Development of Clinical Decision Support Systems based on Mathematical Models of Physiological Systems

In the last years of research, I focused my studies on different physiological problems. Together with my supervisors, I developed/improved different mathematical models in order to create valid tools useful for a better understanding of important clinical issues. The aim of all this work is to develop tools for learning and understanding cardiac and cerebrovascular physiology as well as pathology, generating research questions and developing clinical decision support systems useful for intensive care unit patients. I. ICP-model Designed for Medical Education We developed a comprehensive cerebral blood flow and intracranial pressure model to simulate and study the complex interactions in cerebrovascular dynamics caused by multiple simultaneous alterations, including normal and abnormal functional states of auto-regulation of the brain. Individual published equations (derived from prior animal and human studies) were implemented into a comprehensive simulation program. Included in the normal physiological modelling was: intracranial pressure, cerebral blood flow, blood pressure, and carbon dioxide (CO2) partial pressure. We also added external and pathological perturbations, such as head up position and intracranial haemorrhage. The model performed clinically realistically given inputs of published traumatized patients, and cases encountered by clinicians. The pulsatile nature of the output graphics was easy for clinicians to interpret. The manoeuvres simulated include changes of basic physiological inputs (e.g. blood pressure, central venous pressure, CO2 tension, head up position, and respiratory effects on vascular pressures) as well as pathological inputs (e.g. acute intracranial bleeding, and obstruction of cerebrospinal outflow). Based on the results, we believe the model would be useful to teach complex relationships of brain haemodynamics and study clinical research questions such as the optimal head-up position, the effects of intracranial haemorrhage on cerebral haemodynamics, as well as the best CO2 concentration to reach the optimal compromise between intracranial pressure and perfusion. We believe this model would be useful for both beginners and advanced learners. It could be used by practicing clinicians to model individual patients (entering the effects of needed clinical manipulations, and then running the model to test for optimal combinations of therapeutic manoeuvres). II. A Heterogeneous Cerebrovascular Mathematical Model Cerebrovascular pathologies are extremely complex, due to the multitude of factors acting simultaneously on cerebral haemodynamics. In this work, the mathematical model of cerebral haemodynamics and intracranial pressure dynamics, described in the point I, is extended to account for heterogeneity in cerebral blood flow. The model includes the Circle of Willis, six regional districts independently regulated by autoregulation and CO2 reactivity, distal cortical anastomoses, venous circulation, the cerebrospinal fluid circulation, and the intracranial pressure-volume relationship. Results agree with data in the literature and highlight the existence of a monotonic relationship between transient hyperemic response and the autoregulation gain. During unilateral internal carotid artery stenosis, local blood flow regulation is progressively lost in the ipsilateral territory with the presence of a steal phenomenon, while the anterior communicating artery plays the major role to redistribute the available blood flow. Conversely, distal collateral circulation plays a major role during unilateral occlusion of the middle cerebral artery. In conclusion, the model is able to reproduce several different pathological conditions characterized by heterogeneity in cerebrovascular haemodynamics and can not only explain generalized results in terms of physiological mechanisms involved, but also, by individualizing parameters, may represent a valuable tool to help with difficult clinical decisions. III. Effect of Cushing Response on Systemic Arterial Pressure. During cerebral hypoxic conditions, the sympathetic system causes an increase in arterial pressure (Cushing response), creating a link between the cerebral and the systemic circulation. This work investigates the complex relationships among cerebrovascular dynamics, intracranial pressure, Cushing response, and short-term systemic regulation, during plateau waves, by means of an original mathematical model. The model incorporates the pulsating heart, the pulmonary circulation and the systemic circulation, with an accurate description of the cerebral circulation and the intracranial pressure dynamics (same model as in the first paragraph). Various regulatory mechanisms are included: cerebral autoregulation, local blood flow control by oxygen (O2) and/or CO2 changes, sympathetic and vagal regulation of cardiovascular parameters by several reflex mechanisms (chemoreceptors, lung-stretch receptors, baroreceptors). The Cushing response has been described assuming a dramatic increase in sympathetic activity to vessels during a fall in brain O2 delivery. With this assumption, the model is able to simulate the cardiovascular effects experimentally observed when intracranial pressure is artificially elevated and maintained at constant level (arterial pressure increase and bradicardia). According to the model, these effects arise from the interaction between the Cushing response and the baroreflex response (secondary to arterial pressure increase). Then, patients with severe head injury have been simulated by reducing intracranial compliance and cerebrospinal fluid reabsorption. With these changes, oscillations with plateau waves developed. In these conditions, model results indicate that the Cushing response may have both positive effects, reducing the duration of the plateau phase via an increase in cerebral perfusion pressure, and negative effects, increasing the intracranial pressure plateau level, with a risk of greater compression of the cerebral vessels. This model may be of value to assist clinicians in finding the balance between clinical benefits of the Cushing response and its shortcomings. IV. Comprehensive Cardiopulmonary Simulation Model for the Analysis of Hypercapnic Respiratory Failure We developed a new comprehensive cardiopulmonary model that takes into account the mutual interactions between the cardiovascular and the respiratory systems along with their short-term regulatory mechanisms. The model includes the heart, systemic and pulmonary circulations, lung mechanics, gas exchange and transport equations, and cardio-ventilatory control. Results show good agreement with published patient data in case of normoxic and hyperoxic hypercapnia simulations. In particular, simulations predict a moderate increase in mean systemic arterial pressure and heart rate, with almost no change in cardiac output, paralleled by a relevant increase in minute ventilation, tidal volume and respiratory rate. The model can represent a valid tool for clinical practice and medical research, providing an alternative way to experience-based clinical decisions. In conclusion, models are not only capable of summarizing current knowledge, but also identifying missing knowledge. In the former case they can serve as training aids for teaching the operation of complex systems, especially if the model can be used to demonstrate the outcome of experiments. In the latter case they generate experiments to be performed to gather the missing data.

