Colon cancer is the fourth most common cause of cancer death in the world. It kills approximately 529,000 people annually and around two thirds of these deaths are in the developed world. These figures can be attributed to the fact that colorectal cancers are well advanced before they are detected. Effective prevention of the disease is early detection and removal of pre-cancerous polyps. In cases where cancer has already developed, early detection still significantly improves the chances of cure by surgically removing the cancer before the disease is able to metastasise. However, in metastatic colorectal cancers, in order to ascertain an effective treatment regimen and determine the prognosis of a patient after surgery a prognostic tool that accurately portrays the extent of the disease needs to be developed. Currently, the most commonly used prognostic tool to assess colorectal cancer spread is the clinicopathological staging system. However, there is a need for additional markers of metastasis as nearly one-third of patients with a clinical diagnosis of Dukes' B, a commonly used pathological staging system for colorectal cancer prognosis, will die of the disease despite complete resection of the primary tumour. In several human cancers such as breast, prostate and the lung, tumour vascularity has been shown to be of prognostic value. However, studies correlating the significance of the number of tumour vessels to prognosis in colorectal cancers are relatively lacking or show conflicting results. Moreover, it is not yet fully understood if factors involved in the complicated cascade of tumour blood vessel formation (tumour angiogenesis), such as proteases cathepsin B and dipeptidyl peptidase IV aid colorectal cancer progression. Two of the most potent angiogenic growth factors: vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) playa significant role in the development of tumour vessels; however, their influence on the production of these proteases is not clear. Therefore, this study set out to i) establish a reliable method to quantify colorectal tumour vessels ii) to assess the correlation between vessel counts and prognostic parameters associated with metastasis iii) to ascertain the pattern of spatial distribution of tumour vessels in order to defme the relationship between the positions of the vessels in relation to areas of tumour growth iv) investigate the levels of the enzyme expression of tumour associated proteases cathepsin B and dipeptidyl peptidase IV, at both protein and mRNA level, in colorectal tumours of varying clinicopathological grades and to v) assess the influence of VEGF and bFGF on CB and DPPIV proteolytic enzyme activity in human colon, rectal cancer cells and normal human umbilical vein endothelial cells. The study established that an effective method to examine tumour vascularity, was by immunolocalising tumour endothelial cells by CD31 and quantifying all of stained vessels present within each cross-sectional area. As a result of tumour endothelial cell marker assessment it was noted that CD34 was highly specific to certain vessels and distinctly immunonegative to others and that the same vessels were positive to CD31. These vessels were morphologically assessed by using the standard histological criteria identified as lymph vessels. Tumour blood and lymph vessels were quantified and a positive correlation to prognostic parameters relating to cancer spread was identified. The pattern of distribution of colorectal tumour vessels was also examined and a distinct pattern was observed in metastatic tumours with greater numbers of vessels in the peripheral regions and the invasive fronts. Qualitative analysis of protease expression and mRNA intensity, in colorectal tumours, revealed increased levels of CB and DPPIV in tumours with clinicopathological parameters associated with metastasis. mRNA localization near tumour vessels highlighted the potential for, not only cancer cells but also tumour endothelial cells, to produce proteolytic enzymes to aid the process of tumour angiogenesis and hence tumour growth and metastasis. The study also demonstrated that the angiogenic factors VEGF and bFGF up-regulated CB and DPPIV activity in human colon, rectal cancer cells and normal human umbilical vein endothelial cells.The presence of tumour lymph vessels and their positive correlation to metastatic parameters signifies an important role for such vessels in the process of colorectal cancer spread. The positive relationship of tumour blood vessels to parameters associated with metastasis re-instates the important role of tumour angiogenesis in colorectal cancer. Other factors that were investigated such as tumour associated proteases CB and DPPIV and the influence of the potent angiogenic proteins upon their activity suggests that these factors have a direct role in colorectal cancer metastasis. Therefore, it can be concluded from the results of this thesis that tumour blood vessel counts can be used as a reliable prognostic marker in colorectal cancer. Tumour angiogenic factors as well as the colorectal tumour lymph vessels have the potential to be used as additional prognostic markers in clinical prognostic evaluations. This has important implications in allowing clinicians to accurately assess post-operative survival rates and to devise an effective treatment regimen in order to prolong the lives and possibly cure colorectal cancer patients.

