Mathematical models for wound healing lymphangiogenesis and other biomedical phenomena

In this thesis we explore the mathematical modelling of wound healing lymphangiogenesis, tumour neoneurogenesis and Drosophila courtship behaviour. We begin by focussing on the mathematical modelling of lymphatic regeneration in wound healing. Indeed, several studies suggest that one possible cause of impaired wound healing is failed or insu cient lymphangiogenesis, that is the formation of new lymphatic capillaries. Although many mathematical models have been developed to describe the formation of blood capillaries (angiogenesis), very few have been proposed for the regeneration of the lymphatic network. In Chapter 2 a model of five ordinary differential equations is presented to describe lymphangiogenesis in a skin wound. The variables represent different cell densities and growth factor concentrations, and where possible the parameters are estimated from experimental and clinical data. The system output is compared with the available biological literature and, based on parameter sensitivity analysis, new therapeutic approaches are suggested to enhance lymphangiogenesis in diabetic wounds. Chapter 3 extends the aforementioned work to two PDE systems aimed at describing two possible hypotheses for the lymphangiogenesis process: 1) lymphatic capillaries sprout from existing and interrupted capillaries at the edge of the wound, in analogy to the blood angiogenesis case; 2) lymphatic endothelial cells first collect together in the wound region through following the lymph flow and then begin to form a network. Furthermore, we include the effect of advection from both background interstitial flow and additional lymph flow from the open capillaries, andaddress the question of their relative importance in the lymphangiogenesis process. Malignant tumours induce not only the formation of a lymphatic and a blood vascular network, but also innervation around themselves. However, the relationship between tumour progression and the nervous system is still poorly understood. In Chapter 4 we study the interactions between the nervous system and tumour cells through an 8-dimensional ODE model. The model confirrms experimental observations that a tumour promotes nerve formation around itself, and that high levels of nerve growth factor (NGF) and axon guidance molecules (AGMs) are recorded in the presence of a tumour. Our results also reflect the observation that high stress levels (represented by higher norepinephrine release by sympathetic nerves) contribute to tumour development and spread, indicating a mutually bene cial relationship between tumour cells and neurons. In Chapter 5 a preliminary model for courtship behavioural patterns of Drosophila melanogaster is suggested. Drosophila courtship behaviour is considered a good model to investigate neurodegenerative diseases (such as Parkinson's) in humans. The present chapter illustrates the biological and health-care related background to this topic, and then presents a possible modelling approach based on Pasemann's work on neural networks. We conclude with a brief discussion that summarises the main results and outlines directions for future work

A Mathematical Model for Lymphangiogenesis in Normal and Diabetic Wounds

Several studies suggest that one possible cause of impaired wound healing is failed or insufficient lymphangiogenesis, that is the formation of new lymphatic capillaries. Although many mathematical models have been developed to describe the formation of blood capillaries (angiogenesis) very few have been proposed for the regeneration of the lymphatic network. Moreover, lymphangiogenesis is markedly distinct from angiogenesis, occurring at different times and in a different manner. Here a model of five ordinary differential equations is presented to describe the formation of lymphatic capillaries following a skin wound. The variables represent different cell densities and growth factor concentrations, and where possible the parameters are estimated from experimental and clinical data. The system is then solved numerically and the results are compared with the available biological literature. Finally, a parameter sensitivity analysis of the model is taken as a starting point for suggesting new therapeutic approaches targeting the enhancement of lymphangiogenesis in diabetic wounds. The work provides a deeper understanding of the phenomenon in question, clarifying the main factors involved. In particular, the balance between TGF-$\beta$ and VEGF levels, rather than their absolute values, is identified as crucial to effective lymphangiogenesis. In addition, the results indicate lowering the macrophage-mediated activation of TGF-$\beta$ and increasing the basal lymphatic endothelial cell growth rate, \emph{inter alia}, as potential treatments. It is hoped the findings of this paper may be considered in the development of future experiments investigating novel lymphangiogenic therapies

Stress Hyperglycemia and Complications Following Traumatic Injuries in Individuals With/Without Diabetes: The Case of Orthopedic Surgery

