Designing an Active Valvulated Outflow Conduit for a Continuous-Flow Left Ventricular Assist Device to Increase Pulsatility: A Simulation Study.

The purpose of this work was to investigate, using a lumped parameter model, the feasibility of increasing the pulsatility of a continuous-flow ventricular assist device (VAD) by implanting an active valvulated outflow cannula. A lumped parameter model was adopted for this study. VAD was modeled, starting from its pressure-flow characteristics. The valvulated outflow conduit was modeled as an active resistance described by a square function. Starting from pathologic condition, the following simulations were performed: VAD, VAD and valvulated outflow conduit in copulsation and counterpulsation with different ratios between the VAD valve opening rate and the heart rate, and asynchrony work with the heart with different VAD valve opening intervals. The copulsation 1:1 configuration and the asynchrony 0.3s-close-0.7s-open configurations permit to maximize the hemodynamic benefits provided by the presence of the active VAD outflow valvulated conduit providing an increase of arterial pulsatility from 1.86% to 14.98% without the presence of left ventricular output. The presence of the active VAD valve in the outflow conduit causes a decrement of the left ventricular unloading and of VAD flow and, that can be counteracted by increasing the VAD speed without affecting arterial pulsatility. The valvulated outflow tube provides an increase in arterial pulsatility; it can be driven in different working modality and can be potentially applicable to all types of VADs. However, the valvulated outflow conduit causes a decrement of left ventricular unloading and of the VAD flow that can be counteracted, increasing the VAD speed.

Increasing the pulsatility of continuos flow VAD: comparison between a valvulated outflow cannula and speed modulation by simulation.

To investigate by a lumped parameter model the feasibility of increasing the pulsatility of a continuous flow VAD, implanting an active valvulated outflow cannula and to compare the results with the haemodynamic outcome given by speed modulation methods. The concomitant presence of speed modulation and the active valvulated outflow conduit is also simulated. A lumped parameter model was adopted. VAD was modeled starting from its pressure flow characteristics with a second order polynomial equation. The valvulated outflow conduit was modeled as an active resistance described by a square function. Starting from pathological condition we simulated: VAD; VAD and valvulated outflow conduit in copulsation, counterpulsation and asynchrony work with the heart; VAD and active valvulated outflow tube and speed modulation. Copulsation 1:1 and asynchrony 0.3 s valve close-0.7 s valve open configurations maximised the haemodynamic benefits with the highest increment in pulsatility. The valvulated outflow conduit causes a decrement of the left ventricular unloading and of VAD flow that can be counteracted by increasing the VAD speed without affecting pulsatility. The concomitant use of the speed modulation and the active valvulated outflow conduit can further increase the pulsatility without altering left ventricular unloading and VAD flow. The valvulated outflow tube provide similar increase in pulsatility to speed modulation method but causes a decrement of left ventricular unloading and VAD flow that can be counteracted increasing the VAD speed or allowing a partial support. A valvulated outflow tube can be potentially applied to all continuous flow VADs.

Comparison between two different cardiovascular models during a hemorrhagic shock scenario.

Hemorrhagic shock is a form of hypovolemic shock determined by rapid and large loss of intravascular blood volume and represents the first cause of death in the world, whether on the battlefield or in civilian traumatology. For this, the ability to prevent hemorrhagic shock remains one of the greatest challenges in the medical and engineering fields. The use of mathematical models of the cardiocirculatory system has improved the capacity, on one hand, to predict the risk of hemorrhagic shock and, on the other, to determine efficient treatment strategies. In this paper, a comparison between two mathematical models that simulate several hemorrhagic scenarios is presented. The models considered are the Guyton and the Zenker model. In the vast panorama of existing cardiovascular mathematical models, we decided to compare these two models because they seem to be at the extremes as regards the complexity and the detail of information that they analyze. The Guyton model is a complex and highly structured model that represents a milestone in the study of the cardiovascular system; the Zenker model is a more recent one, developed in 2007, that is relatively simple and easy to implement. The comparison between the two models offers new prospects for the improvement of mathematical models of the cardiovascular system that may prove more effective in the study of hemorrhagic shock.

Closed-loop control of tumor growth by means of anti-angiogenic administration.

A tumor growth model accounting for angiogenic stimulation and inhibition is here considered, and a closed-loop control law is presented with the aim of tumor volume reduction by means of anti-angiogenic administration. To this end the output-feedback linearization theory is exploited, with the feedback designed on the basis of a state observer for nonlinear systems. Measurements are supposed to be acquired at discrete sampling times, and a novel theoretical development in the area of time-delay systems is applied in order to derive a continuous-time observer in spite of the presence of sampled measurements. The overall control scheme allows to set independently the control and the observer parameters thanks to the structural properties of the tumor growth model. Simulations are carried out in order to mimic a real experimental framework on mice. These results seem extremely promising: they provide very good performances according to the measurements sampling interval suggested by the experimental literature, and show a noticeable level of robustness against the observer initial estimate, as well as against the uncertainties affecting the model parameters.

Whi5 phosphorylation embedded in the G1/S network dynamically controls critical cell size and cell fate.

