Influence of genotyping error in linkage mapping for complex traits – an analytic study

<p>Abstract</p> <p>Background</p> <p>Despite the current trend towards large epidemiological studies of unrelated individuals, linkage studies in families are still thoroughly being utilized as tools for disease gene mapping. The use of the single-nucleotide-polymorphisms (SNP) array technology in genotyping of family data has the potential to provide more informative linkage data. Nevertheless, SNP array data are not immune to genotyping error which, as has been suggested in the past, could dramatically affect the evidence for linkage especially in selective designs such as affected sib pair (ASP) designs. The influence of genotyping error on selective designs for continuous traits has not been assessed yet.</p> <p>Results</p> <p>We use the identity-by-descent (IBD) regression-based paradigm for linkage testing to analytically quantify the effect of simple genotyping error models under specific selection schemes for sibling pairs. We show, for example, that in extremely concordant (EC) designs, genotyping error leads to decreased power whereas it leads to increased type I error in extremely discordant (ED) designs. Perhaps surprisingly, the effect of genotyping error on inference is most severe in designs where selection is least extreme. We suggest a genomic control for genotyping errors via a simple modification of the intercept in the regression for linkage.</p> <p>Conclusion</p> <p>This study extends earlier findings: genotyping error can substantially affect type I error and power in selective designs for continuous traits. Designs involving both EC and ED sib pairs are fairly immune to genotyping error. When those designs are not feasible the simple genomic control strategy that we suggest offers the potential to deliver more robust inference, especially if genotyping is carried out by SNP array technology.</p

An association between anti-platelet drug use and reduced cancer prevalence in diabetic patients: results from the Vermont Diabetes Information System Study

<p>Abstract</p> <p>Background</p> <p>Diabetes is associated with an increased risk of several malignancies. Both diabetic patients and patients with cancer have an increase in platelet reactivity and platelet activation has recently emerged as a potential mediator of cancer progression. Drug therapies, such as aspirin, that reduce platelet reactivity reduce both cardiovascular and cancer risk.</p> <p>Methods</p> <p>We performed a cross-sectional analysis to assess the association between history of cancer and current anti-platelet drug use in a primary care population of adults with diabetes enrolled in the Vermont Diabetes Information System.</p> <p>Results</p> <p>Self-reported characteristics, medical history, and a complete medication list were recorded on 1007 diabetic adults. Fifty percent of diabetic patients used an anti-platelet drug. In unadjusted analysis, no association was seen between anti-platelet drug use and cancer history (OR = 0.93; <it>P </it>= .70). Platelet inhibitor use was associated with a decreased patient-reported history of malignancy in a multivariate logistic regression adjusted for age, sex, body mass index, comorbidity, and number of medications (OR = 0.66; CI 0.44-0.99; <it>P </it>= .045). Similar odds of association were seen in both males and females, and for aspirin and non-aspirin platelet inhibitor therapy.</p> <p>Conclusions</p> <p>Our data suggest an association between anti-platelet drug use and reduced cancer prevalence in patients with diabetes. Given the potentially large implications of our observations in the diabetic population, further studies are required to determine if this association is causal.</p

Cell populations in lesions of cutaneous leishmaniasis of leishmania (L.) amazonensis- infected rhesus macaques, Macaca mulatta

The cellular nature of the infiltrate in cutaneous lesion of rhesus monkeys experimentally infected with Leishmania (L.) amazonensis was characterized by immunohistochemistry. Skin biopsies from infected animals with active or healing lesions were compared to non-infected controls (three of each type) to quantitate inflammatory cell types. Inflammatory cells (composed of a mixture of T lymphocyte subpopulations, macrophages and a small number of natural killer cells and granulocytes) were more numerous in active lesions than in healing ones. T-cells accounted for 44.7 ± 13.1% of the infiltrate in active lesions (versus CD2+= 40.3 ± 5.7% in healing lesions) and T-cell ratios favor CD8+ cells in both lesion types. The percentage of cells expressing class II antigen (HLA-DR+) in active lesions (95 ± 7.1%) was significantly higher (P < 0.005) from the healing lesions (42.7 ± 12.7%). Moreover, the expression of the activation molecules CD25 (@ 16%), the receptor for interleukin-2, suggests that many T cells are primed and proliferating in active lesions. Distinct histopathological patterns were observed in lesions at biopsy, but healing lesions contained more organized epithelioid granulomas and activated macrophages, followed by fibrotic substitution. The progression and resolution of skin lesions appears to be very similar to that observed in humans, confirming the potential for this to be used as a viable model to study the immune response in human cutaneous leishmaniasis

Extratropical forcing and tropical rainfall distribution: energetics framework and ocean Ekman advection

