Statistical modelling of transcript profiles of differentially regulated genes

Background: The vast quantities of gene expression profiling data produced in microarray studies, and the more precise quantitative PCR, are often not statistically analysed to their full potential. Previous studies have summarised gene expression profiles using simple descriptive statistics, basic analysis of variance (ANOVA) and the clustering of genes based on simple models fitted to their expression profiles over time. We report the novel application of statistical non-linear regression modelling techniques to describe the shapes of expression profiles for the fungus Agaricus bisporus, quantified by PCR, and for E. coli and Rattus norvegicus, using microarray technology. The use of parametric non-linear regression models provides a more precise description of expression profiles, reducing the "noise" of the raw data to produce a clear "signal" given by the fitted curve, and describing each profile with a small number of biologically interpretable parameters. This approach then allows the direct comparison and clustering of the shapes of response patterns between genes and potentially enables a greater exploration and interpretation of the biological processes driving gene expression. Results: Quantitative reverse transcriptase PCR-derived time-course data of genes were modelled. "Splitline" or "broken-stick" regression identified the initial time of gene up-regulation, enabling the classification of genes into those with primary and secondary responses. Five-day profiles were modelled using the biologically-oriented, critical exponential curve, y(t) = A + (B + Ct)Rt + ε. This non-linear regression approach allowed the expression patterns for different genes to be compared in terms of curve shape, time of maximal transcript level and the decline and asymptotic response levels. Three distinct regulatory patterns were identified for the five genes studied. Applying the regression modelling approach to microarray-derived time course data allowed 11% of the Escherichia coli features to be fitted by an exponential function, and 25% of the Rattus norvegicus features could be described by the critical exponential model, all with statistical significance of p < 0.05. Conclusion: The statistical non-linear regression approaches presented in this study provide detailed biologically oriented descriptions of individual gene expression profiles, using biologically variable data to generate a set of defining parameters. These approaches have application to the modelling and greater interpretation of profiles obtained across a wide range of platforms, such as microarrays. Through careful choice of appropriate model forms, such statistical regression approaches allow an improved comparison of gene expression profiles, and may provide an approach for the greater understanding of common regulatory mechanisms between genes

Aprotinin reduces cardiac troponin I release and inhibits apoptosis of polymorphonuclear cells during off-pump coronary artery bypass surgery

Objectives: In addition to blood-sparing effects, aprotinin may have cardioprotective and anti-inflammatory effects during cardiopulmonary bypass-assisted cardiac surgery. In this study, the authors examined whether aprotinin had cardioprotective and/or anti-inflammatory effects in patients undergoing off-pump coronary artery bypass grafting. Design: A prospective randomized clinical trial. Setting: University hospital. Participants: Fifty patients were randomized to control (n = 25) or aprotinin treatment (n = 25) groups. Interventions: Aprotinin was given as a loading dose (2 x 10(6) KIU) followed by a continuous infusion at 5 x 10(5) KIU/h until skin closure. Measurements and Main Results: Blood samples for cardiac troponin I; interleukin-6, interleukin-8, and interleukin-10; tumor necrosis factor a; and elastase were taken after anesthesia induction, completion of revascularization, and 6 hours, 12 hours, and 24 hours after revascularization. Blood samples were taken to assess for apoptosis in polymorphonuclear cells. Baseline plasma levels for cardiac troponin I did not differ between groups but were significantly lower in aprotinin-treated patients at the time of revascularization (P = 0.03) and 6 hours (p = 0.004) and 24 hours (p = 0.03) later. Aprotinin significantly reduced apoptosis in polymorphonuclear cells compared with control-treated patients (p = 0.04). There were no differences in plasma cytokine or elastase levels between groups. Conclusions: The authors conclude that aprotinin reduces perioperative cardiac troponin I release and attenuates apoptosis in polymorphonuclear cells but has no significant effects on plasma cytokine levels in patients undergoing off-pump coronary artery bypass graft surgery

Are tibial angles measured with inertial sensors useful surrogates for frontal plane projection angles using 2-dimensional video analysis during single leg squat tasks? A reliability and agreement analysis in elite football (soccer) players

