Further evidence for increased macrophage migration inhibitory factor expression in prostate cancer

BACKGROUND: Macrophage migration inhibitory factor (MIF) is a cytokine associated with prostate cancer, based on histologic evidence and circulating (serum) levels. Recent studies from another laboratory failed to document these results. This study's aims were to extend and confirm our previous data, as well as to define possible mechanisms for the discrepant results. Additional aims were to examine MIF expression, as well as the location of MIF's receptor, CD74, in human prostatic adenocarcinoma compared to matched benign prostate. METHODS: MIF amounts were determined in random serum samples remaining following routine PSA screening by ELISA. Native, denaturing and reducing polyacrylamide gels and Western blot analyses determined the MIF form in serum. Prostate tissue arrays were processed for MIF in situ hybridization and immunohistochemistry for MIF and CD74. MIF released into culture medium from normal epithelial, LNCaP and PC-3 cells was detected by Western blot analysis. RESULTS: Median serum MIF amounts were significantly elevated in prostate cancer patients (5.87 ± 3.91 ng/ml; ± interquartile range; n = 115) compared with patients with no documented diagnosis of prostate cancer (2.19 ± 2.65 ng/ml; n = 158). ELISA diluent reagents that included bovine serum albumin (BSA) significantly reduced MIF serum detection (p < 0.01). MIF mRNA was localized to prostatic epithelium in all samples, but cancer showed statistically greater MIF expression. MIF and its receptor (CD74) were localized to prostatic epithelium. Increased secreted MIF was detected in culture medium from prostate cancer cell lines (LNCaP and PC-3). CONCLUSION: Increased serum MIF was associated with prostate cancer. Diluent reagents that included BSA resulted in MIF serum immunoassay interference. In addition, significant amounts of complexed MIF (180 kDa under denaturing conditions by Western blot) found in the serum do not bind to the MIF capture antibody. Increased MIF mRNA expression was observed in prostatic adenocarcinoma compared to benign tissue from matched samples, supporting our earlier finding of increased MIF gene expression in prostate cancer

Effective connectivity reveals strategy differences in an expert calculator

Mathematical reasoning is a core component of cognition and the study of experts defines the upper limits of human cognitive abilities, which is why we are fascinated by peak performers, such as chess masters and mental calculators. Here, we investigated the neural bases of calendrical skills, i.e. the ability to rapidly identify the weekday of a particular date, in a gifted mental calculator who does not fall in the autistic spectrum, using functional MRI. Graph-based mapping of effective connectivity, but not univariate analysis, revealed distinct anatomical location of “cortical hubs” supporting the processing of well-practiced close dates and less-practiced remote dates: the former engaged predominantly occipital and medial temporal areas, whereas the latter were associated mainly with prefrontal, orbitofrontal and anterior cingulate connectivity. These results point to the effect of extensive practice on the development of expertise and long term working memory, and demonstrate the role of frontal networks in supporting performance on less practiced calculations, which incur additional processing demands. Through the example of calendrical skills, our results demonstrate that the ability to perform complex calculations is initially supported by extensive attentional and strategic resources, which, as expertise develops, are gradually replaced by access to long term working memory for familiar material

The Search for Invariance: Repeated Positive Testing Serves the Goals of Causal Learning

Positive testing is characteristic of exploratory behavior, yet it seems to be at odds with the aim of information seeking. After all, repeated demonstrations of one’s current hypothesis often produce the same evidence and fail to distinguish it from potential alternatives. Research on the development of scientific reasoning and adult rule learning have both documented and attempted to explain this behavior. The current chapter reviews this prior work and introduces a novel theoretical account—the Search for Invariance (SI) hypothesis—which suggests that producing multiple positive examples serves the goals of causal learning. This hypothesis draws on the interventionist framework of causal reasoning, which suggests that causal learners are concerned with the invariance of candidate hypotheses. In a probabilistic and interdependent causal world, our primary goal is to determine whether, and in what contexts, our causal hypotheses provide accurate foundations for inference and intervention—not to disconfirm their alternatives. By recognizing the central role of invariance in causal learning, the phenomenon of positive testing may be reinterpreted as a rational information-seeking strategy

