Metabolomic Profiling of End-Stage Heart Failure Secondary to Chronic Chagas Cardiomyopathy

Chronic Chagas cardiomyopathy (CCC) is the most frequent and severe clinical form of chronic Chagas disease, representing one of the leading causes of morbidity and mortality in Latin America, and a growing global public health problem. There is currently no approved treatment for CCC; however, omics technologies have enabled significant progress to be made in the search for new therapeutic targets. The metabolic alterations associated with pathogenic mechanisms of CCC and their relationship to cellular and immunopathogenic processes in cardiac tissue remain largely unknown. This exploratory study aimed to evaluate the potential underlying pathogenic mechanisms in the failing myocardium of patients with end-stage heart failure (ESHF) secondary to CCC by applying an untargeted metabolomic profiling approach. Cardiac tissue samples from the left ventricle of patients with ESHF of CCC etiology (n = 7) and healthy donors (n = 7) were analyzed using liquid chromatography-mass spectrometry. Metabolite profiles showed altered branched-chain amino acid and acylcarnitine levels, decreased fatty acid uptake and oxidation, increased activity of the pentose phosphate pathway, dysregulation of the TCA cycle, and alterations in critical cellular antioxidant systems. These findings suggest processes of energy deficit, alterations in substrate availability, and enhanced production of reactive oxygen species in the affected myocardium. This profile potentially contributes to the development and maintenance of a chronic inflammatory state that leads to progression and severity of CCC. Further studies involving larger sample sizes and comparisons with heart failure patients without CCC are needed to validate these results, opening an avenue to investigate new therapeutic approaches for the treatment and prevention of progression of this unique and severe cardiomyopathy.     

Human magnetic resonance imaging at 8 T

BACKGROUND: Antibodies to Epstein Barr Virus (EBV) antigens have been used for the diagnosis of nasopharyngeal carcinoma (NPC). While immunofluorescence assays (IFA) of IgA antiviral capsid and early antigens have been the mainstay of this diagnosis, enzyme immunoassays (ELISA) of various EBV antigens are now available. However in almost all of these assays, the sensitivities and specificities have been calculated using blood donors and normal hospital staff as controls, who may not be the most appropriate controls. We wanted to evaluate the usefulness of IFA and ELISA of various EBV antigens in a clinical setting to distinguish between patients with NPC and those suspected of NPC but being biopsy negative. METHODS: Between January 1987 and June 1988, 322 consecutive patients suspected of NPC and who had a post-nasal biopsy were studied. Blood was taken for EBV tests before diagnosis. Tests included IFA and ELISA IgA anti-VCA and anti-EA and ELISA IgA and IgG anti-ribonucleotide reductase, a cloned EA antigen. RESULTS: IFA IgA anti-VCA together with IFA IgA anti-EA both at a cut-off of 1:10 gave the best discrimination between patients with NPC and those suspected of NPC but were biopsy negative. CONCLUSION: The ELISA IgG anti-ribonucleotide reductase test is convenient to perform and looks very promising. An ELISA using a cocktail of cloned EA peptides may be even better.     

Memory for serial order: A network model of the phonological loop and its timing.

A connectionist model of human short-term memory is presented that extends the "phonological loop" (A. D. Baddeley, see record 1986-98526-000) to encompass serial order and learning. Psychological and neuropsychological data motivate separate layers of lexical, timing, and input and output phonemic information. Connection weights between layers show Hebbian learning and decay over short and long time scales. At recall, the timing signal is rerun, phonemic information feeds back from output to input, and lexical nodes compete to be selected. The selected node then receives decaying inhibition. The model provides an explanatory mechanism for the phonological loop and for the effects of serial position, presentation modality, lexicality, grouping, and Hebb repetition. It makes new psychological and neuropsychological predictions and is a starting point for understanding the role of the phonological loop in vocabulary acquisition and for interpreting data from functional neuroimaging. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Pathways into Reading: five young people and the development of the English curriculum

This article traces the reading development of five young people over a period of 13 years, from the ages of 4 to 17. It discusses how their attitudes, knowledge and skills have been shaped by their home environment, their school curriculum, their gendered experience and, increasingly, by their use of new computer technologies. The article uses this evidence to explore features of children's reading that are easily overlooked in the classroom and makes a series of recommendations for a curriculum that is responsive to pupils' individual reading patterns.     

Product fragility and damage boundary theory

The theoretical basis for the widely accepted Damage Boundary Curve approach to product fragility and the applicability of its associated ASTM fragility assessment test procedure are first discussed. The basic assumption that the product can be modelled as a collection of linear spring/mass systems is shown to lead to specific characteristics of the product's damage boundary curve which are not borne out by the results of shock tests performed on some common consumer products. Discrepancies between theoretical predictions and experimental results are attributed to the inability of the model to account for progressive failure due to plastic deformation accumulated as a result of repeated shocks. An alternative damage boundary curve for a rigid/perfectly-plastic model is then developed and shown to be a better estimate of fragility for a broader class of products based on the results of shock tests. Modifications to the standard ASTM test procedure required to obtain the damage boundary curve for this type of product are suggested. Finally, the damage boundary theory for a generalized model which incorporates both elastic and plastic properties is developed. The feature of the damage boundary curve which are shown to survive regardless of the choice of model for the product are the critical velocity change and critical acceleration parameters. Those which do not are the shape of the damage region and the associated test procedures.     

Periodic behavior in a random environment.

Studied the tendency of animals to search periodically in temporally random environments by presenting 10 male rats with random-interval (RI) 60- and 120-sec schedules. Power spectra revealed a periodicity of responding of 20–50 sec for all Ss regardless of condition. A 2nd periodicity of 5–20 sec was strongest under the RI 60-sec schedule. Optimality theory suggested that periodic responding is better than random responding in obtaining food sooner on average, but the theory did not account for multiple periodicities. These multiple periodicities also could not be explained by a single-oscillator, information-processing version of the scalar expectancy theory proposed by J. Gibbon and R. M. Church (see record 1992-41865-001) or by the behavioral theory of timing proposed by P. R. Killeen and J. G. Fetterman (see record 1988-28629-001). The periodicities were consistent with a connectionist version of scalar expectancy theory that has nonscalar emergent properties. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Cell population changes during atrophy and regeneration of rat parotid gland

Melan-A/MART-1 is a melanoma differentiation antigen that is recognized by a high proportion of cytolytic T lymphocyte (CTL) clones derived from human leukocyte antigen (HLA)-A2+ melanoma patients. Whereas peptide Melan-A/ MART-1(27-35) was originally defined as the immunodominant CTL epitope, we have previously reported that peptide Melan-A/MART-1(26-35) was recognized more efficiently by the majority of tumor-reactive CTL clones. As demonstrated here, CTL populations generated from blood lymphocytes of either melanoma patients or healthy individuals after in vitro stimulation with peptide Melan-A/MART-1(26-35) killed specifically HLA-A2+ Melan-A+ allogeneic melanoma cells, thus suggesting their potential use in adoptive immunotherapy. We characterized the surface phenotype of the circulating CTL precursors (CTLp), which respond to in vitro stimulation with peptide Melan-A/MART-1(26-35). In melanoma patients, these CTLp predominantly expressed the CD45RO memory marker. In contrast, they were mainly, although not exclusively, found in the CD45RA subpopulation of CD8 T cells in healthy individuals. The demonstration that Melan-A/MART-1-specific CTLp in peripheral blood lymphocytes from HLA-A2+ patients with metastatic melanoma express a memory phenotype provides direct evidence that in vivo priming of this antigen may occur during tumor progression.