Transport of nitrite from large arteries modulates regional blood flow during stress and exercise.

Background: Acute cardiovascular stress increases systemic wall shear stress (WSS)-a frictional force exerted by the flow of blood on vessel walls-which raises plasma nitrite concentration due to enhanced endothelial nitric oxide synthase (eNOS) activity. Upstream eNOS inhibition modulates distal perfusion, and autonomic stress increases both the consumption and vasodilatory effects of endogenous nitrite. Plasma nitrite maintains vascular homeostasis during exercise and disruption of nitrite bioavailability can lead to intermittent claudication. Hypothesis: During acute cardiovascular stress or strenuous exercise, we hypothesize enhanced production of nitric oxide (NO) by vascular endothelial cells raises nitrite concentrations in near-wall layers of flowing blood, resulting in cumulative NO concentrations in downstream arterioles sufficient for vasodilation. Confirmation and implications: Utilizing a multiscale model of nitrite transport in bifurcating arteries, we tested the hypothesis for femoral artery flow under resting and exercised states of cardiovascular stress. Results indicate intravascular transport of nitrite from upstream endothelium could result in vasodilator-active levels of nitrite in downstream resistance vessels. The hypothesis could be confirmed utilizing artery-on-a-chip technology to measure NO production rates directly and help validate numerical model predictions. Further characterization of this mechanism may improve our understanding of symptomatic peripheral artery occlusive disease and exercise physiology.

Method for estimating pulsatile wall shear stress from one-dimensional velocity waveforms.

Wall shear stress (WSS)-a key regulator of endothelial function-is commonly estimated in vivo using simplified mathematical models based on Poiseuille's flow, assuming a quasi-steady parabolic velocity distribution, despite evidence that more rapidly time-varying, pulsatile blood flow during each cardiac cycle modulates flow-mediated dilation (FMD) in large arteries of healthy subjects. More exact and accurate models based on the well-established Womersley solution for rapidly changing blood flow have not been adopted clinically, potentially because the Womersley solution relies on the local pressure gradient, which is difficult to measure non-invasively. We have developed an open-source method for automatic reconstruction of unsteady, Womersley-derived velocity profiles, and WSS in conduit arteries. The proposed method (available online at https://doi.org/10.5281/zenodo.7576408) requires only the time-averaged diameter of the vessel and time-varying velocity data available from non-invasive imaging such as Doppler ultrasound. Validation of the method with subject-specific computational fluid dynamics and application to synthetic velocity waveforms in the common carotid, brachial, and femoral arteries reveals that the Poiseuille solution underestimates peak WSS 38.5%-55.1% during the acceleration and deceleration phases of systole and underestimates or neglects retrograde WSS. Following evidence that oscillatory shear significantly augments vasodilator production, it is plausible that mischaracterization of the shear stimulus by assuming parabolic flow leads to systematic underestimates of important biological effects of time-varying blood velocity in conduit arteries.

On-microscope staging of live cells reveals changes in the dynamics of transcriptional bursting during differentiation.

Determining the mechanisms by which genes are switched on and off during development is a key aim of current biomedical research. Gene transcription has been widely observed to occur in a discontinuous fashion, with short bursts of activity interspersed with periods of inactivity. It is currently not known if or how this dynamic behaviour changes as mammalian cells differentiate. To investigate this, using an on-microscope analysis, we monitored mouse α-globin transcription in live cells throughout erythropoiesis. We find that changes in the overall levels of α-globin transcription are most closely associated with changes in the fraction of time a gene spends in the active transcriptional state. We identify differences in the patterns of transcriptional bursting throughout differentiation, with maximal transcriptional activity occurring in the mid-phase of differentiation. Early in differentiation, we observe increased fluctuation in transcriptional activity whereas at the peak of gene expression, in early erythroblasts, transcription is relatively stable. Later during differentiation as α-globin expression declines, we again observe more variability in transcription within individual cells. We propose that the observed changes in transcriptional behaviour may reflect changes in the stability of active transcriptional compartments as gene expression is regulated during differentiation.

Hemodynamic modeling of the circle of Willis reveals unanticipated functions during cardiovascular stress.