High-resolution stratigraphy of Central and Southern Adriatic Quaternary deposits of sub-Milankovian climate change on Mediterranean circulation

This volume is a collection of the work done in a three years-lasting PhD, focused in the analysis of Central and Southern Adriatic marine sediments, deriving from the collection of a borehole and many cores, achieved thanks to the good seismic-stratigraphic knowledge of the study area. The work was made out within European projects EC-EURODELTA (coordinated by Fabio Trincardi, ISMAR-CNR), EC-EUROSTRATAFORM (coordinated by Phil P. E. Weaver, NOC, UK), and PROMESS1 (coordinated by Serge Bernè, IFREMER, France). The analysed sedimentary successions presented highly expanded stratigraphic intervals, particularly for the last 400 kyr, 60 kyr and 6 kyr BP. These three different time-intervals resulted in a tri-partition of the PhD thesis. The study consisted of the analysis of planktic and benthic foraminifers’ assemblages (more than 560 samples analysed), as well as in preparing the material for oxygen and carbon stable isotope analyses, and interpreting and discussing the obtained dataset. The chronologic framework of the last 400 kyr was achieved for borehole PRAD1-2 (within the work-package WP6 of PROMESS1 project), collected in 186.5 m water depth. The proposed chronology derives from a multi-disciplinary approach, consisting of the integration of numerous and independent proxies, some of which analysed by other specialists within the project. The final framework based on: micropaleontology (calcareous nannofossils and foraminifers’ bioevents), climatic cyclicity (foraminifers’ assemblages), geochemistry (oxygen stable isotope, made out on planktic and benthic records), paleomagnetism, radiometric ages (14C AMS), teprhochronology, identification of sapropel-equivalent levels (Se). It’s worth to note the good consistency between the oxygen stable isotope curve obtained for borehole PRAD1-2 and other deeper Mediterranean records. The studied proxies allowed the recognition of all the isotopic intervals from MIS10 to MIS1 in PRAD1-2 record, and the base of the borehole has been ascribed to the early MIS11. Glacial and interglacial intervals identified in the Central Adriatic record have been analysed in detail for the paleo-environmental reconstruction, as well. For instance, glacial stages MIS6, MIS8 and MIS10 present peculiar foraminifers’ assemblages, composed by benthic species typical of polar regions and no longer living in the Central Adriatic nowadays. Moreover, a deepening trend in the paleo-bathymetry during glacial intervals was observed, from MIS10 (inner-shelf environment) to MIS4 (mid-shelf environment).Ten sapropel-equivalent levels have been recognised in PRAD1-2 Central Adriatic record. They showed different planktic foraminifers’ assemblages, which allowed the first distinction of events occurred during warm-climate (Se5, Se7), cold-climate (Se4, Se6 and Se8) and temperate-intermediate-climate (Se1, Se3, Se9, Se’, Se10) conditions, consistently with literature. Cold-climate sapropel equivalents are characterised by the absence of an oligotrophic phase, whereas warm-temeprate-climate sapropel equivalents present both the oligotrophic and the eutrophic phases (except for Se1). Sea floor conditions vary, according to benthic foraminifers’ assemblages, from relatively well oxygenated (Se1, Se3), to dysoxic (Se9, Se’, Se10), to highly dysoxic (Se4, Se6, Se8) to events during which benthic foraminifers are absent (Se5, Se7). These