Undifferentiated spondyloarthritis following allogeneic stem cell transplantation

<p>Abstract</p> <p>Background</p> <p>Stem cell transplant has been utilized in the treatment of malignancies and rheumatic disease. Rheumatic disease may be transferred from the donor with active disease or may be developed in a recipient de novo as a late complication of SCT.</p> <p>Case Presentation</p> <p>We here report the rare case of a 26-year old male patient, who has been diagnosed with undifferentiated spondyloarthropathy after unique circumstance. The patient suffered from intermittent inflammatory back pain and peripheral joint swelling for several years and did not find relief through multiple emergency room visits at different medical facilities. After a thorough history and physical exam, it was noted that our patient had developed signs of axial disease along with dactylitis and overall that he had been insidiously developing an undifferentiated spondyloarthopathy after allogeneic stem cell transplantation.</p> <p>Conclusion</p> <p>Our observation supports the hypothesis that de novo rheumatic disease can develop after stem cell transplant for a variety of reasons. Thus, larger studies and awareness of this association are needed to delineate the exact underlying mechanism(s).</p

Dietary intake of micronutrients and the risk of developing bladder cancer: results from the Belgian case–control study on bladder cancer risk

OBJECTIVE: We aimed to investigate the effect of dietary intake of micronutrients that are metabolized and excreted via the urinary tract on bladder cancer risk. METHODS: A semi-quantitative 322 item food frequency questionnaire (FFQ) was used to collect dietary data from 200 bladder cancer cases and 386 control subjects participating in the Belgian case-control study on bladder cancer risk. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using unconditional logistic regression adjusting for age, sex, smoking characteristics, occupational exposures, and energy intake. RESULTS: We observed a positive association between calcium intake and bladder cancer (OR: 1.77; 95% CI: 1.00-3.15; p-trend = 0.049) and increased odds, although not statistically significant, for highest tertile of phosphorus intake (OR: 1.82; 95% CI: 0.95-3.49; p-trend = 0.06). We identified possible modification of the effects of both calcium and phosphorus by level of magnesium intake. Increased odds of bladder cancer were also observed for participants with highest intake of phosphorus and lowest intake of vitamin D (OR: 4.25; 95% CI: 1.44-12.55) and among older participants with the highest intakes of calcium (OR: 1.90; 95% CI: 1.08-3.36) and phosphorus (OR: 2.02; 95% CI: 1.05-3.92). CONCLUSION: The positive associations we observed between bladder cancer and intake of calcium and phosphorus require confirmation by other studies. The balances between inter-related micronutrients also warrant further examination

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

Increased Expression of Beta-Defensin 1 (DEFB1) in Chronic Obstructive Pulmonary Disease

On-going airway inflammation is characteristic for the pathophysiology of chronic obstructive pulmonary disease (COPD). However, the key factors determining the decrease in lung function, an important clinical parameter of COPD, are not clear. Genome-wide linkage analyses provide evidence for significant linkage to airway obstruction susceptibility loci on chromosome 8p23, the location of the human defensin gene cluster. Moreover, a genetic variation in the defensin beta 1 (DEFB1) gene was found to be associated with COPD. Therefore, we hypothesized that DEFB1 is differently regulated and expressed in human lungs during COPD progression. Gene expression of DEFB1 was assessed in bronchial epithelium and BAL fluid cells of healthy controls and patients with COPD and using bisulfite sequencing and ChIP analysis, the epigenetic control of DEFB1 mRNA expression was investigated. We can demonstrate that DEFB1 mRNA expression was significantly increased in bronchopulmonary specimen of patients with COPD (n = 34) vs. healthy controls (n = 10) (p<0.0001). Furthermore, a significant correlation could be detected between DEFB1 and functional parameters such as FEV1 (p = 0.0024) and the FEV1/VC ratio (p = 0.0005). Upregulation of DEFB1 mRNA was paralleled by changes in HDAC1-3, HDAC5 and HDAC8 mRNA expression. Whereas bisulfite sequencing revealed no differences in the methylation state of DEFB1 promoter between patients with COPD and controls, ChIP analysis showed that enhanced DEFB1 mRNA expression was associated with the establishment of an active histone code. Thus, expression of human DEFB1 is upregulated and related to the decrease in pulmonary function in patients with COPD