The circle of Willis (CW) allows blood to be redistributed throughout the brain during local ischemia; however, it is unlikely that the anatomic persistence of the CW across mammalian species is driven by natural selection of individuals with resistance to cerebrovascular disease typically occurring in elderly humans. To determine the effects of communicating arteries (CoAs) in the CW on cerebral pulse wave propagation and blood flow velocity, we simulated young, active adult humans undergoing different states of cardiovascular stress (i.e., fear and aerobic exercise) using discrete transmission line segments with stress-adjusted cardiac output, peripheral resistance, and arterial compliance. Phase delays between vertebrobasilar and carotid pulses allowed bidirectional shunting through CoAs: both posteroanterior shunting before the peak of the pulse waveform and anteroposterior shunting after internal carotid pressure exceeded posterior cerebral pressure. Relative to an absent CW without intact CoAs, the complete CW blunted anterior pulse waveforms, although limited to 3% and 6% reductions in peak pressure and pulse pressure, respectively. Systolic rate of change in pressure (i.e., ∂P/∂t) was reduced 15%-24% in the anterior vasculature and increased 23%-41% in the posterior vasculature. Bidirectional shunting through posterior CoAs was amplified during cardiovascular stress and increased peak velocity by 25%, diastolic-to-systolic velocity range by 44%, and blood velocity acceleration by 134% in the vertebrobasilar arteries. This effect may facilitate stress-related increases in blood flow to the cerebellum (improving motor coordination) and reticular-activating system (enhancing attention and focus) via a nitric oxide-dependent mechanism, thereby improving survival in fight-or-flight situations.NEW & NOTEWORTHY Hemodynamic modeling reveals potential evolutionary benefits of the intact circle of Willis (CW) during fear and aerobic exercise. The CW equalizes pulse waveforms due to bidirectional shunting of blood flow through communicating arteries, which boosts vertebrobasilar blood flow velocity and acceleration. These phenomena may enhance perfusion of the brainstem and cerebellum via nitric oxide-mediated vasodilation, improving performance of the reticular-activating system and motor coordination in survival situations.

A comparison of feature selection methods for the detection of breast cancers in mammograms: adaptive sequential floating search vs. genetic algorithm.

This paper presents a comparison of feature selection methods for a unified detection of breast cancers in mammograms. A set of features, including curvilinear features, texture features, Gabor features, and multi-resolution features, were extracted from a region of 512x512 pixels containing normal tissue or breast cancer. Adaptive floating search and genetic algorithm were used for the feature selection, and a linear discriminant analysis (LDA) was used for the classification of cancer regions from normal regions. The performance is evaluated using Az the area under ROC curve. On a dataset consisting 296 normal regions and 164 cancer regions (53 masses, 56 spiculated lesions, and 55 calcifications), adaptive floating search achieved Az = 0.96 with comparison to Az = 0.93 of CHC genetic algorithm and Az = 0.90 of simple genetic algorithm.

Opiate withdrawal syndrome mimicking postoperative intestinal obstruction.

Patients with complicated inflammatory bowel disease commonly undergo repeated surgical procedures, often against a background of chronic opiate use. We describe a case in which a postoperative attempt to withdraw opiate analgesia on two separate occasions led to a clinical syndrome strongly suggestive of intestinal obstruction, the signs and symptoms of which settled rapidly on re-introduction of opiates. Small bowel contrast studies indicated a level of obstruction which not only fluctuated, but occurred at an unusual site for mechanical obstruction. In patients with a history of long-standing opiate use, postoperative opiate withdrawal can cause a significant, functional bowel disorder and should be borne in mind in the differential diagnosis of postoperative intestinal obstruction. Patients can be treated effectively with clonidine.

Normal mammogram classification based on a support vector machine utilizing crossed distribution features.

Automatic classification of normal mammograms, which constitute a majority of screening mammograms, is a new approach to computer-aided diagnosis of breast cancer. This approach may be limited, however, by non-separable "crossed" distributions of features that are extracted from digitized mammograms. This work presents a method of mapping such non-separable input features into a new set of separable features that can be utilized, together with ordinary "uncrossed" features, by a support vector machine (SVM) classifier. The results of the proposed scheme show improved performance with 80% sensitivity and 95% specificity.

Consensus evidence evaluation in resuscitation research: analysis of Type I and Type II errors.