Intense tropical rainfall occurs in a narrow belt near the equator, called the inter-tropical convergence zone (ITCZ). In the past decade, the atmospheric energy budget has been used to explain changes in the zonal-mean ITCZ position. The energetics framework provides a mechanism for extratropics-to-tropics teleconnections, which have been postulated from paleoclimate records. In atmosphere models coupled with a motionless slab ocean, the ITCZ shifts toward the warmed hemisphere in order for the Hadley circulation to transport energy toward the colder hemisphere. However, recent studies using fully coupled models show that tropical rainfall can be rather insensitive to extratropical forcing when ocean dynamics is included. Here, we explore the effect of meridional Ekman heat advection while neglecting the upwelling effect on the ITCZ response to prescribed extratropical thermal forcing. The tropical component of Ekman advection is a negative feedback that partially compensates the prescribed forcing, whereas the extratropical component is a positive feedback that amplifies the prescribed forcing. Overall, the tropical negative feedback dominates over the extratropical positive feedback. Thus, including Ekman advection reduces the need for atmospheric energy transport, dampening the ITCZ response. We propose to build a hierarchy of ocean models to systematically explore the full dynamical response of the coupled climate system

Exploration, Explanation, and Parent–Child Interaction in Museums

Young children develop causal knowledge through everyday family conversations and activities. Children's museums are an informative setting for studying the social context of causal learning because family members engage together in everyday scientific thinking as they play in museums. In this multisite collaborative project, we investigate children's developing causal thinking in the context of family interaction at museum exhibits. We focus on explaining and exploring as two fundamental collaborative processes in parent–child interaction, investigating how families explain and explore in open-ended collaboration at gear exhibits in three children's museums in Providence, RI, San Jose, CA, and Austin, TX. Our main research questions examined (a) how open-ended family exploration and explanation relate to one another to form a dynamic for children's learning; (b) how that dynamic differs for families using different interaction styles, and relates to contextual factors such as families' science background, and (c) how that dynamic predicts children's independent causal thinking when given more structured tasks. We summarize findings on exploring, explaining, and parent–child interaction (PCI) styles. We then present findings on how these measures related to one another, and finally how that dynamic predicts children's causal thinking. In studying children's exploring we described two types of behaviors of importance for causal thinking: (a) Systematic Exploration: Connecting gears to form a gear machine followed by spinning the gear machine. (b) Resolute Behavior: Problem-solving behaviors, in which children attempted to connect or spin a particular set of gears, hit an obstacle, and then persisted to succeed (as opposed to moving on to another behavior). Older children engaged in both behaviors more than younger children, and the proportion of these behaviors were correlated with one another. Parents and children talked to each other while interacting with the exhibits. We coded causal language, as well as other types of utterances. Parents' causal language predicted children's causal language, independent of age. The proportion of parents' causal language also predicted the proportion of children's systematic exploration. Resolute behavior on the part of children did not correlate with parents' causal language, but did correlate with children's own talk about actions and the exhibit. We next considered who set goals for the play in a more holistic measure of parent–child interaction style, identifying dyads as parent-directed, child-directed, or jointly-directed in their interaction with one another. Children in different parent–child interaction styles engaged in different amounts of systematic exploration and had parents who engaged in different amounts of causal language. Resolute behavior and the language related to children engaging in such troubleshooting, seemed more consistent across the three parent–child interaction styles. Using general linear mixed modeling, we considered relations within sequences of action and talk. We found that the timing of parents' causal language was crucial to whether children engaged in systematic exploration. Parents' causal talk was a predictor of children's systematic exploration only if it occurred prior to the act of spinning the gears (while children were building gear machines). We did not observe an effect of causal language when it occurred concurrently with or after children's spinning. Similarly, children's talk about their actions and the exhibit predicted their resolute behavior, but only when the talk occurred while the child was encountering the problem. No effects were found for models where the talk happened concurrently or after resolving the problem. Finally, we considered how explaining and exploring related to children's causal thinking. We analyzed measures of children's causal thinking about gears and a free play measure with a novel set of gears. Principal component analysis revealed a latent factor of causal thinking in these measures. Structural equation modeling examined how parents' background in science related to children's systematic exploration, parents' causal language, and parent–child interaction style, and then how those factors predicted children's causal thinking. In a full model, with children's age and gender included, children's systematic exploration related to children's causal thinking. Overall, these data demonstrate that children's systematic exploration and parents' causal explanation are best studied in relation to one another, because both contributed to children's learning while playing at a museum exhibit. Children engaged in systematic exploration, which supported their causal thinking. Parents' causal talk supported children's exploration when it was presented at certain times during the interaction. In contrast, children's persistence in problem solving was less sensitive to parents' talk or interaction style, and more related to children's own language, which may act as a form of self-explanation. We discuss the findings in light of ongoing approaches to promote the benefit of parent–child interaction during play for children's learning and problem solving. We also examine the implications of these findings for formal and informal learning settings, and for theoretical integration of constructivist and sociocultural approaches in the study of children's causal thinking.National Science Foundation under Grants 1420259, 1420241, and 1420548

NG2 and phosphacan are present in the astroglial scar after human traumatic spinal cord injury