Orientador: Rosemeire Cristina Linhari Rodrigues Pietro / Banca: Rosemeire Cristina Linhari Rodrigues Pietro / Banca: Luis Carlos Marques / Banca: Taís Maria Bauab / Resumo: Embora milhares de espécies vegetais sejam utilizadas na medicina tradicional do mundo, estima-se que apenas 1% são conhecidas por estudos científicos, com valor terapêutico demonstrado. As espécies Polygonum acre e Synadenium carinatum são de fácil cultivo, estando largamente distribuídas no Brasil, e possuindo um alto índice de utilização na medicina popular. Entre os usos populares da espécie Polygonum acre podem ser citados: anti-séptico, antiinflamatório, hipotensor, anti-hemorroidal, diurético, vermicida e anti-diarréico. A espécie Synadenium carinatum é popularmente utilizada para o tratamento de cânceres. No entanto, não existem estudos científicos que comprovem esses efeitos, nem informações sobre a segurança de utilização dessas drogas pelos seres humanos além de haver poucos estudos fitoquímicos destas espécies. Neste trabalho foram realizados os estudos fitoquímico, microbiológico, a busca de atividades biológicas dos extratos dessas plantas e a investigação de aspectos relativos à segurança de utilização. Os testes fitoquímicos indicaram a presença de flavonóides, taninos, saponinas, mono, sesqui e diterpenos, e derivados cinâmicos nas espécies P. acre e S. carinatum, enquanto que apenas a espécie P. acre respondeu positivamente quanto à presença de proantocianidinas condensadas e leucoantocianidinas. Na avaliação da atividade antimicrobiana através do método de difusão em ágar e da técnica de Concentração Inibitória Mínima, a espécie P. acre apresentou atividade antimicrobiana nas concentrações de 300 mg/mL, enquanto a atividade antimicrobiana para os extratos de S. carinatum não foi evidenciada. Nos testes de toxicidade aguda, pode-se observar que na dose de 2 g/kg, o extrato etanólico 70% de P. acre apresentou taxa de mortalidade de 50%, enquanto o extrato etanólico 70% de S. carinatum não apresentou toxicidade ... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Although there are thousands of plant species used in traditional medicines in the world, it is estimated that only 1% are known by scientific studies with demonstrated therapeutic value. The species Polygonum acre and Synadenium carinatum are easy to culture, being widely distributed in Brazil, and having a high rate of use in folk medicine. Among the popular uses of the species Polygonum acre may be cited anti-septic, anti-inflammatory, hypotensive, anti-hemorrhoid, diuretic, vermifuge, and anti-diarrheal. The Synadenium carinatum species is popularly used in the treatment against cancer. However, there are no scientific studies that show these effects, no information about the safe use of these drugs by human beings and there are few phytochemical studies of this species. In this work, the phytochemical study and microbiological quality control, the search for biological activities of the extracts of plants and the investigation of aspects related to safe use were done. The phytochemical tests indicated the presence of flavonoids, tannins, saponins, mono, sesqui and diterpenes, and cinnamic derivatives in P. acre and S. carinatum species, while only the species P. acre responded positively about the presence of condensed proanthocyanidins and leucoanthocianidins. In the evaluation of antimicrobial activity by the ágar diffusion method and Minimum Inhibitory Concentration technique, the P. acre species had antimicrobial activity at concentrations of 300 mg / mL, while the antimicrobial activity for the extracts of S. carinatum was not demonstrated. In the tests of acute toxicity the ethanol extract 70% of P. acre at a dose of 2 g/kg showed 50% of mortality while the ethanol extract 70% of S. carinatum has no toxicity. At the dose of 1 g/kg the 70% ethanol extract of P. acre showed 50% of mortality while the latex of S. carinatum caused 100% of death the mice... (Complete abstract click electronic access below) / Mestre

Strenuous exercise presents a significant challenge to the cardiovascular system, such that it is widely assumed that the heart largely governs short, high-intensity aerobic exercise performance. Despite considerable investigation of this topic, the haemodynamic responses to maximal exercise are still not well understood, mostly due to insufficient measurement methods unable to quantify the beat-to-beat response of the cardiovascular system during dynamic exercise. In this thesis, two novel approaches (bioreactance and pulse contour analysis calibrated by lithium dilution) for the continuous assessment of exercise haemodynamics in a healthy, trained population were evaluated. In study I, bioreactance was found to considerably underestimate cardiac output (Q) in comparison with contemporaneous measurements with inert gas rebreathing. In studies II and III, we evaluated pulse contour analysis, calibrated by lithium indicator dilution. Our findings indicated that the timing of calibration was central to the accuracy of measurements made during exercise using this method, perhaps due to alterations in vascular compliance throughout exercise'. In study IV, optimising the calibration of this method during exercise permitted the evaluation of the haemodynamic response to maximal and supramaximal (10% greater than maximal) exercise on a beat-to-beat basis, with the finding that cardiac power output, a measure of cardiac work, was higher during supramaximal exercise despite a similar Q and oxygen consumption (V02) between the two workloads. This finding is important for the understanding of factors limiting exercise performance for it indicates that there is cardiac functional reserve at exhaustion during testing for V02max, thus indicating that the heart is unlikely to be responsible for the termination of exercise as it can be considered to be working submaximally.

