Physiological system modelling and clinical simulation for diagnosis

Chapter 0 Contains the thesis introduction thesis and concepts of NDIs, derivations and applications. It also summarizes the PNDIs that are derived in the subsequent chapters. Chapter 1 Introduces the concept of using Physiological Non-Dimensional Indexes (PNDI) for distinguishing or classifying patients who were diabetic from non-diabetic and those who are the risk of becoming diabetic. In the authors work, he has also demonstrated that those who were diabetic were actually at-risk and those who were normal were in fact at the rim of becoming diabetic. All the works were verified against with clinical data by parametric identification techniques. Chapter 2 Using the findings of the above chapter, the author conceptualized, and design and simulated a dynamic activity-based insulin infusion system. He has used the clinical data of diabetic patients in the above chapter for demonstrating the operations of the system. He has even demonstrated the stability of the system by having continual simulations till 4-hour. Chapter 3 In this chapter, the author has derived a series of system equations for identification of pulmonary diseases based in the inhale and exhale gas mixtures concentrations and volume space. Chapter 4 In this chapter, the author has derived a series of system equations for identification of diseased lungs based of the lungs’ pressurevolume graphs. He has even demonstrated the techniques of obtaining the Cardiac Output (CO) non-invasively. Chapter 5 The author has demonstrated how to obtain the relative urine outflow non-invasively for normal kidneys. Chapter 6 The author has described the significance and derivation background of PNDI

Movement correction by object recognition-based anatomical tracking in functional magnetic resonance urography (fMRU): Proof of principle

Breathing motion is a challenge to analysis of imaging time series in many settings, especially in thorax and abdomen. We investigated in a software phantom as proof of principle, whether object recognition based tracking is capable of intensity-time-curve analysis. Images-time-series (no respiratory gating) of 100 kidneys were artificially generated (Matlab, TheMathworks, Natick, NA, USA). Respiratory movement was implemented by a sinusoidal coordinate shift with an amplitude of 3 cm and frequency of about 6 min-1. Renal intensity changes after contrast application were modeled using gamma functions for three anatomical compartments: cortex, pyramids and renal pelvis. Movement correction was carried out for half of the study population. Intensity-time-curves were extracted using automatically placed regions of interest relative to central coordinates of the kidney on the first image. Intensity changes over time extracted from the ROIs were subtracted from known intensity changes of the software model. Differences were assessed using Wilcox-Signed-Rank test for 50 kidneys with and 50 without movement correction. We used Bonferroni method to correct for multiple testing. Mean sum of differences between predicted and observed intensities across all kidneys and compartments was 0,072 with and 7,3 without movement correction. Significant difference between observation and model was not seen in any compartments of the tracking group (mean z-score: -0.8), whereas there was in 66 compartments in the non-tracking group (mean z-score: -3.2), signifying good agreement between theoretical model and observed intensity changes with object recognition-based tracking, and suboptimal agreement in the non-tracking-group due to movement artifacts. We conclude that object-recognition based anatomical tracking is feasible in fMRU as an alternative or addition to respiration gating. This may allow a higher temporal resolution of these studies in the future

Kidney segmentation in 4-dimensional dynamic contrast- enhanced MR images : A physiological approach

Master'sMASTER OF ENGINEERIN

Effects of sterile vesicoureteric reflux on renal growth and function

Vesicoureteric reflux (VUR) is predominantly a disorder of childhood associated with urinary infection and renal scarring. It is recognised that, in the absence of urinary infection, scarring can be avoided despite continuing VUR; however, the effects of VUR per se on the growing kidney are unknown and this question formed the primary concern of this thesis. The effects of sterile VUR on renal growth and function in the absence of scarring were investigated in young pigs from soon after birth to about 6 months of age. Two parallel experiments were performed in pig models with either a solitary kidney following unilateral nephrectomy (Experiment I) or with paired kidneys(Experiment II). In both experiments the effects of VUR were examined in the presence of both normal and abnormal bladder function by including pigs with and without bladder outflow obstruction, as well as appropriate 'non-refluxing' controls. Bladder function was assessed by urodynamic studies. Renal growth was measured from the weight of the kidneys at the end of the study. Renal function was measured by 51Cr-Edetic acid glomerular filtration rate (GFR), urinary concentrating ability and renal uptake of 99mTc-dimercaptosuccinic acid (DMSA). Regression analysis was applied separately to the results from each experiment. There was no interaction between VUR and bladder function on any outcome measure and for each of them the 95% confidence intervals were calculated for the effects of VUR.In Experiment I, kidney weight and all parameters of renal function were examined. There was no significant effect of VUR on renal growth or GFR. The renal uptake of 99mTc-DMSA was reduced by VUR but was significant only at the 5% level. Urinary concentrating ability was significantly impaired by VUR (P<0.01). In Experiment II the effects of VUR on kidney weight and on uptake of 99rr>TC_DMSA were compared in pigs with and without unilateral VUR. There was no significant effect of VUR on relative uptake of 99mTc-DMSA or on relative kidney growth