Purpose: Hyperglycemia in trauma patients may stem from metabolic response to stress, both in the presence and the absence of underlying diabetes. We aimed to test the association of stress hyperglycemia with risks of adverse events subjects undergoing orthopedic surgery. Patients and Methods: In a prospective observational study, we enrolled 202 consecutive patients with hyperglycemia at hospital admission for trauma injuries requiring orthopedic surgery. Based on history, diabetes was present in 183, and 13 more were defined as unknown diabetes on the basis of HbA1c ≥48mmol/mol. Stress hyperglycemia was defined in subjects with/without diabetes by a stress hyperglycemia ratio (SHR) >1.14, calculated as admission glucose/average glucose, estimated from glycosylated hemoglobin. Logistic regression analysis was used to calculate the risk of post-surgery adverse events associated with different states of hyperglycemia, after correction for demographic and clinical confounders. Results: Stress hyperglycemia was diagnosed, either as superimposed to diabetes (54/196 cases, 27.6%) as well as in the 6 cases without diabetes. At least one complication was recorded in 68 cases (33.7%), the most common being systemic infection (22.8% of cases). In the total cohort, stress hyperglycemia, irrespective of the presence of diabetes, increased the risk of adverse events (any events, odds ratio [OR], 4.43; 95% confidence interval [CI], 2.11–9.30), cardiovascular events (OR, 7.09; 95% CI, 2.47–19.91), systemic infections (OR, 4.21; 95% CI, 1.97–9.03) and other adverse events (OR, 6.30; 95% CI, 1.41–28.03), after adjustment for confounders; hospital stay was much longer. The same was true when the analysis was limited to the diabetes cohort or by comparing pure stress hyperglycemia vs diabetes without stress hyperglycemia. Conclusion: The study highlights the importance of stress hyperglycemia for adverse events in the setting of orthopedic surgery following trauma injuries. This condition requires stricter management, considering the much longer length of hospital stay and higher costs

In vitro probiotic properties and in vivo anti-ageing effects of Lactoplantibacillus plantarum PFA2018AU strain isolated from carrots on Caenorhabditis elegans

Lactic acid bacteria (LAB) share and provide several beneficial effects on human health, such as the release of bioactive metabolites, pathogen competition, and immune stimulation. The two major reservoirs of probiotic microorganisms are the human gastro-intestinal tract and fermented dairy products. However, other sources, such as plant-based foods, represent important alternatives thanks to their large distribution and nutritive value. Here, the probiotic potential of autochthonous Lactiplantibacillus plantarum PFA2018AU, isolated from carrots harvested in Fucino highland, Abruzzo (Italy), was investigated through in vitro and in vivo approaches. The strain was sent to the biobank of Istituto Zooprofilattico Sperimentale della Lombardia ed Emilia Romagna in Italy for the purpose of patent procedures under the Budapest Treaty. The isolate showed high survival capability under in vitro simulated gastro-intestinal conditions, antibiotic susceptibility, hydrophobicity, aggregation, and the ability to inhibit the in vitro growth of Salmonella enterica serovar Typhimurium, Listeria monocytogenes, Pseudomonas aeruginosa, and Staphylococcus aureus pathogens. Caenorhabditis elegans was used as the in vivo model in order to analyse prolongevity and anti-ageing effects. L. plantarum PFA2018AU significantly colonised the gut of the worms, extended their lifespan, and stimulated their innate immunity. Overall, these results showed that autochthonous LAB from vegetables, such as carrots, have functional features that can be considered novel probiotic candidates

Wandering spleen with a ten-time twisted vascular pedicle

Torsion of a wandering spleen is a rare cause of acute abdomen in children, usually diagnosed with color-Doppler ultrasonography and enhanced computed tomography. We report a pediatric case of torsion of wandering spleen

Wandering spleen with a ten-time twisted vascular pedicle

Torsion of a wandering spleen is a rare cause of acute abdomen in children, usually diagnosed with color-Doppler ultrasonography and enhanced computed tomography. We report a pediatric case of torsion of wandering spleen

