Peroxisome Proliferator-Activated Receptor alpha (PPAR alpha) down-regulation in cystic fibrosis lymphocytes

Background: PPARs exhibit anti-inflammatory capacities and are potential modulators of the inflammatory response. We hypothesized that their expression and/or function may be altered in cystic fibrosis (CF), a disorder characterized by an excessive host inflammatory response. Methods: PPARα, β and γ mRNA levels were measured in peripheral blood cells of CF patients and healthy subjects via RT-PCR. PPARα protein expression and subcellular localization was determined via western blot and immunofluorescence, respectively. The activity of PPARα was analyzed by gel shift assay. Results: In lymphocytes, the expression of PPARα mRNA, but not of PPARβ, was reduced (-37%; p < 0.002) in CF patients compared with healthy persons and was therefore further analyzed. A similar reduction of PPARα was observed at protein level (-26%; p < 0.05). The transcription factor was mainly expressed in the cytosol of lymphocytes, with low expression in the nucleus. Moreover, DNA binding activity of the transcription factor was 36% less in lymphocytes of patients (p < 0.01). For PPARα and PPARβ mRNA expression in monocytes and neutrophils, no significant differences were observed between CF patients and healthy persons. In all cells, PPARγ mRNA levels were below the detection limit. Conclusion: Lymphocytes are important regulators of the inflammatory response by releasing cytokines and antibodies. The diminished lymphocytic expression and activity of PPARα may therefore contribute to the inflammatory processes that are observed in CF

Peptide-MHC Cellular Microarray with Innovative Data Analysis System for Simultaneously Detecting Multiple CD4 T-Cell Responses

Peptide:MHC cellular microarrays have been proposed to simultaneously characterize multiple Ag-specific populations of T cells. The practice of studying immune responses to complicated pathogens with this tool demands extensive knowledge of T cell epitopes and the availability of peptide:MHC complexes for array fabrication as well as a specialized data analysis approach for result interpretation. T cell cultures. A novel statistical methodology was also developed to facilitate batch processing of raw array-like data into standardized endpoint scores, which linearly correlated with total Ag-specific T cell inputs. Applying these methods to analyze Influenza A viral antigen-specific T cell responses, we not only revealed the most prominent viral epitopes, but also demonstrated the heterogeneity of anti-viral cellular responses in healthy individuals. Applying these methods to examine the insulin producing beta-cell autoantigen specific T cell responses, we observed little difference between autoimmune diabetic patients and healthy individuals, suggesting a more subtle association between diabetes status and peripheral autoreactive T cells.The data analysis system is reliable for T cell specificity and functional testing. Peptide:MHC cellular microarrays can be used to obtain multi-parametric results using limited blood samples in a variety of translational settings

Supporting families in the context of adult traumatic brain injury

Families are fundamental to the wellbeing, quality of life and functional and social outcomes of individuals who sustain traumatic brain injury (TBI). However, the family is often vulnerable and at risk from the challenge of supporting an individual who has been left with long-term neurological disability. Considering the young population often affected, the resulting conditions can have significant emotional and financial burden for families and service providing for their long-term needs. The National Service Framework for Long-term Conditions acknowledges that the whole family is affected by neurological disability and it suggests that a 'whole-family' approach to managing TBI may be useful. This paper will argue that both family systems theory and family-centred care are frameworks that may be helpful in achieving the 'whole-family' approach in practice. However, future research is needed that will assess the efficacy of these and other approaches so that health-care services know the true value of any such intervention.N/

Measurement of the Bottom-Strange Meson Mixing Phase in the Full CDF Data Set

We report a measurement of the bottom-strange meson mixing phase \beta_s using the time evolution of B0_s -> J/\psi (->\mu+\mu-) \phi (-> K+ K-) decays in which the quark-flavor content of the bottom-strange meson is identified at production. This measurement uses the full data set of proton-antiproton collisions at sqrt(s)= 1.96 TeV collected by the Collider Detector experiment at the Fermilab Tevatron, corresponding to 9.6 fb-1 of integrated luminosity. We report confidence regions in the two-dimensional space of \beta_s and the B0_s decay-width difference \Delta\Gamma_s, and measure \beta_s in [-\pi/2, -1.51] U [-0.06, 0.30] U [1.26, \pi/2] at the 68% confidence level, in agreement with the standard model expectation. Assuming the standard model value of \beta_s, we also determine \Delta\Gamma_s = 0.068 +- 0.026 (stat) +- 0.009 (syst) ps-1 and the mean B0_s lifetime, \tau_s = 1.528 +- 0.019 (stat) +- 0.009 (syst) ps, which are consistent and competitive with determinations by other experiments.Comment: 8 pages, 2 figures, Phys. Rev. Lett 109, 171802 (2012

Pre-Stressor Interference Control and Intrusive Memories

Although intrusive imagery is a common response in the aftermath of a stressful or traumatic event, only a minority of trauma victims show persistent re-experiencing and related psychopathology. Individual differences in pre-trauma executive control possibly play a critical role. Therefore, this study investigated whether a relatively poor pre-stressor ability to resist proactive interference in working memory might increase risk for experiencing undesirable intrusive memories after being exposed to a stressful event. Non-clinical participants (N = 85) completed a modified version of a widely used test of interference control in working memory (CVLT; Kramer and Delis 1991) and subsequently watched an emotional film fragment. Following presentation of the fragment, intrusive memories were recorded in a 1-week diary and at a follow up session 7 days later. A relatively poor ability to resist proactive interference was related to a relatively high frequency of film-related intrusive memories. This relationship was independent of neuroticism and gender. These findings are consistent with the idea that a pre-morbid deficit in the ability to resist proactive interference reflects a vulnerability factor for experiencing intrusive memories after trauma exposure