During single leg squats (SLS), tibial angle (TA) quantification using inertial measurement units (IMU) may offer a practical alternative to frontal plane projection angle (FPPA) measurement using 2-dimensional (2D) video analysis. This study determined: (i) the reliability of IMUs and 2D video analysis for TA measurement, and 2D video analysis for FPPA measurement; (ii) the agreement between IMU TA and both 2D video TA and FPPA measurements during single leg squats in elite footballers. 18 players were tested on consecutive days. Absolute TA (ATA) and relative TA (RTA) were measured with IMUs. ATA and FPPA were measured concurrently using 2D video analysis. Within-session reliability for all measurements varied across days (intraclass correlation coefficient (ICC) range=0.27–0.83, standard error of measurement (SEM) range=2.12–6.23°, minimal detectable change (MDC) range=5.87–17.26°). Between-sessions, ATA reliability was good for both systems (ICCs=0.70–0.74, SEMs=1.64–7.53°, MDCs=4.55–7.01°), while IMU RTA and 2D FPPA reliability ranged from poor to good (ICCs=0.39–0.72, SEMs=2.60–5.99°, MDCs=7.20–16.61°). All limits of agreement exceeded a 5° acceptability threshold. Both systems were reliable for between-session ATA, although agreement was poor. IMU RTA and 2D video FPPA reliability was variable. For SLS assessment, IMU derived TAs are not useful surrogates for 2D video FPPA measures in this population

Towards a functional model of mental disorders incorporating the laws of thermodynamics

The current paper presents the hypothesis that the understanding of mental disorders can be advanced by incorporating the laws of thermodynamics, specifically relating to energy conservation and energy transfer. These ideas, along with the introduction of the notion that entropic activities are symptomatic of inefficient energy transfer or disorder, were used to propose a model of understanding mental ill health as resulting from the interaction of entropy, capacity and work (environmental demands). The model was applied to Attention Deficit Hyperactivity Disorder, and was shown to be compatible with current thinking about this condition, as well as emerging models of mental disorders as complex networks. A key implication of the proposed model is that it argues that all mental disorders require a systemic functional approach, with the advantage that it offers a number of routes into the assessment, formulation and treatment for mental health problems

Toll-like receptor variation in the bottlenecked population of the Seychelles warbler: computer simulations see the ‘ghost of selection past’ and quantify the ‘drift debt’

Balancing selection can maintain immunogenetic variation within host populations, but detecting its signal in a post-bottlenecked population is challenging due to the potentially overriding effects of drift. Toll-like receptor genes (TLRs) play a fundamental role in vertebrate immune defence and are predicted to be under balancing selection. We previously characterised variation at TLR loci in the Seychelles warbler (Acrocephalus sechellensis), an endemic passerine that has undergone a historical bottleneck. Five out of seven TLR loci were polymorphic, which is in sharp contrast to the low genome-wide variation observed. However standard population genetic statistical methods failed to detect a contemporary signature of selection at any TLR loci. We examined whether the observed TLR polymorphism could be explained by neutral evolution, simulating the population's demography in the software DIYABC. This showed that the posterior distributions of mutation rates had to be unrealistically high to explain the observed genetic variation. We then conducted simulations with an agent-based model using typical values for the mutation rate, which indicated that weak balancing selection has acted on the three TLR genes. The model was able to detect evidence of past selection elevating TLR polymorphism in the pre-bottleneck populations, but was unable to discern any effects of balancing selection in the contemporary population. Our results show drift is the overriding evolutionary force that has shaped TLR variation in the contemporary Seychelles warbler population, and the observed TLR polymorphisms might be merely the ‘ghost of selection past’. Forecast models predict immunogenetic variation in this species will continue to be eroded in the absence of contemporary balancing selection. Such ‘drift debt’ occurs when a genepool has not yet reached its new equilibrium level of polymorphism, and this loss could be an important threat to many recently bottlenecked populations

The value of tibial mounted inertial measurement units to quantify running kinetics in elite football (soccer) players. A reliability and agreement study using a research orientated and a clinically orientated system

In elite football, measurement of running kinetics with inertial measurement units (IMUs) may be useful as a component of periodic health examination (PHE). This study determined the reliability of, and agreement between a research orientated IMU and clinically orientated IMU system for initial peak acceleration (IPA) and IPA symmetry index (SI) measurement during running in elite footballers. On consecutive days, 16 participants performed treadmill running at 14kmph and 18kmph. Both IMUs measured IPA and IPA SI concurrently. All measurements had good or excellent within-session reliability (intraclass correlation coefficient (ICC2,1) range = 0.79-0.96, IPA standard error of measurement (SEM) range = 0.19-0.62 g, IPA SI SEM range = 2.50-8.05%). Only the research orientated IMU demonstrated acceptable minimal detectable changes (MDCs) for IPA at 14kmph (range = 7.46-9.80%) and IPA SI at both speeds (range = 6.92-9.21%). Considering both systems, between-session IPA reliability ranged from fair to good (ICC2,1 range = 0.63-0.87, SEM range = 0.51-1.10 g) and poor to fair for IPA SI (ICC2,1 range = 0.32-0.65, SEM range = 8.07-11.18%). All MDCs were >10%. For IPA and SI, the 95% levels of agreement indicated poor between system agreement. Therefore, the use of IMUs to evaluate treadmill running kinetics cannot be recommended in this population as a PHE test to identify prognostic factors for injuries or for rehabilitation purposes