Optical Coherence Tomography as a Diagnostic Tool in Renal Transplant and Cancer Imaging

This dissertation aims to investigate optical coherence tomography (OCT) as a diagnostic technology in renal imaging through two main arenas: renal transplantation and renal cancer. Part 1: Ischemia-reperfusion injury, which frequently occurs after kidney transplant, is a major contributing factor in delayed-graft function leading to varying degrees of early renal dysfunction. Real-time assessment of graft morphological and hemodynamic changes could help to evaluate graft condition and offer valuable information to predict the prognosis of graft injury for patient-specific management strategies. Previous studies have shown the ability of OCT to monitor structural changes associated with ischemia-reperfusion injury in vivo. Therefore, we investigated the ability of Doppler OCT (DOCT) to image microcirculatory changes in real time in the kidney glomerulus in vivo in an animal model and quantified observed changes in blood flow in 3D. Then, we translated OCT/DOCT technology into clinical testing for renal imaging during transplantation procedures and demonstrated the ability of OCT/DOCT to reveal renal tubular morphology and blood flow immediately following reperfusion. Part 2: For solid renal masses, nephron sparing procedures have been developed as an alternative to radical nephrectomy. However, achieving a negative tumor margin is critical to ensuring the best oncological efficacy for precluding tumor recurrence. OCT is a high-resolution, real-time imaging technology that has shown the ability to distinguish cancerous tissue from normal in several systems of the body based on changes in tissue optical properties. Therefore, we investigated the capability of OCT to quantify differences in optical properties between tumor and normal renal tissue. However, we did not observe a significant difference in optical attenuation between tumor and normal tissue in ex vivo specimens. These results suggest that further studies or possible alternative metrics need to be investigated to determine if OCT is able to detect renal neoplasms

The effect of a maternal low protein diet on renal development and function in the offspring

A poor maternal diet leads to offspring with a greater risk of developing chronic diseases later in life. This thesis considered whether a low protein diet during pregnancy in sheep affected the development of the fetal kidney, and how this impacted upon adult renal function when challenged by obesity. Pregnant ewes were fed either a control diet or a diet that was isocaloric but contained only 50% of the protein, in either early or late gestation. The effects of the diet were assessed on the ewe, day 65 fetuses (0.44 gestation), and two year old offspring which had been subjected to an obesogenic environment (ab libitum feed and reduced exercise). Few effects were observed on the ewe, confirming that the nutritional insult was relatively mild. Fetal renal vasculature (assessed by vascular corrosion casts) was not different between groups, although the microvasculature was significantly reduced in the early protein group, as evidenced by CD34+ staining of endothelial cells. This was accompanied by a reduction in angiogenic factors compared to control animals. Protein-energy malnutrition in the ewe led to reduced urea in maternal and fetal plasma, along with a concomitant reduction in ornithine in the fetal plasma and amniotic fluid. Other amino acids were relatively unaffected. In the adult sheep there were no effects on long-term renal function in the group fed low protein late in pregnancy, despite the lambs having lower birth weights and a period of postnatal catch up growth compared to the other groups. However, the group fed low protein during early pregnancy had reduced nephron number, microalbumuria and reduced renal function as assessed by gamma scintigraphy. There was also evidence of microvascular rarefaction which may have been exacerbated by obesity. This study did not reveal any consistent sex-specific effects of the maternal low protein diet. This study emphasises the importance of diet quality rather than quantity, and the importance of consuming a well-balanced diet during pregnancy to protect against future chronic diseases

