Uncovering the dynamics of cardiac systems using stochastic pacing and frequency domain analyses

Alternans of cardiac action potential duration (APD) is a well-known arrhythmogenic mechanism which results from dynamical instabilities. The propensity to alternans is classically investigated by examining APD restitution and by deriving APD restitution slopes as predictive markers. However, experiments have shown that such markers are not always accurate for the prediction of alternans. Using a mathematical ventricular cell model known to exhibit unstable dynamics of both membrane potential and Ca2+ cycling, we demonstrate that an accurate marker can be obtained by pacing at cycle lengths (CLs) varying randomly around a basic CL (BCL) and by evaluating the transfer function between the time series of CLs and APDs using an autoregressive-moving-average (ARMA) model. The first pole of this transfer function corresponds to the eigenvalue (λalt) of the dominant eigenmode of the cardiac system, which predicts that alternans occurs when λalt≤−1. For different BCLs, control values of λalt were obtained using eigenmode analysis and compared to the first pole of the transfer function estimated using ARMA model fitting in simulations of random pacing protocols. In all versions of the cell model, this pole provided an accurate estimation of λalt. Furthermore, during slow ramp decreases of BCL or simulated drug application, this approach predicted the onset of alternans by extrapolating the time course of the estimated λalt. In conclusion, stochastic pacing and ARMA model identification represents a novel approach to predict alternans without making any assumptions about its ionic mechanisms. It should therefore be applicable experimentally for any type of myocardial cell.

Temporal trends in the systemic inflammatory response syndrome, sepsis, and medical coding of sepsis.

BACKGROUND Recent reports using administrative claims data suggest the incidence of community- and hospital-onset sepsis is increasing. Whether this reflects changing epidemiology, more effective diagnostic methods, or changes in physician documentation and medical coding practices is unclear. METHODS We performed a temporal-trend study from 2008 to 2012 using administrative claims data and patient-level clinical data of adult patients admitted to Barnes-Jewish Hospital in St. Louis, Missouri. Temporal-trend and annual percent change were estimated using regression models with autoregressive integrated moving average errors. RESULTS We analyzed 62,261 inpatient admissions during the 5-year study period. 'Any SIRS' (i.e., SIRS on a single calendar day during the hospitalization) and 'multi-day SIRS' (i.e., SIRS on 3 or more calendar days), which both use patient-level data, and medical coding for sepsis (i.e., ICD-9-CM discharge diagnosis codes 995.91, 995.92, or 785.52) were present in 35.3 %, 17.3 %, and 3.3 % of admissions, respectively. The incidence of admissions coded for sepsis increased 9.7 % (95 % CI: 6.1, 13.4) per year, while the patient data-defined events of 'any SIRS' decreased by 1.8 % (95 % CI: -3.2, -0.5) and 'multi-day SIRS' did not change significantly over the study period. Clinically-defined sepsis (defined as SIRS plus bacteremia) and severe sepsis (defined as SIRS plus hypotension and bacteremia) decreased at statistically significant rates of 5.7 % (95 % CI: -9.0, -2.4) and 8.6 % (95 % CI: -4.4, -12.6) annually. All-cause mortality, SIRS mortality, and SIRS and clinically-defined sepsis case fatality did not change significantly during the study period. Sepsis mortality, based on ICD-9-CM codes, however, increased by 8.8 % (95 % CI: 1.9, 16.2) annually. CONCLUSIONS The incidence of sepsis, defined by ICD-9-CM codes, and sepsis mortality increased steadily without a concomitant increase in SIRS or clinically-defined sepsis. Our results highlight the need to develop strategies to integrate clinical patient-level data with administrative data to draw more accurate conclusions about the epidemiology of sepsis.