BACKGROUND: A major class of axon growth-repulsive molecules associated with CNS scar tissue is the family of chondroitin sulphate proteoglycans (CSPGs). Experimental spinal cord injury (SCI) has demonstrated rapid re-expression of CSPGs at and around the lesion site. The pharmacological digestion of CSPGs in such lesion models results in substantially enhanced axonal regeneration and a significant functional recovery. The potential therapeutic relevance of interfering with CSPG expression or function following experimental injuries seems clear, however, the spatio-temporal pattern of expression of individual members of the CSPG family following human spinal cord injury is only poorly defined. In the present correlative investigation, the expression pattern of CSPG family members NG2, neurocan, versican and phosphacan was studied in the human spinal cord. METHODS: An immunohistochemical investigation in post mortem samples of control and lesioned human spinal cords was performed. All patients with traumatic SCI had been clinically diagnosed as having "complete" injuries and presented lesions of the maceration type. RESULTS: In sections from control spinal cord, NG2 immunoreactivity was restricted to stellate-shaped cells corresponding to oligodendrocyte precursor cells. The distribution patterns of phosphacan, neurocan and versican in control human spinal cord parenchyma were similar, with a fine reticular pattern being observed in white matter (but also located in gray matter for phosphacan). Neurocan staining was also associated with blood vessel walls. Furthermore, phosphacan, neurocan and versican were present in the myelin sheaths of ventral and dorsal nerve roots axons. After human SCI, NG2 and phosphacan were both detected in the evolving astroglial scar. Neurocan and versican were detected exclusively in the lesion epicentre, being associated with infiltrating Schwann cells in the myelin sheaths of invading peripheral nerve fibres from lesioned dorsal roots. CONCLUSION: NG2 and phosphacan were both present in the evolving astroglial scar and, therefore, might play an important role in the blockade of successful CNS regeneration. Neurocan and versican, however, were located at the lesion epicentre, associated with Schwann cell myelin on regenerating peripheral nerve fibres, a distribution that was unlikely to contribute to failed CNS axon regeneration. The present data points to the importance of such correlative investigations for demonstrating the clinical relevance of experimental data

Illness behavior in patients on long-term sick leave due to chronic musculoskeletal pain

Background and purpose Methods for identification of patients with illness behavior in orthopedic settings are still being debated. The purpose of this study was to test the association between illness behavior, depressed mood, pain intensity, self-rated disability, and clinical status in patients with chronic musculoskeletal pain (CMP)

Idiopathic toe-walking in children, adolescents and young adults: a matter of local or generalised stiffness?

<p>Abstract</p> <p>Background</p> <p>Idiopathic Toe Walking (ITW) is present in children older than 3 years of age still walking on their toes without signs of neurological, orthopaedic or psychiatric diseases. ITW has been estimated to occur in 7% to 24% of the childhood population. To study associations between Idiopathic Toe Walking (ITW) and decrease in range of joint motion of the ankle joint. To study associations between ITW (with stiff ankles) and stiffness in other joints, muscle strength and bone density.</p> <p>Methods</p> <p>In a cross-sectional study, 362 healthy children, adolescents and young adults (mean age (sd): 14.2 (3.9) years) participated. Range of joint motion (ROM), muscle strength, anthropometrics sport activities and bone density were measured.</p> <p>Results</p> <p>A prevalence of 12% of ITW was found. Nine percent had ITW and severely restricted ROM of the ankle joint. Children with ITW had three times higher chance of severe ROM restriction of the ankle joint. Participants with ITW and stiff ankle joints had a decreased ROM in other joints, whereas bone density and muscle strength were comparable.</p> <p>Conclusion</p> <p>ITW and a decrease in ankle joint ROM might be due to local stiffness. Differential etiological diagnosis should be considered.</p

Aminoglycoside Resistance Rates, Phenotypes, and Mechanisms of Gram-Negative Bacteria from Infected Patients in Upper Egypt

With the re-emergence of older antibiotics as valuable choices for treatment of serious infections, we studied the aminoglycoside resistance of Gram-negative bacteria isolated from patients with ear, urinary tract, skin, and gastrointestinal tract infections at Minia university hospital in Egypt. Escherichia coli (mainly from urinary tract and gastrointestinal tract infections) was the most prevalent isolate (28.57%), followed by Pseudomonas aeruginosa (25.7%) (mainly from ear discharge and skin infections). Isolates exhibited maximal resistance against streptomycin (83.4%), and minimal resistance against amikacin (17.7%) and intermediate degrees of resistance against neomycin, kanamycin, gentamicin, and tobramycin. Resistance to older aminoglycosides was higher than newer aminoglycoides. The most common aminoglycoside resistance phenotype was that of streptomycin resistance, present as a single phenotype or in combination, followed by kanamycin-neomycin as determined by interpretative reading. The resistant Pseudomonas aeruginosa strains were capable of producing aminoglycoside-modifying enzymes and using efflux as mechanisms of resistance. Using checkerboard titration method, the most frequently-observed outcome in combinations of aminoglycosides with β-lactams or quinolones was synergism. The most effective combination was amikacin with ciprofloxacin (100% Synergism), whereas the least effective combination was gentamicin with amoxicillin (53.3% Synergistic, 26.7% additive, and 20% indifferent FIC indices). Whereas the studied combinations were additive and indifferent against few of the tested strains, antagonism was never observed. The high resistance rates to aminoglycosides exhibited by Gram-negative bacteria in this study could be attributed to the selective pressure of aminoglycoside usage which could be controlled by successful implementation of infection control measures