In budding yeast, overcoming of a critical size to enter S phase and the mitosis/mating switch--two central cell fate events--take place in the G1 phase of the cell cycle. Here we present a mathematical model of the basic molecular mechanism controlling the G1/S transition, whose major regulatory feature is multisite phosphorylation of nuclear Whi5. Cln3-Cdk1, whose nuclear amount is proportional to cell size, and then Cln1,2-Cdk1, randomly phosphorylate both decoy and functional Whi5 sites. Full phosphorylation of functional sites releases Whi5 inhibitory activity, activating G1/S transcription. Simulation analysis shows that this mechanism ensures coherent release of Whi5 inhibitory action and accounts for many experimentally observed properties of mitotically growing or conjugating G1 cells. Cell cycle progression and transcriptional analyses of a Whi5 phosphomimetic mutant verify the model prediction that coherent transcription of the G1/S regulon and ensuing G1/S transition requires full phosphorylation of Whi5 functional sites.

Stochastic modeling of expression kinetics identifies messenger half-lives and reveals sequential waves of co-ordinated transcription and decay.

The transcriptome in a cell is finely regulated by a large number of molecular mechanisms able to control the balance between mRNA production and degradation. Recent experimental findings have evidenced that fine and specific regulation of degradation is needed for proper orchestration of a global cell response to environmental conditions. We developed a computational technique based on stochastic modeling, to infer condition-specific individual mRNA half-lives directly from gene expression time-courses. Predictions from our method were validated by experimentally measured mRNA decay rates during the intraerythrocytic developmental cycle of Plasmodium falciparum. We then applied our methodology to publicly available data on the reproductive and metabolic cycle of budding yeast. Strikingly, our analysis revealed, in all cases, the presence of periodic changes in decay rates of sequentially induced genes and co-ordination strategies between transcription and degradation, thus suggesting a general principle for the proper coordination of transcription and degradation machinery in response to internal and/or external stimuli.

Observer-based techniques for the identification and analysis of avascular tumor growth.

Cancer represents one of the most challenging issues for the biomedical research, due its large impact on the public health state. For this reason, many mathematical methods have been proposed to forecast the time evolution of cancer size and invasion. In this paper, we study how to apply the Gompertz's model to describe the growth of an avascular tumor in a realistic setting. To this aim, we introduce mathematical techniques to discretize the model, an important requirement when discrete-time measurements are available. Additionally, we describe observed-based techniques, borrowed from the field of automation theory, as a tool to estimate the model unknown parameters. This identification approach is a promising alternative to traditional statistical methods, and it can be easily extended to other models of cancer growth as well as to the evaluation of not measurable variables, on the basis of the available measurements. We show an application of this method to the analysis of solid tumor growth and parameters estimation in presence of a chemotherapy agent.

Video-rhino-hygrometer: a new method for evaluation of nasal breathing after nasal surgery.

BACKGROUND: Nasal obstruction is one of the most frequent symptoms in the ear, nose, and throat (ENT) setting. It can be evaluated either subjectively or objectively. In a subjective way, a visual analog scale (VAS) and the Sino-Nasal Outcome Test 20 (SNOT 20) can rapidly quantify the degree of obstruction, whereas the most commonly used objective methods are nasal endoscopy and active anterior rhinomanometry (AAR). It is still a matter of controversy to what extent the sense of nasal obstruction is associated with objective measures for nasal space and airflow. The aim of the study was to evaluate nasal breathing before and after functional nasal surgery by video-rhino-hygrometer (VRH) comparing the results with widely accepted methods. METHODS: Twenty patient candidates for septoplasty and inferior turbinate reduction were included in the study. SNOT-20, VAS, nasal endoscopy, and AAR were analyzed and compared with VRH values. RESULTS: Before surgery VRH showed variability of nasal respiratory flow between individuals and between nostrils. After surgery we had an increase (p < 0.05) of airflow in both nostrils. VRH data were found to be correlated with VAS and SNOT-20 values (p < 0.05) both pre- and postoperatively. Despite the statistically significant correlation of AAR with SNOT-20 and VAS, no statistically significant correlation between AAR and VRH was found. CONCLUSION: VRH provides an immediate, easy, and noninvasive assessment of nasal respiration. For these reasons it can be used, in association with rhinoscopic data and other instrumental tests, to evaluate nasal breathing in daily ENT practice.

Video-Rhino-Hygrometer (VRH).

Rhinomanometry includes a set of methodologies to diagnose pathological alterations of the nostrils and nasal cavities. Some anatomic variations could cause partial or sub total obstruction of one or both nostrils, leading to insufficient nasal respiration. Rhinomanometry measures the airflow through one nostril at time, while a pad occludes the other. This method has some drawbacks, such as the alteration of airflow in the not-occluded nostril due to the presence of the pad, the low reproducibility, and a reduced patient comfort. In this paper we propose a new methodologies that, we call Video-Rhino- Hygrometer (VRH) and illustrate specific device to perform it. VRH may be considered as an automatized evolution of the classical Glatzel methods, because it infers information on clinical parameters analysing the image produced by the condense of the breath on a suitable surface. Specifically, VRH uses a web-cam to record these images and, after a suitable processing, it is able to compute a set of clinical features useful to perform diagnosis. Encouraging clinical tests show that the proposed approach provides results comparable with classical rhinomanometry tools without using the pad, obtaining reproducibility results, with an higher comfort for the patient and with a reduced examination time.