Variability analysis of discrete event series and wavefront patterns in surface electrocardiogram: contributions to psychophysiological and clinical research

The surface electrocardiogram (ECG) is an established diagnostic tool for the detection of abnormalities in the electrical activity of the heart. The interest of the ECG, however, extends beyond the diagnostic purpose. In recent years, studies in cognitive psychophysiology have related heart rate variability (HRV) to memory performance and mental workload. The aim of this thesis was to analyze the variability of surface ECG derived rhythms, at two different time scales: the discrete-event time scale, typical of beat-related features (Objective I), and the “continuous” time scale of separated sources in the ECG (Objective II), in selected scenarios relevant to psychophysiological and clinical research, respectively. Objective I) Joint time-frequency and non-linear analysis of HRV was carried out, with the goal of assessing psychophysiological workload (PPW) in response to working memory engaging tasks. Results from fourteen healthy young subjects suggest the potential use of the proposed indices in discriminating PPW levels in response to varying memory-search task difficulty. Objective II) A novel source-cancellation method based on morphology clustering was proposed for the estimation of the atrial wavefront in atrial fibrillation (AF) from body surface potential maps. Strong direct correlation between spectral concentration (SC) of atrial wavefront and temporal variability of the spectral distribution was shown in persistent AF patients, suggesting that with higher SC, shorter observation time is required to collect spectral distribution, from which the fibrillatory rate is estimated. This could be time and cost effective in clinical decision-making. The results held for reduced leads sets, suggesting that a simplified setup could also be considered, further reducing the costs. In designing the methods of this thesis, an online signal processing approach was kept, with the goal of contributing to real-world applicability. An algorithm for automatic assessment of ambulatory ECG quality, and an automatic ECG delineation algorithm were designed and validated.

Development of new therapeutic approaches in the treatments of Inflammatory Bowel Diseases: functional food and nutraceuticals vs synthetic peptides based vaccines

Inflammatory Bowel Diseases (IBD) are intestinal chronic relapsing diseases which ethiopathogenesis remains uncertain. Several group have attempted to study the role of factors involved such as genetic susceptibility, environmental factors such as smoke, diet, sex, immunological factors as well as the microbioma. None of the treatments available satisfy several criteria at the same time such as safety, long-term remission, histopatological healing, and specificity. We used two different approaches for the development of new therapeutic treatment for Inflammatory Bowel Disease. The first is focused on the understanding of the potential role of functional food and nutraceuticals nutrients in the treatment of IBD. To do so, we investigated the role of Curcuma longa in the treatment of chemical induced colitis in mice model. Since Curcma Longa has been investigated for its antinflammatory role related to the TNFα pathway as well investigators have reported few cases of patients with ulcerative colites treated with this herbs, we harbored the hypothesis of a role of Curcuma Longa in the treatment f IBD as well as we decided to assess its role in intestinal motility. The second part is based on an immunological approach to develop new drugs to induce suppression in Crohn’s disease or to induce mucosa immunity such as in colonrectal tumor. The main idea behind this approach is that we could manipulate relevant cell-cell interactions using synthetic peptides. We demonstrated the role of the unique interaction between molecules expressed on intestinal epithelial cells such as CD1d and CEACAM5 and on CD8+ T cells. In normal condition this interaction has a role for the expansion of the suppressor CD8+ T cells. Here, we characterized this interaction, we defined which are the epitope involved in the binding and we attempted to develop synthetic peptides from the N domain of CEACAM5 in order to manipulate it.

Sense development through non verbal signs: early infancy and clinical psychoterapy

This thesis will describe the development of a relationship which is not necessarily verbal, but which generates communication, creates sense and meaning between human beings and produces “becomings” in the body that feels, perceives and physically transforms itself. This leads to a biosemiotic understanding of both the seen and unseen figure.