A Randomized Trial Evaluating Prosaptide™ for HIV-Associated Sensory Neuropathies: Use of an Electronic Diary to Record Neuropathic Pain

Objectives: To examine the efficacy and safety of Prosaptide™ (PRO) for the treatment of painful HIV-associated sensory neuropathies (HIV-SN). Design: A randomized, double-blind, placebo-controlled, multicenter study in participants with sensory neuropathy. Pain modulating therapy was discontinued prior to baseline. Participants were stratified by sural sensory nerve action potential (SNAP) amplitude. Participants were trained to use an electronic diary (ED) to record pain. Setting: Peripheral neuropathies are common complications of HIV infection. The pathogenesis is unknown and currently treatments are restricted to symptomatic measures. We examined PRO against placebo (PBO) for treatment of painful HIV-SN and performed a post-hoc evaluation of an electronic diary (ED) to record HIV-associated neuropathic pain. Participants: Eligible participants included adults with neurologist-confirmed painful HIV-SN.Interventions 2, 4, 8, or 16 mg/d PRO or PBO administered via subcutaneous (SC) injection for six weeks. Neurotoxic antiretroviral drug usage was held constant.Outcome Measures Changes from baseline in the weekly average of evaluable daily random prompts measuring pain using the Gracely pain scale and adverse events. Results: 237 participants were randomized. The study was stopped after a planned futility analysis. There were no between-group differences in the frequency of adverse events or laboratory toxicities. The 6-week mean (sd) Gracely pain scale changes were −0.12 (0.23), −0.24 (0.35), −0.15 (0.32), −0.18 (0.34), and −0.18 (0.32) for the 2, 4, 8, 16 mg, and PBO arms respectively. A similar variability of pain changes recorded using the ED were noted compared to previous trials that used paper collection methods.Conclusions 6-week treatment with PRO was safe but not effective at reducing HIV-associated neuropathic pain. Use of an ED to record neuropathic pain is novel in HIV-SN, resulted in reasonable compliance in recording pain data, but did not decrease the variability of pain scores compared to historical paper collection methods. Trial Registration: Current Controlled Trials NCT0028637

Prospective functional classification of all possible missense variants in PPARG.

Clinical exome sequencing routinely identifies missense variants in disease-related genes, but functional characterization is rarely undertaken, leading to diagnostic uncertainty. For example, mutations in PPARG cause Mendelian lipodystrophy and increase risk of type 2 diabetes (T2D). Although approximately 1 in 500 people harbor missense variants in PPARG, most are of unknown consequence. To prospectively characterize PPARγ variants, we used highly parallel oligonucleotide synthesis to construct a library encoding all 9,595 possible single-amino acid substitutions. We developed a pooled functional assay in human macrophages, experimentally evaluated all protein variants, and used the experimental data to train a variant classifier by supervised machine learning. When applied to 55 new missense variants identified in population-based and clinical sequencing, the classifier annotated 6 variants as pathogenic; these were subsequently validated by single-variant assays. Saturation mutagenesis and prospective experimental characterization can support immediate diagnostic interpretation of newly discovered missense variants in disease-related genes.This work was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (1K08DK102877-01, to A.R.M.; 1R01DK097768-01, to D.A.), NIH/Harvard Catalyst (1KL2TR001100-01, to A.R.M.), the Broad Institute (SPARC award, to A.R.M. and T.M.), and the Wellcome Trust (095564, to K.C.; 107064, to D.B.S.).This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.370

The Hubbard model within the equations of motion approach

The Hubbard model has a special role in Condensed Matter Theory as it is considered as the simplest Hamiltonian model one can write in order to describe anomalous physical properties of some class of real materials. Unfortunately, this model is not exactly solved except for some limits and therefore one should resort to analytical methods, like the Equations of Motion Approach, or to numerical techniques in order to attain a description of its relevant features in the whole range of physical parameters (interaction, filling and temperature). In this manuscript, the Composite Operator Method, which exploits the above mentioned analytical technique, is presented and systematically applied in order to get information about the behavior of all relevant properties of the model (local, thermodynamic, single- and two- particle ones) in comparison with many other analytical techniques, the above cited known limits and numerical simulations. Within this approach, the Hubbard model is shown to be also capable to describe some anomalous behaviors of the cuprate superconductors.Comment: 232 pages, more than 300 figures, more than 500 reference