Preliminary Investigation Into the Effect of ACTN3 and ACE Polymorphisms on Muscle and Performance Characteristics

Preliminary investigation into the effect of ACTN3 and ACE polymorphisms on muscle and performance characteristics. J Strength Cond Res XX(X): 000-000, 2018-The purpose of this investigation was to explore the phenotypic and performance outcomes associated with ACTN3 and ACE polymorphisms. Ten trained men (age = 25.8 ± 3.0 years, height = 183.3 ± 4.1 cm, body mass = 92.3 ± 9.3 kg, and back squat to body mass ratio = 1.8 ± 0.3) participated. Blood samples were analyzed to determine ACTN3 and ACE polymorphisms. Standing ultrasonography images of the vastus lateralis (VL) were collected to determine whole muscle cross-sectional area (CSA-M), and a percutaneous muscle biopsy of the VL was collected to determine type I-specific CSA (CSA-T1), type II-specific CSA (CSA-T2), and type II to type I CSA ratio (CSA-R). Isometric squats were performed on force platforms with data used to determine peak force (IPF), allometrically scaled peak force (IPFa), and rate of force development (RFD) at various timepoints. One repetition maximum back squats were performed, whereby allometrically scaled dynamic strength (DSa) was determined. Cohen\u27s d effect sizes revealed ACTN3 RR and ACE DD tended to result in greater CSA-M but differ in how they contribute to performance. ACTN3 RR\u27s influence seems to be in the type II fibers, altering maximal strength, and ACE DD may influence RFD capabilities through a favorable CSA-R. Although the findings of the current investigation are limited by the sample size, the findings demonstrate the potential influence of ACTN3 and ACE polymorphisms on isometric and dynamic strength testing. This study may serve as a framework to generate hypotheses regarding the effect of genetics on performance

Time to positivity in blood cultures of adults with Streptococcus pneumoniae bacteremia

BACKGROUND: previous studies have established that bacterial blood concentration is related with clinical outcome. Time to positivity of blood cultures (TTP) has relationship with bacterial blood concentration and could be related with prognosis. As there is scarce information about the usefulness of TTP, we study the relationship of TTP with clinical parameters in patients with Streptococcus pneumoniae bacteremia. METHODS: TTP of all cases of Streptococcus pneumoniae bacteremia, detected between January 1995 and December 2004 using the BacT/Alert automated blood culture system in a teaching community hospital was analyzed. When multiple cultures were positive only the shortest TTP was selected for the analysis. RESULTS: in the study period 105 patients with Streptococcus pneumoniae bacteremia were detected. Median TTP was 14.1 hours (range 1.2 h to 127 h). Immunosuppressed patients (n = 5), patients with confusion (n = 19), severe sepsis or shock at the time of blood culture extraction (n = 12), those with a diagnosis of meningitis (n = 7) and those admitted to the ICU (n = 14) had lower TTP. Patients with TTP in the first quartile were more frequently hospitalized, admitted to the ICU, had meningitis, a non-pneumonic origin of the bacteremia, and a higher number of positive blood cultures than patients with TTP in the fourth quartile. None of the patients with TTP in the 90(th )decile had any of these factors associated with shorter TTP, and eight out of ten patients with TTP in the 10(th )decile had at least one of these factors. The number of positive blood cultures had an inverse correlation with TTP, suggesting a relationship of TTP with bacterial blood concentration. CONCLUSION: Our data support the relationship of TTP with several clinical parameters in patients with Streptococcus pneumoniae bacteremia, and its potential usefulness as a surrogate marker of outcome

Food intake by Patient-Generated Subjective Global Assessment (PG-SGA)corresponds to energy and protein intake as well as weight change in patients with advanced cancer