Towards Rapid Environmental Assessment and Coastal Forecasting in the Northern Adriatic Sea

A new Coastal Rapid Environmental Assessment (CREA) strategy has been developed and successfully applied to the Northern Adriatic Sea. CREA strategy exploits the recent advent of operational oceanography to establish a CREA system based on an operational regional forecasting system and coastal monitoring networks of opportunity. The methodology wishes to initialize a coastal high resolution model, nested within the regional forecasting system, blending the large scale parent model fields with the available coastal observations to generate the requisite field estimates. CREA modeling system consists of a high resolution, O(800m), Adriatic SHELF model (ASHELF) implemented into the Northern Adriatic basin and nested within the Adriatic Forecasting System (AFS) (Oddo et al. 2006). The observational system is composed by the coastal networks established in the framework of ADRICOSM (ADRiatic sea integrated COastal areaS and river basin Managment system) Pilot Project. An assimilation technique exerts a correction of the initial field provided by AFS on the basis of the available observations. The blending of the two data sets has been carried out through a multi-scale optimal interpolation technique developed by Mariano and Brown (1992). Two CREA weekly exercises have been conducted: the first, at the beginning of May (spring experiment); the second in middle August (summer experiment). The weeks have been chosen looking at the availability of all coastal observations in the initialization day and one week later to validate model results, verifying our predictive skills. ASHELF spin up time has been investigated too, through a dedicated experiment, in order to obtain the maximum forecast accuracy within a minimum time. Energetic evaluations show that for the Northern Adriatic Sea and for the forcing applied, a spin-up period of one week allows ASHELF to generate new circulation features enabled by the increased resolution and its total kinetic energy to establish a new dynamical balance. CREA results, evaluated by mean of standard statistics between ASHELF and coastal CTDs, show improvement deriving from the initialization technique and a good model performance in the coastal areas of the Northern Adriatic basin, characterized by a shallow and wide continental shelf subject to substantial freshwater influence from rivers. Results demonstrate the feasibility of our CREA strategy to support coastal zone management and wish an additional establishment of operational coastal monitoring activities to advance it.

Sustainability indicators for environmental management and decision making

The general objective of this research is to explore theories and methodologies of sustainability indicators, environmental management and decision making disciplines with the operational purpose of producing scientific, robust and relevant information for supporting system understanding and decision making in real case studies. Several tools have been applied in order to increase the understanding of socio-ecological systems as well as providing relevant information on the choice between alternatives. These tools have always been applied having in mind the complexity of the issues and the uncertainty tied to the partial knowledge of the systems under study. Two case studies with specific application to performances measurement (environmental performances in the case of the K8 approach and sustainable development performances in the case of the EU Sustainable Development Strategy) and a case study about the selection of sustainable development indicators amongst Municipalities in Scotland, are discussed in the first part of the work. In the second part of the work, the common denominator among subjects consists in the application of spatial indices and indicators to address operational problems in land use management within the territory of the Ravenna province (Italy). The main conclusion of the thesis is that a ‘perfect’ methodological approach which always produces the best results in assessing sustainability performances does not exist. Rather, there is a pool of correct approaches answering different evaluation questions, to be used when methodologies fit the purpose of the analysis. For this reason, methodological limits and conceptual assumptions as well as consistency and transparency of the assessment, become the key factors for assessing the quality of the analysis.

Phytoplankton Response to Environmental Variables and Organic Pollutants. Laboratory Cultures and Numerical Simulations Experiments

Herbicides are becoming emergent contaminants in Italian surface, coastal and ground waters, due to their intensive use in agriculture. In marine environments herbicides have adverse effects on non-target organisms, as primary producers, resulting in oxygen depletion and decreased primary productivity. Alterations of species composition in algal communities can also occur due to the different sensitivity among the species. In the present thesis the effects of herbicides, widely used in the Northern Adriatic Sea, on different algal species were studied. The main goal of this work was to study the influence of temperature on algal growth in the presence of the triazinic herbicide terbuthylazine (TBA), and the cellular responses adopted to counteract the toxic effects of the pollutant (Chapter 1 and 2). The development of simulation models to be applied in environmental management are needed to organize and track information in a way that would not be possible otherwise and simulate an ecological prospective. The data collected from laboratory experiments were used to simulate algal responses to the TBA exposure at increasing temperature conditions (Chapter 3). Part of the thesis was conducted in foreign countries. The work presented in Chapter 4 was focused on the effect of high light on growth, toxicity and mixotrophy of the ichtyotoxic species Prymnesium parvum. In addition, a mesocosm experiment was conducted in order to study the synergic effect of the pollutant emamectin benzoate with other anthropogenic stressors, such as oil pollution and induced phytoplankton blooms (Chapter 5).

