conclusions. Parmi plus de 2000 pousses de l'année précédente examinées, les dégâts d'insectes étaient présents sur 20,40% des pousses, mais les pycnides n'ont été trouvées que sur environ 5% d'entre elles. Bien que peu fréquent chez ces trois plantations, S. sapinea a été trouvé associé aux pousses de l'année précédente, 3 fois plus fréquemment chez celles endommagées par les insectes que chez les non endommagées. Pour huit isolats pris au hasard, les marqueurs RAPD ont indiqué leur appartenance au groupe A de S. sapinea qui peut être agressif sur P. resinosa. Cette aptitude de S. sapineaà utiliser les pousses endommagées par les insects peut faciliter sa persistance à long terme à des niveaux bas d'abondance et de dégâts. Le rôle potentiel des blessures d'insectes comme voies d'infection, et des insectes comme vecteurs du champignon parasite mérite d'être étudié. Zusammenfassung Es wurde die Assoziation zwischen Sphaeropsis sapinea (Erreger von Triebsterben und Rindennekrosen) und Schädigung an Trieben und Zapfen von Pinus resinosa untersucht, durch Insekten (vorwiegend Dioryctria sp.) untersucht. Proben von einer ca. 35 Jahre alten Plantage in Sauk Co., Wisconsin und von drei 40-50jährigen Plantagen mit Dioryctria -Befall im Vorjahr in Adams Co., Wisconsin wurden makroskopisch untersucht. Die Proben am ersten Standort wurden von Bäumen entnommen, die im Mai gefällt wurden (willkürliche Auswahl). Pyknidien und Schädigung durch Insekten wurden an 56/91 (62%) der geschlossenen Zapfen und an 17/165 (7%) der vorjährigen Triebe beobachtet. An Organen ohne Schädigung durch Insekten wurden die Pyknidien des Pathogens nur bei 8/91 (9%) der geschlossenen Zapfen und in keinem Fall an den vorjährigen Trieben nachgewiesen. In den anderen drei Plantagen wurden Mitte Juni je 10 Bäume entlang von Transekten untersucht; pro Baum wurde aus dem unteren Kronenbereich ein Ast abgeschnitten und sowohl die diesjährigen als auch die vorjährigen Triebe wurden untersucht. An den diesjährigen Triebabschnitten waren sowohl Schädigungen durch Insekten als auch Pyknidien von S. sapinea zu selten, um daraus Schlüsse zu ziehen. An den vorjährigen Triebabschnitten kamen Insektenschäden an 20,40% von über 2,000 untersuchten Objekten vor, aber Pyknidien des Pathogens wurden nur in 5% der Fälle nachgewiesen. Trotz des geringen Vorkommens wurde S. sapinea auf den vorjährigen und von Insekten beschädigten Trieben dreimal häufiger nachgewiesen als an Trieben ohne Beschädigung. Acht zufällig ausgewählte Isolate wurden anhand von RAPD Markern der Gruppe A von S. sapinea zugeordnet, die auf P. resinosa agressiv sein kann. Die Fähigkeit von S. sapinea, durch Insekten beschädigte Triebe zu nutzen, kann das Überdauern des Pilzes auf einem niedrigen Befallsniveau erleichtern. Die Bedeutung von Wunden, die durch Insekten verursacht werden, als Infektionspforten und die mögliche Rolle von Insekten als Vektoren dieses wichigen Pathogens sollte in weiteren Untersuchungen geklärt werden. [source] | |||||||||||||||||||||||||||||||||||||||||||||||||