Summary: Background & aims: The aim of this study was to test how well the Patient-Generated Subjective Global Assessment (PG-SGA) question about food intake correlates with a well-established measurement of food intake. Furthermore, we wanted to examine if there were any associations between the patients ratings to the question and weight change. Methods: Data at baseline and after 4–6 weeks was drawn from two studies which combined provided a sample of 85 patients with lung and pancreatic cancer; one of the studies were an intervention study, the other a prospective, observational study. All patients completed the PG-SGA questionnaire, and rated their food intake the past month as unchanged, increased or less than usual. Energy and protein intake was estimated based upon a 24-h dietary recall. Results: Patients reporting a food intake less than usual had a lower energy (24.2 vs 30.3 kcal/kg/day, p = 0.02) and protein (1.0 vs 1.2 g/kg/day, p = 0.07) intake at baseline compared to patients reporting unchanged or increased food intake. After comparison at 4–6 weeks, patients reporting a food intake less than usual, had a lower energy (24.5 vs 31.7 kcal/kg/day, p = 0.07) and protein (0.9 vs 1.3 g/kg/day, p = 0.003) intake. Patients reporting a food intake less than usual the past month lost more weight than patients with an unchanged or increased intake (−2.6 kg versus 0.7 kg respectively, p < 0.001). Conclusions: This study show that self-reported food intake measured by PG-SGA corresponds to measured energy and protein intake as well to weight change on a group level. This indicates that patients self-report of food intake can be used as a valid indication of food intake in patients with advanced cancer. Further investigation of the psychometric properties of the question is necessary to evaluate how well the question performs on an individual level. Keywords: Cancer, Food intake, SGA, PG-SGA, 24-H dietary recall, Weight los

Comparison of risk-scoring systems in the prediction of outcome after liver resection

Background: Risk prediction techniques commonly used in liver surgery include the American Society of Anesthesiologists (ASA) grading, Charlson Comorbidity Index (CCI) and cardiopulmonary exercise tests (CPET). This study compares the utility of these techniques along with the number of segments resected as predictive tools in liver surgery. Methods: A review of a unit database of patients undergoing liver resection between February 2008 and January 2015 was undertaken. Patient demographics, ASA, CCI and CPET variables were recorded along with resection size. Clavien-Dindo grade III–V complications were used as a composite outcome in analyses. Association between predictive variables and outcome was assessed by univariate and multivariate techniques. Results: One hundred and seventy-two resections in 168 patients were identified. Grade III–V complications occurred after 42 (24.4%) liver resections. In univariate analysis of CPET variables, ventilatory equivalents for CO2 (VEqCO2) was associated with outcome. CCI score, but not ASA grade, was also associated with outcome. In multivariate analysis, the odds ratio of developing grade III–V complications for incremental increases in VEqCO2, CCI and number of liver segments resected were 1.09, 1.49 and 2.94, respectively. Conclusions: Of the techniques evaluated, resection size provides the simplest and most discriminating predictor of significant complications following liver surgery

Heterogeneity assessment of functional T cell avidity.

The potency of cellular immune responses strongly depends on T cell avidity to antigen. Yet, functional avidity measurements are rarely performed in patients, mainly due to the technical challenges of characterizing heterogeneous T cells. The mean functional T cell avidity can be determined by the IFN-γ Elispot assay, with titrated amounts of peptide. Using this assay, we developed a method revealing the heterogeneity of functional avidity, represented by the steepness/hillslope of the peptide titration curve, documented by proof of principle experiments and mathematical modeling. Our data show that not only natural polyclonal CD8 T cell populations from cancer patients, but also monoclonal T cells differ strongly in their heterogeneity of functional avidity. Interestingly, clones and polyclonal cells displayed comparable ranges of heterogeneity. We conclude that besides the mean functional avidity, it is feasible and useful to determine its heterogeneity (hillslope) for characterizing T cell responses in basic research and patient investigation

Functional interplay between p63 and p53 controls RUNX1 function in the transition from proliferation to differentiation in human keratinocytes