Pre-clinical and clinical development of leukemia stem cell inhibitors in acute leukemias

In Leukemias, recent developments have demonstrated that the Hedgehog pathway plays a key-role in the peculiar ability of self renewal of leukemia stem cells. The aim of this research activity was to investigate, through a first in man, Phase I, open label, clinical trial, the role and the impact, mainly in terms of safety profile, adverse events and pharmacokinetics, of a Sonic Hedgehog inhibitor compound on a population of heavely pretreated patients affected by AML, CML, MF, or MDS, resistant or refractory to standard chemotherapy. Thirty-five patients have been enrolled. The drug was administered orally, in 28 days cycles, without rest periods. The compound showed a good safety profile. The half life was of 17-35 hours, justifying the daily administration. Significant signs of activity, in terms of reduction of bone marrow blast cell amount were seen in most of the patients enrolled. Interestingly, correlative biological studies demonstrated that, comparing the gene expression profyiling signature of separated CD34+ cells before and after one cycle of treatment, the most variably expressed genes were involved in the Hh pathway. Moreover, we observed that many genes involved in MDR (multidrug resistance)were significantly down regulated after treatment. These data might lead to future clinical trials based on combinatory approaches, including, for instance, Hh inhibitors and conventional chemotherapy.

CYP17A1 polymorphisms and clinical outcome of patients with metastatic castration-resistant prostate cancer treated with abiraterone

Background. Abiraterone acetate is a potent inhibitor of cytochrome P450 17 α-hydrolase (CYP17A1) that causes a reduction in the synthesis of testosterone in the adrenal glands, testes and tumor microenvironment. Blocking androgen production, abiraterone has been shown to prolong progression-free survival (PFS) and overall survival (OS) in patients with metastatic castration-resistant prostate cancer (CRPC) previously submitted to chemotherapy. The aim of our study was to verify the role of single nucleotide polymorphisms (SNPs) in predicting clinical outcome in CRPC patients treated with abiraterone after chemotherapy. Methods. We analyzed 48 CRPC consecutive patients treated with abiraterone after at least one chemotherapeutic regimen with docetaxel. DNA was extracted from peripheral blood and genotyped for four polymorphisms in the CYP17A1 gene (rs743572, rs10883783, rs17115100, rs284849). PFS and OS survival curves were used to identify statistical associations between haplotypes and clinical outcome. Results. Forty-eight Caucasian patients with metastatic CRPC treated with abiraterone were genotyped for polymorphisms in the CYP17A1 gene. All samples were evaluable for both sequencing and TaqMan Genotyping assay. The CRPC patients treated with abiraterone had a median PFS and OS of 7.6 months (95% CI: 4.3-10.5) and 17.6 months (95% CI: 10.5-19.0), respectively Statistical analyses highlighted a difference approaching statistical significance (log-rank test p = 0.0534) between rs10883783 and PFS. Other polymorphisms were not associated with a benefit from treatment with abiraterone. Conclusions. In our case series of 48 treated patients, rs10883783 only was identified as a possible predictive marker, results showing a trend toward statistical significance. Further analysis of this polymorphism is needed in larger series of patients to confirm our findings.

Evaluation of the photosynthetic efficiency of sweet sorghum under drought and cold conditions

Sweet sorghum, a C4 crop of tropical origin, is gaining momentum as a multipurpose feedstock to tackle the growing environmental, food and energy security demands. Under temperate climates sweet sorghum is considered as a potential bioethanol feedstock, however, being a relatively new crop in such areas its physiological and metabolic adaptability has to be evaluated; especially to the more frequent and severe drought spells occurring throughout the growing season and to the cold temperatures during the establishment period of the crop. The objective of this thesis was to evaluate some adaptive photosynthetic traits of sweet sorghum to drought and cold stress, both under field and controlled conditions. To meet such goal, a series of experiments were carried out. A new cold-tolerant sweet sorghum genotype was sown in rhizotrons of 1 m3 in order to evaluate its tolerance to progressive drought until plant death at young and mature stages. Young plants were able to retain high photosynthetic rate for 10 days longer than mature plants. Such response was associated to the efficient PSII down-regulation capacity mediated by light energy dissipation, closure of reaction centers (JIP-test parameters), and accumulation of glucose and sucrose. On the other hand, when sweet sorghum plants went into blooming stage, neither energy dissipation nor sugar accumulation counteracted the negative effect of drought. Two hybrids with contrastable cold tolerance, selected from an early sowing field trial were subjected to chilling temperatures under controlled growth conditions to evaluate in deep their physiological and metabolic cold adaptation mechanisms. The hybrid which poorly performed under field conditions (ICSSH31), showed earlier metabolic changes (Chl a + b, xanthophyll cycle) and greater inhibition of enzymatic activity (Rubisco and PEPcase activity) than the cold tolerant hybrid (Bulldozer). Important insights on the potential adaptability of sweet sorghum to temperate climates are given.