two latter levels are also characterised by the lamination of the sediment, feature never observed in literature in such shallow records. The enhanced stratification of the water column during the events Se8, Se7, Se6, Se5, Se4, and the concurring strong dilution of shallow water, pointed out by the isotope record, lead to the hypothesis of a period of intense precipitation in the Central Adriatic region, possibly due to a northward shift of the African Monsoon. Finally, the expression of Central Adriatic PRAD1-2 Se5 equivalent was compared with the same event, as registered in other Eastern Mediterranean areas. The sequence of substantially the same planktic foraminifers’ bioevents has been consistently recognised, indicating a similar evolution of the water column all over the Eastern Mediterranean; yet, the synchronism of these events cannot be demonstrated. A high resolution analysis of late Holocene (last 6000 years BP) climate change was carried out for the Adriatic area, through the recognition of planktic and benthic foraminifers’ bioevents. In particular, peaks of planktic Globigerinoides sacculifer (four during the last 5500 years BP in the most expanded core) have been interpreted, based on the ecological requirements of this species, as warm-climate, arid intervals, correspondent to periods of relative climatic optimum, such as, for instance, the Medieval Warm Period, the Roman Age, the Late Bronze Age and the Copper Age. Consequently, the minima in the abundance of this biomarker could correspond to relatively cooler and more rainy periods. These conclusions are in good agreement with the isotopic and the pollen data. The Last Occurrence (LO) of G. sacculifer has been dated in this work at an average age of 550 years BP, and it is the best bioevent approximating the base of the Little Ice Age in the Adriatic. Recent literature reports the same bioevent in the Levantine Basin, showing a rather consistent age. Therefore, the LO of G. sacculifer has the potential to be extended to all the Eastern Mediterranean. Within the Little Ice Age, benthic foraminifer V. complanata shows two distinct peaks in the shallower Adriatic cores analysed, collected hundred kilometres apart, inside the mud belt environment. Based on the ecological requirements of this species, these two peaks have been interpreted as the more intense (cold and rainy) oscillations inside the LIA. The chronologic framework of the analysed cores is robust, being based on several range-finding 14C AMS ages, on estimates of the secular variation of the magnetic field, on geochemical estimates of the activity depth of 210Pb short-lived radionuclide (for the core-top ages), and is in good agreement with tephrochronologic, pollen and foraminiferal data. The intra-holocenic climate oscillations find out in the Adriatic have been compared with those pointed out in literature from other records of the Northern Hemisphere, and the chronologic constraint seems quite good. Finally, the sedimentary successions analysed allowed the review and the update of the foraminifers’ ecobiostratigraphy available from literature for the Adriatic region, thanks to the achievement of 16 ecobiozones for the last 60 kyr BP. Some bioevents are restricted to the Central Adriatic (for instance the LO of benthic Hyalinea balthica , approximating the MIS3/MIS2 boundary), others occur all over the Adriatic basin (for instance the LO of planktic Globorotalia inflata during MIS3, individuating Dansgaard-Oeschger cycle 8 (Denekamp)).