Improving of psychological status and inflammatory biomarkers during omalizumab for chronic spontaneous urticaria

Background: Depression and anxiety are the most common psychiatric comorbidities in chronic spontaneous urticaria (CSU). Omalizumab is a monoclonal antibody approved for CSU treatment. We evaluated the prevalence of anxiety and depression in CSU patients before and after treatment with omalizumab. Materials & methods: A total of 30 patients were enrolled in the study: 15 patients affected by CSU and treated with omalizumab and the other 15 healthy subjects did not receive any systemic therapy. All patients were evaluated using Hospital Anxiety and Depression Scale, CRP and erythrocyte sedimentation rate, at baseline and after 6 months. Results: The omalizumab group after 6 months of therapy had a decrease of all the scores and biomarkers. Conclusion: Omalizumab allowed an improvement of urticaria and mental comorbidities

An internet-based approach for lifestyle changes in patients with NAFLD: Two-year effects on weight loss and surrogate markers

Background & Aims Interventions aimed at lifestyle changes are pivotal for the treatment of non-alcoholic fatty liver disease (NAFLD), and web-based programs might help remove barriers in both patients and therapists. Methods In the period 2010–15, 716 consecutive NAFLD cases (mean age, 52; type 2 diabetes, 33%) were treated in our Department with structured programs. The usual protocol included motivational interviewing and a group-based intervention (GBI), chaired by physicians, dietitians and psychologists (five weekly meetings, n = 438). Individuals who could not attend GBI entered a web-based intervention (WBI, n = 278) derived from GBI, with interactive games, learning tests, motivational tests, and mail contacts with the center. The primary outcome was weight loss ≥10%; secondary outcomes were alanine aminotransferase within normal limits, changes in lifestyle, weight, alanine aminotransferase, and surrogate markers of steatosis and fibrosis. Results GBI and WBI cohorts had similar body mass index (mean, 33 kg/m2), with more males (67% vs. 45%), younger age, higher education, and more physical activity in the WBI group. The two-year attrition rate was higher in the WBI group. Healthy lifestyle changes were observed in both groups and body mass index decreased by almost two points; the 10% weight target was reached in 20% of WBI cases vs. 15% in GBI (not significant). In logistic regression analysis, after adjustment for confounders and attrition rates, WBI was not associated with a reduction of patients reaching short- and long-term 10% weight targets. Liver enzymes decreased in both groups, and normalized more frequently in WBI. Fatty liver index was reduced, whereas fibrosis remained stable (NAFLD fibrosis score) or similarly decreased (Fib-4). Conclusion WBI is not less effective than common lifestyle programs, as measured by significant clinical outcomes associated with improved histological outcomes in NAFLD. eHealth programs may effectively contribute to NAFLD control. Lay summary In patients with non-alcoholic fatty liver disease, participation in structured lifestyle programs may be jeopardized by job and time constraints. A web-based intervention may be better suited for young, busy patients, and for those living far from liver units. The study shows that, following a structured motivational approach, a web-based, interactive intervention coupled with six-month face-to-face meetings is not inferior to a standard group-based intervention with respect to weight loss, adherence to healthy diet and habitual physical activity, normalization of liver enzymes, and stable surrogate markers of fibrosis

A novel mutation in NDUFB11 unveils a new clinical phenotype associated with lactic acidosis and sideroblastic anemia

NDUFB11, a component of mitochondrial complex I, is a relatively small integral membrane protein, belonging to the 'supernumerary' group of subunits, but proved to be absolutely essential for the assembly of an active complex I. Mutations in in the X-linked nuclear encoded NDUFB11 gene have recently been discovered in association with two distinct phenotypes, i.e. microphthalmia with linear skin defects and histiocytoid cardiomyopathy. We report on a male with complex I deficiency, caused by a de novo mutation in NDUFB11 and displaying early onset sideroblastic anemia as the unique feature. This is the third report that describes a mutation in NDUFB11 but all are associated to a different phenotype. Our results further expand the molecular spectrum and associated clinical phenotype of NDUFB11 defects