Sodium bicarbonate supplementation improves severe-intensity intermittent exercise under moderate acute hypoxic conditions

Acute moderate hypoxic exposure can substantially impair exercise performance, which occurs with a concurrent exacerbated rise in hydrogen cation (H+) production. The purpose of this study was therefore, to alleviate this acidic stress through sodium bicarbonate (NaHCO3) supplementation and determine the corresponding effects on severe intensity intermittent exercise performance. Eleven recreationally active individuals participated in this randomised, double-blind, crossover study performed under acute normobaric hypoxic conditions (FiO2% = 14.5%). Pre-experimental trials involved the determination of time to attain peak bicarbonate anion concentrations ([HCO3-]) following NaHCO3 ingestion. The intermittent exercise tests involved repeated 60 s work in their severe intensity domain and 30 s recovery at 20 W to exhaustion. Participants ingested either 0.3 g·kg bm-1 of NaHCO3 or a matched placebo of 0.21 g·kg bm-1 of sodium chloride prior to exercise. Exercise tolerance (+110.9 ± 100.6 s; 95% CI: 43.3 to 178 s; g = 1.0) and work performed in the severe intensity domain (+5.8 ± 6.6 kJ; 95% CI: 1.3 to 9.9 kJ; g = 0.8) were enhanced with NaHCO3 supplementation. Furthermore, a larger post-exercise blood lactate concentration was reported in the experimental group (+4 ± 2.4 mmol·l-1; 95% CI: 2.2 to 5.9; g = 1.8), while blood [HCO3-] and pH remained elevated in the NaHCO3 condition throughout experimentation. In conclusion, this study reported a positive effect of NaHCO3 under acute moderate hypoxic conditions during intermittent exercise and therefore, may offer an ergogenic strategy to mitigate hypoxic induced declines in exercise performance

Bladder inflammatory transcriptome in response to tachykinins: Neurokinin 1 receptor-dependent genes and transcription regulatory elements

Background Tachykinins (TK), such as substance P, and their neurokinin receptors which are ubiquitously expressed in the human urinary tract, represent an endogenous system regulating bladder inflammatory, immune responses, and visceral hypersensitivity. Increasing evidence correlates alterations in the TK system with urinary tract diseases such as neurogenic bladders, outflow obstruction, idiopathic detrusor instability, and interstitial cystitis. However, despite promising effects in animal models, there seems to be no published clinical study showing that NK-receptor antagonists are an effective treatment of pain in general or urinary tract disorders, such as detrusor overactivity. In order to search for therapeutic targets that could block the tachykinin system, we set forth to determine the regulatory network downstream of NK1 receptor activation. First, NK1R-dependent transcripts were determined and used to query known databases for their respective transcription regulatory elements (TREs). Methods: An expression analysis was performed using urinary bladders isolated from sensitized wild type (WT) and NK1R-/- mice that were stimulated with saline, LPS, or antigen to provoke inflammation. Based on cDNA array results, NK1R-dependent genes were selected. PAINT software was used to query TRANSFAC database and to retrieve upstream TREs that were confirmed by electrophoretic mobility shift assays. Results: The regulatory network of TREs driving NK1R-dependent genes presented cRel in a central position driving 22% of all genes, followed by AP-1, NF-kappaB, v-Myb, CRE-BP1/c-Jun, USF, Pax-6, Efr-1, Egr-3, and AREB6. A comparison between NK1R-dependent and NK1R-independent genes revealed Nkx-2.5 as a unique discriminator. In the presence of NK1R, Nkx2-5 _01 was significantly correlated with 36 transcripts which included several candidates for mediating bladder development (FGF) and inflammation (PAR-3, IL-1R, IL-6, α-NGF, TSP2). In the absence of NK1R, the matrix Nkx2-5_02 had a predominant participation driving 8 transcripts, which includes those involved in cancer (EYA1, Trail, HSF1, and ELK-1), smooth-to-skeletal muscle trans-differentiation, and Z01, a tight-junction protein, expression. Electrophoretic mobility shift assays confirmed that, in the mouse urinary bladder, activation of NK1R by substance P (SP) induces both NKx-2.5 and NF-kappaB translocations. Conclusion: This is the first report describing a role for Nkx2.5 in the urinary tract. As Nkx2.5 is the unique discriminator of NK1R-modulated inflammation, it can be imagined that in the near future, new based therapies selective for controlling Nkx2.5 activity in the urinary tract may be used in the treatment in a number of bladder disorders