Imagery of a moving object: the role of occipital cortex and human MT/V5+

Visual imagery – similar to visual perception – activates feature-specific and category-specific visual areas. This is frequently observed in experiments where the instruction is to imagine stimuli that have been shown immediately before the imagery task. Hence, feature-specific activation could be related to the short-term memory retrieval of previously presented sensory information. Here, we investigated mental imagery of stimuli that subjects had not seen before, eliminating the effects of short-term memory. We recorded brain activation using fMRI while subjects performed a behaviourally controlled guided imagery task in predefined retinotopic coordinates to optimize sensitivity in early visual areas. Whole brain analyses revealed activation in a parieto-frontal network and lateral–occipital cortex. Region of interest (ROI) based analyses showed activation in left hMT/V5+. Granger causality mapping taking left hMT/V5+ as source revealed an imagery-specific directed influence from the left inferior parietal lobule (IPL). Interestingly, we observed a negative BOLD response in V1–3 during imagery, modulated by the retinotopic location of the imagined motion trace. Our results indicate that rule-based motion imagery can activate higher-order visual areas involved in motion perception, with a role for top-down directed influences originating in IPL. Lower-order visual areas (V1, V2 and V3) were down-regulated during this type of imagery, possibly reflecting inhibition to avoid visual input from interfering with the imagery construction. This suggests that the activation in early visual areas observed in previous studies might be related to short- or long-term memory retrieval of specific sensory experiences.

Interactions between short-term and long-term plasticity: shooting for a moving target

Far from being static transmission units, synapses are highly dynamical elements that change over multiple time scales depending on the history of the neural activity of both the pre- and postsynaptic neuron. Moreover, synaptic changes on different time scales interact: long-term plasticity (LTP) can modify the properties of short-term plasticity (STP) in the same synapse. Most existing theories of synaptic plasticity focus on only one of these time scales (either STP or LTP or late-LTP) and the theoretical principles underlying their interactions are thus largely unknown. Here we develop a normative model of synaptic plasticity that combines both STP and LTP and predicts specific patterns for their interactions. Recently, it has been proposed that STP arranges for the local postsynaptic membrane potential at a synapse to behave as an optimal estimator of the presynaptic membrane potential based on the incoming spikes. Here we generalize this approach by considering an optimal estimator of a non-linear function of the membrane potential and the long-term synaptic efficacy—which itself may be subject to change on a slower time scale. We find that an increase in the long-term synaptic efficacy necessitates changes in the dynamics of STP. More precisely, for a realistic non-linear function to be estimated, our model predicts that after the induction of LTP, causing long-term synaptic efficacy to increase, a depressing synapse should become even more depressing. That is, in a protocol using trains of presynaptic stimuli, as the initial EPSP becomes stronger due to LTP, subsequent EPSPs should become weakened and this weakening should be more pronounced with LTP. This form of redistribution of synaptic efficacies agrees well with electrophysiological data on synapses connecting layer 5 pyramidal neurons.

Moving along the mental number line: Interactions between whole-body motion and numerical cognition

Active head turns to the left and right have recently been shown to influence numerical cognition by shifting attention along the mental number line. In the present study, we found that passive whole-body motion influences numerical cognition. In a random-number generation task (Experiment 1), leftward and downward displacement of participants facilitated small number generation, whereas rightward and upward displacement facilitated the generation of large numbers. Influences of leftward and rightward motion were also found for the processing of auditorily presented numbers in a magnitude-judgment task (Experiment 2). Additionally, we investigated the reverse effect of the number-space association (Experiment 3). Participants were displaced leftward or rightward and asked to detect motion direction as fast as possible while small or large numbers were auditorily presented. When motion detection was difficult, leftward motion was detected faster when hearing small number and rightward motion when hearing large number. We provide new evidence that bottom-up vestibular activation is sufficient to interact with the higher-order spatial representation underlying numerical cognition. The results show that action planning or motor activity is not necessary to influence spatial attention. Moreover, our results suggest that self-motion perception and numerical cognition can mutually influence each other.