Owing to an increase in the number of doping cases with performance enhanc-ing drugs (PEDs), mainly anabolic androgenic steroids (AASs), and the limitations of urinalysis and self-reports, there is an ever increasing need to develop new methods for detecting doping. This thesis reports the development and application of a series of nov¬el analytical methods for the detection of frequently used AASs in hair and other matri¬ces using liquid-chromatography tandem mass-spectrometry (LC-MS/MS). Assays capable of detecting 0.5 pg/mg stanozolol and 3.0 pg/mg nandralane (with 20 mg hair) were developed. Hair samples from 180 subjects (108 males, 72 fe-males) were screened using ELISA, which revealed 16 subjects to be positive for stanozolol and 3 for nandrolone. LC-MS/MS analysis confirmed that only 11 subjects were positive for stanozolol (5.0 pg/mg to 86.3 pg/mg) and just 1 for nandralane (14.0 pg/mg), thus showing the inaccuracy of using ELISA screening alone. The analytical fmdings were successfully employed to verify self-reported drug use data. An assay capable of detecting 0.1 pg/mg testosterone (T) and 0.25 pg/mg epitestosterone (E) (with 50 mg hair) was developed. Seventy-five hair samples were collected from healthy volunteers (49 males, 26 females), with the natural levels of T 0.7-11.81 pg/mg and 0.33-6.05 pg/mg and the natural levels ofE 0.63-8.27 pg/mg and 0.52-3.88 pg/mg, in males and in females respectively. This thesis reports for the first time the TÆ ratio in hair, 0.5-3.37 in males and 0.56-1.81 in females. Assays capable of detecting 0.125 pg/mg stanozolol/0.25 pg/mg 3'-hydroxystano-zolol (with 50 mg rat hair) and 0.063 ng/mL stanozolol/0.125 ng/mL 3'-hydroxystanozolol (with 100 uL of rat urine or serum) were developed. Diclofenac was found to significantly reduce the urinary excretion of 3'-hydroxystanozolol, but did not influence the concentration of both compounds in hair. This is the first in vivo study to report this effect. Assays capable of detecting 0.25 pg/mL stanozolol and 0.5 pg/mL of 3'-hydroxystanozolol in 5 mL aqueous matrices were developed in order to investigate en-vironmental contamination. Three out of six samples from the River Danube, collected from December '09 to November '10, were found to contain stanozolol, (upto 1.82 pg/mL). In contrast, stanozolol was detected only once (1.19 pg/mL) in tap water from Budapest city.

Diabetes mellitus was responsible for 4.8 million deaths worldwide in 2012. Cardiovascular diseases arising from the condition are responsible for half of all diabetes related deaths. The loss of insulin due to pancreatic beta cell death can be restored by replacement with transplanted islets from a donor. However, beta cell replacement is limited by the number of donors and the limited capacity of the beta cell to proliferate. Attempts to stimulate beta cell proliferation and improve islet transplantation methods are successful in the short term, however preventing beta cell death after transplant and inducing growth with continued long-lasting insulin secretion is still the aim to prevent hypoglycaemia in patients with diabetes. Elucidating the mechanisms required for beta cell survival and proliferation would allow successful restoration of blood glucose regulation. Secreted Protein Acidic and Rich in Cysteine (SPARC) is secreted by stromal cells such as fibroblasts and endothelial cells and binds collagen. In adults it is expressed in tissues that have a high rate of proliferation and during tissue remodelling. Experimentally, SPARC has been found to prevent cell growth in vitro in certain cell types, as well as promoting cell rounding and detachment. The aims of this study were to determine whether SPARC had inhibitory effects on β cell growth and signalling as tested in the cell line INS-1, and whether this translated to islet cells tested ex vivo. SPARC was found to be sparsely located within islets to stromal cell types and peri-islet basement membranes. The expression of SPARC was higher in a 4 week pancreas compared to 12 week pancreas (p = 0.012) and was higher in a pre-diabetic model than in control pancreas (p = 0.008). This suggests the involvement of SPARC in early development of the pancreatic islets and indicates that SPARC may be important in the islet during the progression of diabetes. SPARC prevented IGF-1-induced INS-1 proliferation (p < 0.001) and islet survival (p = 0.045). Presence of a stellate cell line PS-1 in co-culture with islets was also found necessary for their survival (p = 0.010). The interference of SPARC with the growth-factor response was also demonstrated by the prevention of signalling protein Akt and ERK 1/2 activation in both INS-1 cells and islets. This study established that SPARC had a detrimental effect on beta cell lines and dispersed islet cells and was over-expressed in diabetic pancreas. SPARC as a regulator of beta cell growth may be promising as a target for diabetes therapy.