Adulthood with Turner Syndrome: Quality of life, psychosocial adjustment and clinical management in 70 Italian women

Abstract Background: Turner syndrome (TS) is a chromosomal abnormality (total or partial absence of one of the sexual chromosomes in some or all cells of the body), which affects approximately 1:2000 female. Principal characteristics are short stature and gonadal disgenesis. Clinical management consist of Growth Hormone (GH) treatment and oestrogen replacement therapy (HRT), to induce development of secondary characteristics and to avoid the sequelae of oestrogen deficiency. Aim of the study: To assess clinical management, quality of life (QoL) and general psychosocial adjustment of women with TS. Population: 70 adult Caucasian females with TS (mean age: 27.8, ± 7.6; range 18-48 y.). Setting: Specialist service for Rare Disease care, University Hospital. Methods: Subjects were required to fill in questionnaires collecting ASR, WHOQOL, and 8 open questions. Data were compared with those of the Italian population or to those collected in a comparison group (70 healthy females, mean age: 27.9, ±7.3, range 21-48 y.). Results: Women with TS are educated as well as the Italian Population, but they have a less successful professional life. They show good QoL in general, but they appeared less satisfied in social area. They had statistically higher scores than the comparison group for depression, anxiety and withdrawal. Are less involved in a love relationship. Diagnosis communication was mostly performed by doctors or parents, satisfaction was higher when information was given by parents. Main preoccupation about TS are infertility, feeling of being different and future health problem. Conclusions: Italian people with TS were generally well adapted and have a good QoL, but lived more often with parents and show impaired sentimental and sexual life. They have higher degree of psychological distress compared to a comparison group. Psychological intervention should firstly address parents in order to encourage an open communication on diagnosis issues and on sexual education.

Volunteer-based coral reef monitoring: reliability of data, environmental education and implications for conservation

Coral reefs are the most biodiverse ecosystems of the ocean and they provide notable ecosystem services. Nowadays, they are facing a number of local anthropogenic threats and environmental change is threatening their survivorship on a global scale. Large-scale monitoring is necessary to understand environmental changes and to perform useful conservation measurements. Governmental agencies are often underfunded and are not able of sustain the necessary spatial and temporal large-scale monitoring. To overcome the economic constrains, in some cases scientists can engage volunteers in environmental monitoring. Citizen Science enables the collection and analysis of scientific data at larger spatial and temporal scales than otherwise possible, addressing issues that are otherwise logistically or financially unfeasible. “STE: Scuba Tourism for the Environment” was a volunteer-based Red Sea coral reef biodiversity monitoring program. SCUBA divers and snorkelers were involved in the collection of data for 72 taxa, by completing survey questionnaires after their dives. In my thesis, I evaluated the reliability of the data collected by volunteers, comparing their questionnaires with those completed by professional scientists. Validation trials showed a sufficient level of reliability, indicating that non-specialists performed similarly to conservation volunteer divers on accurate transects. Using the data collected by volunteers, I developed a biodiversity index that revealed spatial trends across surveyed areas. The project results provided important feedbacks to the local authorities on the current health status of Red Sea coral reefs and on the effectiveness of the environmental management. I also analysed the spatial and temporal distribution of each surveyed taxa, identifying abundance trends related with anthropogenic impacts. Finally, I evaluated the effectiveness of the project to increase the environmental education of volunteers and showed that the participation in STEproject significantly increased both the knowledge on coral reef biology and ecology and the awareness of human behavioural impacts on the environment.