Study of the circulation processes in the northern Adriatic sea - coastal area and Venice lagoon inlets

This work is a detailed study of hydrodynamic processes in a defined area, the littoral in front of the Venice Lagoon and its inlets, which are complex morphological areas of interconnection. A finite element hydrodynamic model of the Venice Lagoon and the Adriatic Sea has been developed in order to study the coastal current patterns and the exchanges at the inlets of the Venice Lagoon. This is the first work in this area that tries to model the interaction dynamics, running together a model for the lagoon and the Adriatic Sea. First the barotropic processes near the inlets of the Venice Lagoon have been studied. Data from more than ten tide gauges displaced in the Adriatic Sea have been used in the calibration of the simulated water levels. To validate the model results, empirical flux data measured by ADCP probes installed inside the inlets of Lido and Malamocco have been used and the exchanges through the three inlets of the Venice Lagoon have been analyzed. The comparison between modelled and measured fluxes at the inlets outlined the efficiency of the model to reproduce both tide and wind induced water exchanges between the sea and the lagoon. As a second step, also small scale processes around the inlets that connect the Venice lagoon with the Northern Adriatic Sea have been investigated by means of 3D simulations. Maps of vorticity have been produced, considering the influence of tidal flows and wind stress in the area. A sensitivity analysis has been carried out to define the importance of the advection and of the baroclinic pressure gradients in the development of vortical processes seen along the littoral close to the inlets. Finally a comparison with real data measurements, surface velocity data from HF Radar near the Venice inlets, has been performed, which allows for a better understanding of the processes and their seasonal dynamics. The results outline the predominance of wind and tidal forcing in the coastal area. Wind forcing acts mainly on the mean coastal current inducing its detachment offshore during Sirocco events and an increase of littoral currents during Bora events. The Bora action is more homogeneous on the whole coastal area whereas the Sirocco strengthens its impact in the South, near Chioggia inlet. Tidal forcing at the inlets is mainly barotropic. The sensitivity analysis shows how advection is the main physical process responsible for the persistent vortical structures present along the littoral between the Venice Lagoon inlets. The comparison with measurements from HF Radar not only permitted a validation the model results, but also a description of different patterns in specific periods of the year. The success of the 2D and the 3D simulations on the reproduction both of the SSE, inside and outside the Venice Lagoon, of the tidal flow, through the lagoon inlets, and of the small scale phenomena, occurring along the littoral, indicates that the finite element approach is the most suitable tool for the investigation of coastal processes. For the first time, as shown by the flux modeling, the physical processes that drive the interaction between the two basins were reproduced.

Outcome respiratorio a lungo termine nei soggetti affetti da cardiopatia congenita sottoposti ad intervento cardiochirurgico