According to the World Health Organisation, 422 million adults worldwide are currently suffering from either type 1 diabetes or type 2 diabetes and this number is continuously on the rise. Sufferers of type 1 diabetes have a near complete deficiency in islet β cells, while patients with type 2 diabetes have an insufficient number of functioning islet β cells. The apparent solution to treat diabetes would be to replace the damaged and non-viable β-cells, with healthy and functioning ones by either endogenous regeneration of β cells or exogenous transplantation of β-cells. Even though transplantation is a viable option, the number of available donors is insufficient to meet the demands. Expanding a patient's own β-cells could theoretically provide an unlimited supply of β cells and restor glycaemic control, but current protocols have been unable to generate insulin producing β cells with high mitotic index. Rab7 is a smal GTPase regulatory protein responsible for membrane trafficing. Recent research has found that Rab proteins are crucial for the regulation of signalling receptors. Following internalisation of cell membrane components, cell surface receptors either become degraded or recycled back to the cell surface. Some cell surface receptors are responsible for activation of cellular proliferation, differentiation and inhibition of apoptosis. The aim of this study was to determine the effect of Rab7 knockdown on β cell survival, growth and signalling. We hypothesise that attenuation of Rab7 will increase the number of growht factors and as a result increase ERK1/2 signalling, which will lead to enhanced survival. Here, we show that attenuation of Rab7 in β-cells increases levels of insulin growth factor receptor by 60% (p= 4.2 x 10[to the power of]-8) and the c-Met receptor by 70% (p = 0.03) in INs-1 cells. This indicates a role of Rab7 in the trafficking of both receptors. In addition, ERK1/2 phosphorylation in response to growth factors was greatly enhanced in the Rab7 knockdown group of both INS-1 cells and islets. β cells of type 2 diabetes patients typically have increased autophagy due to high levels of circulating free fatty acids that are cytoxic to β cells. Furthermore, Rab7 is also known to be involved in the regulation of autophagy, and there is growing evidence that the autophagy pathway is important for β cell survival in type 2 diabetes patients and therefore inhibiting autophagy could have a detrimental role. Our data shows that free fatty acids activate both autophagy and caspase pathways in β cells, and inhibit β cell growth. Our data indicates that Rab7 knockdown does not alter autophagy and reduces β cell death and caspase-3 activation under conditions of free fatty acid exposure, such as are found in type 2 diabetes patients. These results suggest that Rab7 inhibition has a beneficial role against cell death and increased proliferation of β cell mass.