Image Processing and Analysis for Preclinical and Clinical Applications

Radiomics is one of the most successful branches of research in the field of image processing and analysis, as it provides valuable quantitative information for the personalized medicine. It has the potential to discover features of the disease that cannot be appreciated with the naked eye in both preclinical and clinical studies. In general, all quantitative approaches based on biomedical images, such as positron emission tomography (PET), computed tomography (CT) and magnetic resonance imaging (MRI), have a positive clinical impact in the detection of biological processes and diseases as well as in predicting response to treatment. This Special Issue, “Image Processing and Analysis for Preclinical and Clinical Applications”, addresses some gaps in this field to improve the quality of research in the clinical and preclinical environment. It consists of fourteen peer-reviewed papers covering a range of topics and applications related to biomedical image processing and analysis

[¹⁸F]fluorination of biorelevant arylboronic acid pinacol ester scaffolds synthesized by convergence techniques

Aim: The development of small molecules through convergent multicomponent reactions (MCR) has been boosted during the last decade due to the ability to synthesize, virtually without any side-products, numerous small drug-like molecules with several degrees of structural diversity.(1) The association of positron emission tomography (PET) labeling techniques in line with the “one-pot” development of biologically active compounds has the potential to become relevant not only for the evaluation and characterization of those MCR products through molecular imaging, but also to increase the library of radiotracers available. Therefore, since the [18F]fluorination of arylboronic acid pinacol ester derivatives tolerates electron-poor and electro-rich arenes and various functional groups,(2) the main goal of this research work was to achieve the 18F-radiolabeling of several different molecules synthesized through MCR. Materials and Methods: [18F]Fluorination of boronic acid pinacol esters was first extensively optimized using a benzaldehyde derivative in relation to the ideal amount of Cu(II) catalyst and precursor to be used, as well as the reaction solvent. Radiochemical conversion (RCC) yields were assessed by TLC-SG. The optimized radiolabeling conditions were subsequently applied to several structurally different MCR scaffolds comprising biologically relevant pharmacophores (e.g. β-lactam, morpholine, tetrazole, oxazole) that were synthesized to specifically contain a boronic acid pinacol ester group. Results: Radiolabeling with fluorine-18 was achieved with volumes (800 μl) and activities (≤ 2 GBq) compatible with most radiochemistry techniques and modules. In summary, an increase in the quantities of precursor or Cu(II) catalyst lead to higher conversion yields. An optimal amount of precursor (0.06 mmol) and Cu(OTf)2(py)4 (0.04 mmol) was defined for further reactions, with DMA being a preferential solvent over DMF. RCC yields from 15% to 76%, depending on the scaffold, were reproducibly achieved. Interestingly, it was noticed that the structure of the scaffolds, beyond the arylboronic acid, exerts some influence in the final RCC, with electron-withdrawing groups in the para position apparently enhancing the radiolabeling yield. Conclusion: The developed method with high RCC and reproducibility has the potential to be applied in line with MCR and also has a possibility to be incorporated in a later stage of this convergent “one-pot” synthesis strategy. Further studies are currently ongoing to apply this radiolabeling concept to fluorine-containing approved drugs whose boronic acid pinacol ester precursors can be synthesized through MCR (e.g. atorvastatin)

Preclinical MRI of the Kidney

This Open Access volume provides readers with an open access protocol collection and wide-ranging recommendations for preclinical renal MRI used in translational research. The chapters in this book are interdisciplinary in nature and bridge the gaps between physics, physiology, and medicine. They are designed to enhance training in renal MRI sciences and improve the reproducibility of renal imaging research. Chapters provide guidance for exploring, using and developing small animal renal MRI in your laboratory as a unique tool for advanced in vivo phenotyping, diagnostic imaging, and research into potential new therapies. Written in the highly successful Methods in Molecular Biology series format, chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls. Cutting-edge and thorough, Preclinical MRI of the Kidney: Methods and Protocols is a valuable resource and will be of importance to anyone interested in the preclinical aspect of renal and cardiorenal diseases in the fields of physiology, nephrology, radiology, and cardiology. This publication is based upon work from COST Action PARENCHIMA, supported by European Cooperation in Science and Technology (COST). COST (www.cost.eu) is a funding agency for research and innovation networks. COST Actions help connect research initiatives across Europe and enable scientists to grow their ideas by sharing them with their peers. This boosts their research, career and innovation. PARENCHIMA (renalmri.org) is a community-driven Action in the COST program of the European Union, which unites more than 200 experts in renal MRI from 30 countries with the aim to improve the reproducibility and standardization of renal MRI biomarkers