Prognostic factors associated with failure of total elbow arthroplasty

AimsThe aims of this study were to identify and evaluate the current literature examining the prognostic factors which are associated with failure of total elbow arthroplasty (TEA).MethodsElectronic literature searches were conducted using MEDLINE, Embase, PubMed, and Cochrane. All studies reporting prognostic estimates for factors associated with the revision of a primary TEA were included. The risk of bias was assessed using the Quality In Prognosis Studies (QUIPS) tool, and the quality of evidence was assessed using the modified Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework. Due to low quality of theevidence and the heterogeneous nature of the studies, a narrative synthesis was used.ResultsA total of 19 studies met the inclusion criteria, investigating 28 possible prognostic factors. Most QUIPS domains (84%) were rated as moderate to high risk of bias. The quality of the evidence was low or very low for all prognostic factors. In low-quality evidence, prognostic factors with consistent associations with failure of TEA in more than one study were: the sequelae of trauma leading to TEA, either independently or combined with acute trauma, and male sex. Severalother studies investigating sex reported no association. The evidence for other factors was of very low quality and mostly involved exploratory studies.ConclusionThe current evidence investigating the prognostic factors associated with failure of TEA is of low or very low quality, and studies generally have a moderate to high risk of bias. Prognostic factors are subject to uncertainty, should be interpreted with caution, and are of little clinical value. Higher-quality evidence is required to determine robust prognostic factors for failure of TEA

Changes in neuropsychological functioning following temporal lobectomy in patients with temporal lobe epilepsy

Purpose: This study was conducted to evaluate the changes in neuropsychological functioning in patients with temporal lobe epilepsy (TLE) after temporal lobe resection. Methods: Fifty-four TLE patients were evaluated before and after surgery using comprehensive neuropsychological tests to assess general intelligence, executive functioning, language, verbal and visual memory, working memory, visuo-spatial ability, attention and motor function. Results: The patients with left TLE showed no impairment of neuropsychological functioning after surgery, with the exception of auditory immediate memory. Furthermore, they showed significant improvement in performance IQ, executive function, working memory, visual memory, attention and psychomotor speed. The patients with right TLE did not show any significant impairment in post-operative neuropsychological functioning. They showed improvements in intellectual and executive functions, language, visual memory, visuo-spatial ability, attention and motor function post-operatively. The patients with hippocampal sclerosis showed greater post-operative improvements than the patients without hippocampal sclerosis regardless of the side. Patients with better pre-operative neuropsychological function had a higher chance of successfully discontinuing all seizure medications after surgery. Discussion: The results of this study suggest that temporal lobectomy does not harm the neuropsychological functioning of patients with intractable TLE and that it improves cognitive functions of the contralateral hemisphere. © 2009 W. S. Maney & Son Ltd

Novel translocation responses of cytosolic phospholipase A2α fluorescent proteins

AbstractCytosolic phospholipase A2 (cPLA2)α responds to the rise in cytosolic Ca2+ ([Ca2+]i) attending cell stimulation by moving to intracellular membranes, releasing arachidonic acid (AA) from these membranes, and thereby initiating the synthesis of various lipid mediators. Under some conditions, however, cPLA2α translocation occurs without any corresponding changes in [Ca2+]i. The signal for such responses has not been identified. Using confocal microscopy to track fluorescent proteins fused to cPLA2α or cPLA2α's C2 domain, we find that AA mimics Ca2+ ionophores in stimulating cPLA2α translocations to the perinuclear ER and to a novel site, the lipid body. Unlike the ionophores, AA acted independently of [Ca2+]i rises and did not translocate the proteins to the Golgi. AA's action did not involve its metabolism to eicosanoids or acylation into cellular lipids. Receptor agonists also stimulated translocations targeting lipid bodies. We propose that AA is a signal for Ca2+-independent cPLA2α translocation and that lipid bodies are common targets of cPLA2α and contributors to stimulus-induced lipid mediator synthesis