Cardiac physiology and hypertrophy are regulated by the phosphorylation status of most proteins, which is controlled by the opposing reactions of protein kinases and phosphatases (PP). The type 2A protein phosphatase family is comprised of PP2A, PP4 and PP6, due to the high amino acid homology of their catalytic subunits (PP2ACα/β, PP4C and PP6C). The activity and expression of this family are partly regulated by alpha4, a common regulatory protein that is essential in type 2A phosphatase holoenzyme biogenesis. In the heart, more than 98% of protein dephosphorylation is mediated by serine/ threonine protein phosphatases, of which type 2A protein phosphatases along with protein phosphatase 1, contr ibute approximately 90%. Currently, the role(s) of type 2A protein phosphatases and their regulation by alpha4 in the heart is poorly defined and requires detailed investigation. In this study, quantitative PCR analysi s demonstrated that PP2ACβ mRNA was most abundant in H9c2 cardiomyocytes and neonatal rat ventricular myocytes (NRVM) whilst, in adult rat ventricular myocytes (ARVM), PP2ACα mRNA was the most abundantly transcribed. Surprisingly, immunoblotting analysis, using catalytic subunit-specific antibodies, identified the expression of all type 2A protein phosphatase catalytic subunits in H9c2 cardiomyocytes and NRVM, however, ARVM only expressed PP2AC and PP6C protein. PP4C protein expression was only detectable in ARVM following proteasomal inhibition with compound MG132. Using siRNA to selectively knockdown type 2A protein phosphatase catalytic subunits, it was revealed that PP2ACα alone dephosphorylates CaV1.2-Ser1928. The data also suggested that PP2ACα, PP2ACβ and PP4C dephosphorylate phospholemman at both Ser63 and Ser68 in cardiomyocytes. siRNA-mediated knockdown of alpha4 protein expression rapidly reduced the expression of all type 2A catalytic subunits. Interestingly, expression of both PP2AC and alpha4 protein expression was elevated in pressure overload-induced left ventricular (LV) hypertrophy. Even though PP6C expression was unchanged, expression of PP6C regulatory subunits (i) SIT4-associated protein 1 (SAP1) and (ii) ankyrin repeat domain (ANKRD) 28 and 44 proteins were upregulated, whereas SAP2 expression was downregulated in hypertrophied LV tissue. Co-immunoprecipitation experiments revealed that the cellular association between alpha4 protein and PP2AC or PP6C subunits was either unchanged or reduced in hypertrophied LV tissue, respectively. Exposure of cardiomyocytes to hydrogen peroxide increased levels of H2AX phosphorylation (γH2AX), indicating hydrogen peroxide-induced DNA damage, which was unaffected by the knockdown of PP6C, however, levels of both total H2AX and γH2AX were diminished by the knockdown of alpha4 protein. The novel findings in this study collectively, demonstrate the differences in th e expression, stability, substrate specificity and altered alpha4-mediated regulation of the type 2A protein phosphatases in normal and hypertrophied myocardium and provide new insights into the molecular mechanisms involved in cardiac calcium homeostasis and DNA repair and thereby help to identify potential targets for the development of new and improved therapies against cardiac pathological hypertrophy.

Mineral materials include rocks, minerals, fossils, earths, mineraloids, biogenic skeletal remains and synthetic stones. Each of these classes of material has enjoyed much popularity as supposedly therapeutic medicinal ingredients in the history of pharmacy; many have an unbroken record of use since ancient and classical times. The historical materia medica incorporates minerals that have been made use of in both medical folklore and academic analysis. This thesis presents a body of work which develops examples from each class of mineral material, tries to establish their identities, and explores the evolution of their therapeutic use against the backdrop of changing philosophies in the history of medicine. The most rudimentary use of mineral materials was in a magico-medicinal way as amulets wom for protection against harmful influences which might be expressed in the body as loss of health, and as prophylactics against specific diseases and poisons. Amulets were often worn as pendants, necklaces and rings, or appended to the clothing in some way. The humoral system of Greek medicine saw the health of the body as being a state of balance between the four humours. Humoral imbalance was corrected by, amongst other interventions, the application of medicinal simples or 'Galenicals', which were largely unmodified (other than by trituration) herbal, zoological and mineralogical materials. The choice of simple was determined by the Aristotelian qualities ascribed to them, and their perceived efficacy according to the Doctrine of Signatures. This approach to prescribing practice held sway from classical times until the work of Paracelsus at the beginning of the Scientific Revolution which commended the use of only the active ingredients of a particular simple, separated from the remainder by alchemical means. These iatrochemical preparations permitted dosage standardisation and encouraged a more empirical approach to prescribing practice. The mineral materials most closely examined in this thesis in the context of the evolving materia medica are pumice, gemstones, holed flints, amber, unicom horn, Jews' stones (fossil echinoid spines), Porcupine bezoars, otoliths and synthetic stones. The analyses presented here rely on the study of manuscript, archival, printed and material sources.