OBJECTIVE: This paper addresses the following statistical question: 'if genuine improvements in cardiopulmonary resuscitation (CPR) were discovered that doubled the probability of resuscitation success in a series of randomized clinical trials, would they be recognized and incorporated into consensus guidelines?'. METHODS: Statistical powers for hypothetical individual clinical trials comparing experimental and control CPR were computed as a function of the study N when the true probabilities for immediate survival, 24 h survival, and discharge survival in the experimental group were twice those in the control group. Next, the binomial distributions describing the numbers of statistically significant studies in a series of equally powered trials of the same intervention were determined. These were compared with varying criteria for consensus among expert reviewers, expressed in terms of the number of 'positive' studies showing a statistically significant difference that reviewers would require before approving the experimental method. RESULTS: False-negative evaluations (i.e. failures to approve a technique that actually doubled survival) were extremely common under a wide range of realistic assumptions and consensus criteria, especially when simulated long-term survival data were considered. Similar methods showed that false-positive evaluations would be extremely rare, provided that at least two of the clinical trials in a series showed a statistically significant benefit of the experimental method. CONCLUSIONS: Optimization of evidence evaluation can and should be carried out to make better use of available data in creating resuscitation guidelines. One simple approach is the 'two and one quarter test': if at least two well-conducted studies in a series are significantly positive (P<0.05) comprising at least one-quarter of all studies in the series, a positive effect can be inferred with small Type I and Type II errors. In addition, greater reliance on modern, unbiased methods such as cumulative meta-analysis is needed to increase the sensitivity of evidence evaluation for detecting useful innovations in resuscitation.

Biomechanics of heading a soccer ball: implications for player safety.

To better understand the risk and safety of heading a soccer ball, the author created a set of simple mathematical models based upon Newton's second law of motion to describe the physics of heading. These models describe the player, the ball, the flight of the ball before impact, the motion of the head and ball during impact, and the effects of all of these upon the intensity and the duration of acceleration of the head. The calculated head accelerations were compared to those during presumably safe daily activities of jumping, dancing, and head nodding and also were related to established criteria for serious head injury from the motor vehicle crash literature. The results suggest heading is usually safe but occasionally dangerous, depending on key characteristics of both the player and the ball. Safety is greatly improved when players head the ball with greater effective body mass, which is determined by a player"s size, strength, and technique. Smaller youth players, because of their lesser body mass, are more at risk of potentially dangerous headers than are adults, even when using current youth size balls. Lower ball inflation pressure reduces risk of dangerous head accelerations. Lower pressure balls also have greater "touch" and "playability", measured in terms of contact time and contact area between foot and ball during a kick. Focus on teaching proper technique, the re-design of age-appropriate balls for young players with reduced weight and inflation pressure, and avoidance of head contact with fast, rising balls kicked at close range can substantially reduce risk of subtle brain injury in players who head soccer balls.

Efficacy of interposed abdominal compression-cardiopulmonary resuscitation (CPR), active compression and decompression-CPR and Lifestick CPR: basic physiology in a spreadsheet model.

This study was undertaken to understand and predict results of experimental cardiopulmonary resuscitation (CPR) techniques involving compression and decompression of either the chest or the abdomen. Simple mathematical models of the adult human circulation were used. Assumptions of the models are limited to normal human anatomy and physiology, the definition of compliance (volume change/pressure change), and Ohm's law (flow = pressure/resistance). Interposed abdominal compression-CPR, active compression and decompression of the chest, and Lifestick CPR, which combines interposed abdominal compression and active compression and decompression, produce, respectively, 1.9-, 1.2-, and 2.4-fold greater blood flow than standard CPR and systemic perfusion pressures of 45, 30, and 58 mm Hg, respectively. These positive effects are explained by improved pump priming and are consequences of fundamental principles of cardiovascular physiology.

CPR techniques that combine chest and abdominal compression and decompression: hemodynamic insights from a spreadsheet model.

BACKGROUND: This study was done to elucidate mechanisms by which newer cardiopulmonary resuscitation (CPR) techniques, including interposed abdominal compression (IAC), active compression-decompression (ACD), and Lifestick CPR, augment systemic perfusion pressure and forward flow and to compare the 3 techniques in the same test system. METHODS AND RESULTS: Mathematical models describing hemodynamics of the adult human circulation during cardiac arrest and CPR were created and exercised by use of spreadsheet software. Assumptions of the models are limited to normal human anatomy and physiology, the definition of compliance (volume change/pressure change), and Ohm's law (flow=pressure/resistance). Standard CPR generates 1.3 L/min forward and 25 mm Hg systemic perfusion pressure. In otherwise identical models, IAC-CPR generates 2.4 L/min and 45 mm Hg; ACD-CPR, 1.6 L/min and 30 mm Hg; and Lifestick CPR, which combines IAC and ACD, 3.1 L/min and 58 mm Hg. Augmented CPR techniques work by enhanced priming of either chest or abdominal pump mechanisms. CONCLUSIONS: Adjunctive maneuvers, combined with conventional chest compression, can produce substantial hemodynamic benefit in CPR by credible physiological mechanisms.