A hierarchy of effective teaching and learning to acquire competence in evidenced-based medicine

BACKGROUND: A variety of methods exists for teaching and learning evidence-based medicine (EBM). However, there is much debate about the effectiveness of various EBM teaching and learning activities, resulting in a lack of consensus as to what methods constitute the best educational practice. There is a need for a clear hierarchy of educational activities to effectively impart and acquire competence in EBM skills. This paper develops such a hierarchy based on current empirical and theoretical evidence. DISCUSSION: EBM requires that health care decisions be based on the best available valid and relevant evidence. To achieve this, teachers delivering EBM curricula need to inculcate amongst learners the skills to gain, assess, apply, integrate and communicate new knowledge in clinical decision-making. Empirical and theoretical evidence suggests that there is a hierarchy of teaching and learning activities in terms of their educational effectiveness: Level 1, interactive and clinically integrated activities; Level 2(a), interactive but classroom based activities; Level 2(b), didactic but clinically integrated activities; and Level 3, didactic, classroom or standalone teaching. SUMMARY: All health care professionals need to understand and implement the principles of EBM to improve care of their patients. Interactive and clinically integrated teaching and learning activities provide the basis for the best educational practice in this field

Calpain inhibition mediates autophagy-dependent protection against polyglutamine toxicity.

Over recent years, accumulated evidence suggests that autophagy induction is protective in animal models of a number of neurodegenerative diseases. Intense research in the field has elucidated different pathways through which autophagy can be upregulated and it is important to establish how modulation of these pathways impacts upon disease progression in vivo and therefore which, if any, may have further therapeutic relevance. In addition, it is important to understand how alterations in these target pathways may affect normal physiology when constitutively modulated over a long time period, as would be required for treatment of neurodegenerative diseases. Here we evaluate the potential protective effect of downregulation of calpains. We demonstrate, in Drosophila, that calpain knockdown protects against the aggregation and toxicity of proteins, like mutant huntingtin, in an autophagy-dependent fashion. Furthermore, we demonstrate that, overexpression of the calpain inhibitor, calpastatin, increases autophagosome levels and is protective in a mouse model of Huntington's disease, improving motor signs and delaying the onset of tremors. Importantly, long-term inhibition of calpains did not result in any overt deleterious phenotypes in mice. Thus, calpain inhibition, or activation of autophagy pathways downstream of calpains, may be suitable therapeutic targets for diseases like Huntington's disease.This is the published version of the manuscript. It is available online from NPG in Cell Death and Differentiaiton here: http://www.nature.com/cdd/journal/vaop/ncurrent/full/cdd2014151a.html

Genome-level homology and phylogeny of Shewanella (Gammaproteobacteria: lteromonadales: Shewanellaceae)

<p>Abstract</p> <p>Background</p> <p>The explosion in availability of whole genome data provides the opportunity to build phylogenetic hypotheses based on these data as well as the ability to learn more about the genomes themselves. The biological history of genes and genomes can be investigated based on the taxomonic history provided by the phylogeny. A phylogenetic hypothesis based on complete genome data is presented for the genus <it>Shewanella </it>(Gammaproteobacteria: Alteromonadales: Shewanellaceae). Nineteen taxa from <it>Shewanella </it>(16 species and 3 additional strains of one species) as well as three outgroup species representing the genera <it>Aeromonas </it>(Gammaproteobacteria: Aeromonadales: Aeromonadaceae), <it>Alteromonas </it>(Gammaproteobacteria: Alteromonadales: Alteromonadaceae) and <it>Colwellia </it>(Gammaproteobacteria: Alteromonadales: Colwelliaceae) are included for a total of 22 taxa.</p> <p>Results</p> <p>Putatively homologous regions were found across unannotated genomes and tested with a phylogenetic analysis. Two genome-wide data-sets are considered, one including only those genomic regions for which all taxa are represented, which included 3,361,015 aligned nucleotide base-pairs (bp) and a second that additionally includes those regions present in only subsets of taxa, which totaled 12,456,624 aligned bp. Alignment columns in these large data-sets were then randomly sampled to create smaller data-sets. After the phylogenetic hypothesis was generated, genome annotations were projected onto the DNA sequence alignment to compare the historical hypothesis generated by the phylogeny with the functional hypothesis posited by annotation.</p> <p>Conclusions</p> <p>Individual phylogenetic analyses of the 243 locally co-linear genome regions all failed to recover the genome topology, but the smaller data-sets that were random samplings of the large concatenated alignments all produced the genome topology. It is shown that there is not a single orthologous copy of 16S rRNA across the taxon sampling included in this study and that the relationships among the multiple copies are consistent with 16S rRNA undergoing concerted evolution. Unannotated whole genome data can provide excellent raw material for generating hypotheses of historical homology, which can be tested with phylogenetic analysis and compared with hypotheses of gene function.</p