The unique musculoskeletal structure of the human hand brings in wider dexterous capabilities to grasp and manipulate a repertoire of objects than non-human primates. The orientation and the position of the thumb play an important role in this characteristic behaviour. The musculoskeletal arrangement at the base of the thumb facilitates grasp stability, maintains sufficient grasp force, and thumb's larger movement span compared to the fingers. Modelling these complex interactions about the mechanical axes of the joints is a challenging task. Even though there have been numerous attempts to develop anthropomorphic robotic hands, the musculoskeletal arrangement of the foldable palm with the thumb is not explored in detail in thumb kinematic modelling. Furthermore, biomechanical studies indicate that the people who do continuous and repetitive grasping and manipulation tasks are likely to develop thumb related impairments due to excessive musculoskeletal loading at the base joints of the thumb. Consequently, biologically informed wearable robotic assistive mechanisms can provide viable solutions to prevent occuring such injuries. Based on this perspective, this thesis proposes a simplified kinematic model of the thumb using a novel virtual palm-folding axis to abstract the essential musculoskeletal arrangement with the palm. The palmar arch formed when the thumb moves to reach the fingertips with respect to the palm is incorporated as the virtual joint axis in this model. The model validated using human demonstrations of precision grasping is used: 1) to find correlated activity using the thumb joint angles and 2) to test effective thumb assistive force directions when given at the kinematicallu accessible metacarpophalangeal (MCP) joint of the thumb. In this regard, this thesis hypothesizes that an external assistive force exerted at the MCP joint of the thumb will be most effective when applied perpendicular to the palm folding axis in terms of maximising the contribution at the thumb-tip as well as minimizing the projections on the vulnerable base joints of the thumb. The analytical results show strong linear relationships in certain pairs of thumb joint rotations in the torque space. The kinematic model also predicts a range of effective assistive force directions at the MCP joint of the thumb. Experiments conducted using an assistive tendon driven glove on human subjects validated the predictions made by the model showing that the assistive forces at the MCP joint, exerted perpendicular to the palm-folding axis, maximise the force gain at the thumb-tip. Finally, how to provide thumb assistance during reaching to grasp is explored. A single tendon loop configuration anchored to the MCP joint of the thumb is optimized using human thumb grasping data trajectories in order to provide an adaptive resultant assistive force vector in the thumb moving direction during reaching to grasp. In order to expand the resultant assistive force range, a double tendon loop is optimized by combining two separate tendon loops. These findings provide design guidelines for hand assistive mechanisms to maximize the efficacy of thumb external assistance.

Human Fall Detection is a research area with interest from many disciplines and aims to perform for many assisted-living monitoring applications to promptly identify life-threatening situations. A fall occurs when a person is unable to maintain balance due to a variety of issues; physical; mental or environmental. The accurate detection of the fall is crucial as a missed detection can be fatal. Variability of human physiological characteristics is currently unstudied as to the impact on a fall detector's performance as young adults and elderly are expected to fall differently. Another important issue is the scene occlusions. In the use of visual sensors, an occluded fall is treated as a missed detection as the whereabouts of the person is unknown when occluded. Finally, current studies are based on acted fall datasets on which algorithms are trained. These dataset are unrepresentative of real fall events and illustrate the events without occlusions or other scene in uences. Several fall detection algorithms were developed during the study aiming to achieve accuracy in detection falls while fall-like actions such as lying down remain undetected. Human fall datasets were used for training and testing purposes of A machine learning algorithm using data from depth cameras which captured the fall events from different views. A new pathway was introduced tackling the issues of availability issues of data-driven machine learning approaches which was achieved with the use of simulation data. The use of myoskeletal simulation was then selected as a closer representation of the human body in terms of structure and behaviour. With the use of a simulation model, a personalised estimation of the fall event can be achieved as it is parametrised on a physical characteristic such as the height of the falling person. Alternative technologies such as accelerometers have been used for fall detection to prove the validity of this approach on other modalities. A study regarding the impact of occlusions for fall detection which is one of the issues not properly investigated in current work is proposed and examined. Synthetic occlusions were added to existing depth data from publicly available datasets. The research methodologies were evaluated using the most representative depth video and accelerometer data from existing datasets, as well as YouTube videos of real-fall events. The machine learning methodologies achieved good results on similar body variability datasets. A discussion regarding the proof of concept of the simulation-based approach for fall modelling is mentioned given the comparative results against existing methodologies which achieves better than any existing work evaluated against known datasets. The simulation approach is also evaluated against occluded fall and non-fall event data, proving the further robustness of the approach. This platform can be expanded to analyse any type of fall, or body posture (e.g. elderly), without the use of humans to performs fall events.