Moving beyond a descriptive aquatic toxicology: the value of biological process and trait information

In order to improve the ability to link chemical exposure to toxicological and ecological effects, aquatic toxicology will have to move from observing what chemical concentrations induce adverse effects to more explanatory approaches, that are concepts which build on knowledge of biological processes and pathways leading from exposure to adverse effects, as well as on knowledge on stressor vulnerability as given by the genetic, physiological and ecological (e.g., life history) traits of biota. Developing aquatic toxicology in this direction faces a number of challenges, including (i) taking into account species differences in toxicant responses on the basis of the evolutionarily developed diversity of phenotypic vulnerability to environmental stressors, (ii) utilizing diversified biological response profiles to serve as biological read across for prioritizing chemicals, categorizing them according to modes of action, and for guiding targeted toxicity evaluation; (iii) prediction of ecological consequences of toxic exposure from knowledge of how biological processes and phenotypic traits lead to effect propagation across the levels of biological hierarchy; and (iv) the search for concepts to assess the cumulative impact of multiple stressors. An underlying theme in these challenges is that, in addition to the question of what the chemical does to the biological receptor, we should give increasing emphasis to the question how the biological receptor handles the chemicals, i.e., through which pathways the initial chemical-biological interaction extends to the adverse effects, how this extension is modulated by adaptive or compensatory processes as well as by phenotypic traits of the biological receptor.

Effects of Landscape Segregation on Livelihood Vulnerability: Moving From Extensive Shifting Cultivation to Rotational Agriculture and Natural Forests in Northern Laos

This study investigates four decades of socio-economic and environmental change in a shifting cultivation landscape in the northern uplands of Laos. Historical changes in land cover and land use were analyzed using a chronological series of remote sensing data. Impacts of landscape change on local livelihoods were investigated in seven villages through interviews with various stakeholders. The study reveals that the complex mosaics of agriculture and forest patches observed in the study area have long constituted key assets for the resilience of local livelihood systems in the face of environmental and socio-economic risks. However, over the past 20 years, a process of segregating agricultural and forest spaces has increased the vulnerability of local land users. This process is a direct outcome of policies aimed at increasing national forest cover, eradicating shifting cultivation and fostering the emergence of more intensive and commercial agricultural practices. We argue that agriculture-forest segregation should be buffered in such a way that a diversity of livelihood opportunities and economic development pathways can be maintained.

Predicting perceived vulnerability for breast cancer among women with an average breast cancer risk

OBJECTIVES: The purpose of the present study was to investigate predictors of perceived vulnerability for breast cancer in women with an average risk for breast cancer. On the basis of empirical findings that suggested which variables might be associated with perceived vulnerability for breast cancer, we investigated whether knowledge of breast cancer risk factors, cancer worry, intrusions about breast cancer, optimism about not getting cancer and perceived health status have a predictive value for perceived breast cancer vulnerability. DESIGN: In a 3-step approach, we recruited 292 women from the general public in Germany who had neither a family history of breast cancer nor breast cancer themselves. After receiving an initial informational letter about study objectives, the women were interviewed by telephone and then asked to fill in a self-administered questionnaire. METHODS: We used structural equation modelling and hypothesized that each of the included variables has a direct influence on perceived vulnerability for breast cancer. RESULTS: We found a valid model with acceptable fit indices. Optimism about not getting cancer, intrusions about breast cancer and women's perceived health status explained 32% of the variance of perceived vulnerability for breast cancer. Cancer worry and knowledge about breast cancer did not influence perceived vulnerability for breast cancer. CONCLUSION: Perceived vulnerability for breast cancer is associated with health-related variables more than with knowledge about breast cancer risk factors.

Flow cytometry and FISH to measure the average length of telomeres (flow FISH)

Telomeres have emerged as crucial cellular elements in aging and various diseases including cancer. To measure the average length of telomere repeats in cells, we describe our protocols that use fluorescent in situ hybridization (FISH) with labeled peptide nucleic acid (PNA) probes specific for telomere repeats in combination with fluorescence measurements by flow cytometry (flow FISH). Flow FISH analysis can be performed using commercially available flow cytometers, and has the unique advantage over other methods for measuring telomere length of providing multi-parameter information on the length of telomere repeats in thousands of individual cells. The accuracy and reproducibility of the measurements is augmented by the automation of most pipetting (aspiration and dispensing) steps, and by including an internal standard (control cells) with a known telomere length in every tube. The basic protocol for the analysis of nucleated blood cells from 22 different individuals takes about 12 h spread over 2-3 days.