Introduction: In the last years cardiac surgery for congenital heart disease (CHD) reduced dramatically mortality modifying prognosis, but, at the same time, increased morbidity in this patient population. Respiratory and cardiovascular systems are strictly anatomically and functionally connected, so that alterations of pulmonary hemodynamic conditions modify respiratory function. While very short-term alterations of respiratory mechanics after surgery were investigated by many authors, not as much works focused on long-term changes. In these subjects rest respiratory function may be limited by several factor: CHD itself (fetal pulmonary perfusion influences vascular and alveolar development), extracorporeal circulation (CEC), thoracotomy and/or sternotomy, rib and sternal contusions, pleural adhesions and pleural fibrosis, secondary to surgical injury. Moreover inflammatory cascade, triggered by CEC, can cause endothelial damage and compromise gas exchange. Aims: The project was conceived to 1) determine severity of respiratory functional impairement in different CHD undergone to surgical correction/palliation; 2) identify the most and the least CHD involved by pulmonary impairement; 3) find a correlation between a specific hemodynamic condition and functional anomaly, and 4) between rest respiratory function and cardiopulmonary exercise test. Materials and methods: We studied 113 subjects with CHD undergone to surgery, and distinguished by group in accord to pulmonary blood flow (group 0: 28 pts with normal pulmonary flow; group 1: 22 pts with increased flow; group 2: 43 pts with decreased flow; group 3: 20 pts with total cavo-pulmonary anastomosis-TCPC) followed by the Pediatric Cardiology and Cardiac Surgery Unit, and we compare them to 37 age- and sex-matched healthy subjects. In Pediatric Pulmonology Unit all pts performed respiratory function tests (static and dynamic volumes, flow/volume curve, airway resistances-raw- and conductance-gaw-, lung diffusion of CO-DLCO- and DLCO/alveolar volume), and CHD pts the same day had cardiopulmonary test. They all were examined and had allergological tests, and respiratory medical history. Results: restrictive pattern (measured on total lung capacity-TLC- and vital capacity-VC) was in all CHD groups, and up to 45% in group 2 and 3. Comparing all groups, we found a significant difference in TLC between healthy and group 2 (p=0.001) and 3 (p=0.004), and in VC between group 2 and healthy (p=0.001) and group 1(p=0.034). Inspiratory capacity (IC) was decreased in group 2 related to healthy (p<0.001) and group 1 (p=0.037). We showed a direct correlation between TLC and VC with age at surgery (p=0.01) and inverse with number of surgical interventions (p=0.03). Reduced FEV1/FVC ratio, Gaw and increased Raw were mostly present in group 3. DLCO was impaired in all groups, but up to 80% in group 3 and 50% in group 2; when corrected for alveolar volume (DLCO/VA) reduction persisted in group 3 (20%), 2 (6.2%) and 0 (7.1%). Exercise test was impaired in all groups: VO2max and VE markedly reduced in all but especially in group 3, and VE/VCO2 slope, marker of ventilatory response to exercise, is increased (<36) in 62.5% of group 3, where other pts had anyway value>32. Comparing group 3 and 2, the most involved categories, we found difference in VO2max and VE/VCO2 slope (respectively p=0.02 and p<0.0001). We evidenced correlation between rest and exercise tests, especially in group 0 (between VO2max and FVC, FEV1, VC, IC; inverse relation between VE/VCO2slope and FVC, FEV1 and VC), but also in group 1 (VO2max and IC), group 2 (VO2max and FVC and FEV1); never in group 3. Discussion: According with literature, we found a frequent impairment of rest pulmonary function in all groups, but especially in group 2 and 3. Restrictive pattern was the most frequent alteration probably due to compromised pulmonary (vascular and alveolar) development secondary to hypoperfusion in fetal and pre-surgery (and pre-TCPC)life. Parenchymal fibrosis, pleural adhesions and thoracic deformities can add further limitation, as showed by the correlation between group 3 and number of surgical intervention. Exercise tests were limited, particularly in group 3 (complex anatomy and lost of chronotropic response), and we found correlations between rest and exercise tests in all but group 3. We speculate that in this patients hemodynamic exceeds respiratory contribution, though markedly decreased.

Effect of estrogen suppression on lung function in pulmonary Lymphangioleiomyomatosis

Background: Lymphangioleiomyomatosis (LAM), a rare progressive disease, is characterized by the proliferation of abnormal smooth muscle cells (LAM cells) in the lung, which leads to cystic parenchymal destruction and progressive respiratory failure. Estrogen receptors are present in LAM cells. LAM affects almost exclusively women of childbearing age. These findings, along with reports of disease progression during pregnancy or treatment with exogenous estrogens, have led to the assumption that hormonal factors play an important role in the pathogenesis of LAM. So, various therapies aim at preventing estrogen receptors (ER) by lowering circulating estrogen levels, by trying to block ER activity, or by attempting to lower ER expression in LAM. Prior experience have yielded conflicting results. Objective: The goal of this study was to evaluate, retrospectively, the effect of estrogen suppression in 21 patients with LAM. Design: We evaluated hormonal assays, pulmonary function tests and gas-exchange at baseline and after 12, 24 and 36 months after initiating hormonal manipulation. Results: The mean yearly rates of decline in FEV1 and DLCO are lower than those observed in prior studies and just DLCO decline was statistically significant. We also found an improvement of mean value of FVC and PaO2. Conclusions: Estrogen suppression appears to prevent decline in lung function in LAM.