The interfollicular epidermis is continuously renewed, thanks to a regulated balance between proliferation and differentiation. The ΔNp63 transcription factor has a key role in the control of this process. It has been shown that ΔNp63 directly regulates Runt-related transcription factor 1 (RUNX1) transcription factor expression in mouse keratinocytes. The present study showed for the first time that RUNX1 is expressed in normal human interfollicular epidermis and that its expression is tightly regulated during the transition from proliferation to differentiation. It demonstrated that ΔNp63 directly binds two different RUNX1 regulatory DNA sequences and modulates RUNX1 expression differentially in proliferative or differentiated human keratinocytes. It also showed that the regulation of RUNX1 expression by ΔNp63 is dependent on p53 and that this coregulation relies on differential binding and activation of RUNX1 regulatory sequences by ΔNp63 and p53. We also found that RUNX1 inhibits keratinocyte proliferation and activates directly the expression of KRT1, a critical actor in early keratinocyte differentiation. Finally, we described that RUNX1 expression, similar to ΔNp63 and p53, was strongly expressed and downregulated in basal cell carcinomas and squamous cell carcinomas respectively. Taken together, these data shed light on the importance of tight control of the functional interplay between ΔNp63 and p53 in regulating RUNX1 transcription factor expression for proper regulation of interfollicular epidermal homeostasis

The nuclear receptor LXR modulates interleukin-18 levels through multiple mechanisms

IL-18 is a member of the IL-1 family involved in innate immunity and inflammation. Deregulated levels of IL-18 are involved in the pathogenesis of multiple disorders including inflammatory and metabolic diseases, yet relatively little is known regarding its regulation. Liver X receptors or LXRs are key modulators of macrophage cholesterol homeostasis and immune responses. Here we show that LXR ligands negatively regulate LPS-induced mRNA and protein expression of IL-18 in bone marrow-derived macrophages. Consistent with this being an LXR-mediated process, inhibition is abolished in the presence of a specific LXR antagonist and in LXR-deficient macrophages. Additionally, IL-18 processing of its precursor inactive form to its bioactive state is inhibited by LXR through negative regulation of both pro-caspase 1 expression and activation. Finally, LXR ligands further modulate IL-18 levels by inducing the expression of IL-18BP, a potent endogenous inhibitor of IL-18. This regulation occurs via the transcription factor IRF8, thus identifying IL-18BP as a novel LXR and IRF8 target gene. In conclusion, LXR activation inhibits IL-18 production through regulation of its transcription and maturation into an active pro-inflammatory cytokine. This novel regulation of IL-18 by LXR could be applied to modulate the severity of IL-18 driven metabolic and inflammatory disorders

The Human Papillomavirus E6 Oncogene Represses a Cell Adhesion Pathway and Disrupts Focal Adhesion through Degradation of TAp63β upon Transformation

Cervical carcinomas result from cellular transformation by the human papillomavirus (HPV) E6 and E7 oncogenes which are constitutively expressed in cancer cells. The E6 oncogene degrades p53 thereby modulating a large set of p53 target genes as shown previously in the cervical carcinoma cell line HeLa. Here we show that the TAp63β isoform of the p63 transcription factor is also a target of E6. The p63 gene plays an essential role in skin homeostasis and is expressed as at least six isoforms. One of these isoforms, ΔNp63α, has been found overexpressed in squamous cell carcinomas and is shown here to be constitutively expressed in Caski cells associated with HPV16. We therefore explored the role of p63 in these cells by performing microarray analyses after repression of endogenous E6/E7 expression. Upon repression of the oncogenes, a large set of p53 target genes was found activated together with many p63 target genes related to cell adhesion. However, through siRNA silencing and ectopic expression of various p63 isoforms we demonstrated that TAp63β is involved in activation of this cell adhesion pathway instead of the constitutively expressed ΔNp63α and β. Furthermore, we showed in cotransfection experiments, combined with E6AP siRNA silencing, that E6 induces an accelerated degradation of TAp63β although not through the E6AP ubiquitin ligase used for degradation of p53. Repression of E6 transcription also induces stabilization of endogenous TAp63β in cervical carcinoma cells that lead to an increased concentration of focal adhesions at the cell surface. Consequently, TAp63β is the only p63 isoform suppressed by E6 in cervical carcinoma as demonstrated previously for p53. Down-modulation of focal adhesions through disruption of TAp63β therefore appears as a novel E6-dependent pathway in transformation. These findings identify a major physiological role for TAp63β in anchorage independent growth that might represent a new critical pathway in human carcinogenesis