Deconstructing Insight: EEG Correlates of Insightful Problem Solving

Background: Cognitive insight phenomenon lies at the core of numerous discoveries. Behavioral research indicates four salient features of insightful problem solving: (i) mental impasse, followed by (ii) restructuring of the problem representation, which leads to (iii) a deeper understanding of the problem, and finally culminates in (iv) an “Aha!” feeling of suddenness and obviousness of the solution. However, until now no efforts have been made to investigate the neural mechanisms of these constituent features of insight in a unified framework. Methodology/Principal Findings: In an electroencephalographic study using verbal remote associate problems, we identified neural correlates of these four features of insightful problem solving. Hints were provided for unsolved problems or after mental impasse. Subjective ratings of the restructuring process and the feeling of suddenness were obtained on trial-by-trial basis. A negative correlation was found between these two ratings indicating that sudden insightful solutions, where restructuring is a key feature, involve automatic, subconscious recombination of information. Electroencephalogram signals were analyzed in the space×time×frequency domain with a nonparametric cluster randomization test. First, we found strong gamma band responses at parieto-occipital regions which we interpreted as (i) an adjustment of selective attention (leading to a mental impasse or to a correct solution depending on the gamma band power level) and (ii) encoding and retrieval processes for the emergence of spontaneous new solutions. Secondly, we observed an increased upper alpha band response in right temporal regions (suggesting active suppression of weakly activated solution relevant information) for initially unsuccessful trials that after hint presentation led to a correct solution. Finally, for trials with high restructuring, decreased alpha power (suggesting greater cortical excitation) was observed in right prefrontal area. Conclusions/Significance: Our results provide a first account of cognitive insight by dissociating its constituent components and potential neural correlates

The diagnostic and prognostic value of red cell distribution width in cardiovascular disease, current status and prospective

The red blood cell distribution width (RDW) is an index of the heterogeneity of circulating red blood cell size, which along with other standard complete blood count (CBC) parameters are used to identify hematological system diseases. Besides hematological disorders, several clinical studies have shown that an increased in the RDW may be associated with other diseases including acute pancreatitis, chronic kidney disease, gastrointestinal disorders, cancer, and of special interest in this review, cardiovascular disease (CVD). The diagnostic and prognostic value of RDW in different CVD (acute coronary syndrome, ischemic cerebrovascular disease, peripheral artery disease, atrial fibrillation, heart failure, and acute ischemic stroke) has been reviewed in this article, to provide an understanding how its measurement may be applied to improve the management of these conditions.Keywords: RDW, Biomarker, Cardiovascular disease

Psychosocial factors and health as determinants of quality of life in community-dwelling older adults.

PURPOSE: It is important to understand the determinants of differences in quality of life in old age and to include a wide range of possible predictors. The present study investigated the determinants of quality of life in two groups of older adults for whom there was an unusually informative set of possible predictor variables. METHOD: Participants were members of the Lothian Birth Cohorts of 1921 (n = 550) or 1936 (n = 1,091). Four facets of quality of life (QoL) and general QoL were measured using the WHOQOL-BREF. Possible determinants included personality traits, measured with the International Personality Item Pool (IPIP) scales; childhood and old age general cognitive ability, measured with the Moray House Test; minor psychological symptoms, measured with the Hospital Anxiety and Depression Scale (HADS); physical health, assessed by grip strength and cardiovascular disease history; and sociodemographic factors, assessed by interview. RESULTS: Linear regression analyses revealed that HADS depression had the greatest influence on quality of life. Personality traits, most notably Emotional Stability, also predicted quality of life to varying degrees, along with factors reflecting current life circumstances. There were differences between the two cohorts in the variables which predicted quality of life. There were different, conceptually relevant, contributions to the different QoL facets. CONCLUSIONS: Personality traits and minor depressive symptoms have an important influence on self-reported quality of life in old age. Quality of life may be influenced more by current than past circumstances, and this relationship may change with age