Biomarkers in chronic obstructive pulmonary diseases. Clinical and functional correlations.

Asthma and chronic obstructive pulmonary disease (COPD) are two distinct lung diseases with distinctive clinical and inflammatory features. A proportion of asthmatic patients experience a fixed airflow obstruction that persists despite optimal pharmacologic treatment for reasons that are still largely unknown. We found that patients with asthma and COPD sharing a similar fixed airflow obstruction have an increased lung function decline and frequency of exacerbations. Nevertheless, the decline in lung function is associated with specific features of the underlying inflammation. Airway inflammation increases during asthma exacerbation and disease severity. Less is known about the correlations between symptoms and airway inflammation in COPD patients. We found that there is no correlation between symptoms and lung function in COPD patients. Nevertheless symptoms changes are associated with specific inflammatory changes: cough is associated with an increase of sputum neutrophils in COPD, dyspnoea is associated with an increase of eosinophils. The mechanisms of this correlation remain unknown. Neutrophils inflammation is associated with bacterial colonization in stable COPD. Is not known whether inhaled corticosteroids might facilitate bacterial colonization in COPD patients. We found that the use of inhaled corticosteroids in COPD patients is associated with an increase of airway bacterial load and with an increase of airway pathogen detection. Bacterial and viral infections are the main causes of COPD and asthma exacerbations. Impaired innate immune responses to rhinovirus infections have been described in adult patients with atopic asthma. Whether this impaired immune condition is present early in life and whether is modulated by a concomitant atopic condition is currently unknown. We found that deficient innate immune responses to rhinovirus infection are already present early in life in atopic patients without asthma and in asthmatic subjects. These findings generalize the scenario of increased susceptibility to viral infections to other Th2 oriented conditions.

Development of strategies for vascular damage repair in Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a progressive and rare disease with so far unclear pathogenesis, limited treatment options and poor prognosis. Unbalance of proliferation and migration in pulmonary arterial smooth muscle cells (PASMCs) is an important hallmark of PAH. In this research Sodium butyrate (BU) has been evaluated in vitro and in vivo models of PAH. This histone deacetylase inhibitor (HDACi) counteracted platelet-derived growth factor (PDGF)-induced ki67 expression in PASMCs, and arrested cell cycle mainly at G0/G1 phases. Furthermore, BU reduced the transcription of PDGFRbeta, and that of Ednra and Ednrb, two major receptors in PAH progression. Wound healing and pulmonary artery ring assays indicated that BU inhibited PDGF-induced PASMC migration. BU strongly inhibited PDGF-induced Akt phosphorylation, an effect reversed by the phosphatase inhibitor calyculinA. In vivo, BU showed efficacy in monocrotaline-induced PAH in rats. Indeed, the HDACi reduced both thickness of distal pulmonary arteries and right ventricular hypertrophy. Besides these studies, Serial Analysis of Gene Expression (SAGE) has be used to obtain complete transcriptional profiles of peripheral blood mononuclear cells (PBMCs) isolated from PAH and Healthy subjects. SAGE allows quantitative analysis of thousands transcripts, relying on the principle that a short oligonucleotide (tag) can uniquely identify mRNA transcripts. Tag frequency reflects transcript abundance. We enrolled patients naïve for a specific PAH therapy (4 IPAH non-responder, 3 IPAH responder, 6 HeritablePAH), and 8 healthy subjects. Comparative analysis revealed that significant differential expression was only restricted to a hundred of down- or up-regulated genes. Interestingly, these genes can be clustered into functional networks, sharing a number of crucial features in cellular homeostasis and signaling. SAGE can provide affordable analysis of genes amenable for molecular dissection of PAH using PBMCs as a sentinel, surrogate tissue. Altogether, these findings may disclose novel perspectives in the use of HDACi in PAH and potential biomarkers.