A new mouse model of peripheral artery disease: development, validation and assessment of a potential intervention and a therapeutic target

Peripheral arterial disease (PAD) affects more than 200 million people worldwide and is caused by occlusions resulting from atherosclerosis in arteries supplying blood to the lower limbs. Treatments for limb ischaemia in PAD is an unmet medical need. Novel treatments are sought to improve limb blood supply and function in PAD patients unlikely to benefit from existing treatments such as surgical revascularisation, structured exercise programs and cilostozol. Currently, the main pre-clinical experimental model employed in PAD research is based on induction of acute hind limb ischemia (HLI) which results in rapid natural recovery of blood supply to ischaemic tissues. There are concerns regarding the ability to translate findings from this mouse model to PAD patients and a clinically relevant mouse model of HLI is lacking. Evidence suggests metformin may be a potential treatment for PAD and angiotensin converting enzyme 2 (ACE2) may play a role in limb ischaemia. This thesis aimed to develop a clinically relevant mouse model of PAD that involved a two-stage induction of HLI and examine the effect of exercise training, metformin and ACE2 deficiency in the two-stage model of HLI. Two-stage HLI was induced in male Apolipoprotein E (ApoE-/-) deficient mice by slow onset of severe ischemia over 14 days. This 2-stage HLI model was compared to the acute HLI model and sham controls. Limb blood supply was assessed by Laser Doppler Perfusion Imaging (LDI). Ambulatory ability was assessed using a treadmill test and established scoring scales. Running wheel exercise training was examined in the two-stage mouse model and limb function was assessed by a treadmill exercise test and blood supply was assessed by LDI. Next, the effect of metformin on limb ischaemia was assessed by LDI in the two-stage HLI mouse model. Lastly, the effect of ACE2 deficiency (ACE2-/y) on limb ischaemia was examined in the two-stage mouse model of HLI. HLI was significantly more severe in mice receiving the two-stage compared to the acute HLI induction procedure as assessed by LDI (p=0.013), and reflected a higher ischemic score (p=0.003) and lower average distance travelled on a treadmill exercise test (p=0.045). Mice with two-stage HLI receiving exercise training showed significantly greater improvement in their ambulatory ability on a treadmill test than the sedentary control group (p=0.003). However, limb blood supply was comparable between mice receiving exercise compared to controls (p=0.700). Mice with two-stage HLI administered metformin had greater blood supply than mice with two-stage HLI receiving vehicle control (p<0.001). The two-stage HLI mice receiving metformin had increased adenosine monophosphate kinase alpha (AMPKα) activity (p=0.041), endothelial nitric oxide synthase (e-NOS) activity (p=0.031), nitric oxide (NO) bioavailability (p=0.024), peroxisome proliferator activated receptor 1 alpha (PGC1-α) expression (p=0.026) and decreased thioredoxin interacting protein (TXNIP) expression (p=0.038) compared to mice with two-stage HLI receiving vehicle. ACE2-/y in mice with two-stage HLI had comparable limb ischaemia to ACE2 unmodified control mice with two-stage HLI (p=0.263). In conclusion, this thesis showed that the novel two-stage mouse model of HLI had severe ongoing HLI and functional impairment. Exercise training augmented treadmill walking capacity in the new mouse model which was independent of changes to limb blood supply and mirroring patient response to exercise therapy. Metformin administration improved limb blood supply in the two-stage mouse model of ongoing HLI. Improvement in blood supply was associated with the upregulation of AMPKα activity, increased activation of e-NOS in the ischaemic muscles, increased bioavailability of circulating NO, increased expression of PGC1α and reduced expression of TXNIP. This suggests metformin may have potential to be used as a treatment to improve limb blood supply in PAD patients. ACE2-/ did not worsen limb blood supply after two-stage HLI induction suggesting ACE2 may not play an important role in limb ischemia. The results do not encourage the pursuit of ACE2 for pharmacological management of PAD in clinical trials and ACE2 is unlikely to be an important target for improving limb blood supply or function in patients with PAD

Friction Stir Welding of Polycarbonate Butt-Joint: Defects and Remedies

The aim of this work is to study the effect of heating the FSW tool by means of an induction heating on joint strength during joining of polycarbonate (PC) sheets. This material was selected due to its transparency as well as its good photoelastic properties. Therefore, the defects can be easily detected and the residual stresses can be revealed under a polarized optical microscope. Four levels of suggested welding parameters (pin temperature, rotational speed and welding speed) were investigated. Both the mechanical properties and the defect formation were studied in order to achieve a better welding joint. The investigation of samples macrostructure showed that several defects such as islands of melted and non-melted material, discontinuous bonding line, macro-cracks, tunnels, flash formation, surface grooves, voids and root defects were formed as a response to the different interactions between the welding parameters. These defects can be minimized when the welding process is performed at a rotational speed of 1800 rpm, welding speed of 30 mm/min and tool temperature of 50 ◦C. In this situation, the joint efficiency of the welded joint reached 92.2% relative to the base material flexural strength

The University of Gezira Advisory System: Academic Advising of Excellent Students

Excellent students are the promising scientists and leaders of their professions in the future and hence universities must assume full responsibility of supporting and encouraging those students during the undergraduate and postgraduate studies; a policy which can help producing competent graduates who can contribute significantly in the total development of the country. Traditionally excellent students are rewarded by prizes and financial incentives and enrollment in the academic staff as teaching assistants. Although the university rewards are useful in motivating students to achieve excellence, their benefits to the excellent students and the universities are rather limited; they are usually late and do not contribute in strengthening and enriching the curricula. Faculties and departments should have a clear plan of guiding and supporting excellent students; to help them contribute in the academic activities and choose their future careers appropriately. The academic advising system was introduced very early during establishment of the University of Gezira (1975) and has been included in the academic regulations, ever since it has been implemented, upgraded and evaluated several times. Experience showed that it is useful and effective in helping students achieve the University requirements of graduation; teachers and students are now familiar with it. However the system focuses on poor students and neglects excellent students. Following is a proposal of academic advising of excellent students. Examples are drawn from the curriculum of the Faculty of Medicine and the model could be adopted by other faculties

Biochemical and biological effects of irisin in a model of diabetes mellitus

Diabetes mellitus (DM) is a highly prevalent health problem affecting more than 425 million people worldwide. It is associated with several detrimental complications such as neuropathy, nephropathy, retinopathy and cardiovascular diseases. Irisin is a novel hormone that plays a role in metabolism by stimulating the browning of white adipose tissue (WAT) into beige adipose tissue which acquires properties that are similar to those of brown adipose tissue (BAT). Several studies have attempted to characterize the roles of irisin in DM and obesity, however, contradictory results have been reported and physiological roles of irisin have been questioned by several researchers. In our study, we investigated the role of irisin in controlling glucose levels and insulin secretion in STZ-induced DM model and the mechanism by which irisin exerts its beneficial effects both in vivo and in vitro, using a variety of biochemical, morphological and cell biology techniques. We showed that irisin did not cause any significant reduction in weight or fasting blood glucose, however, it caused a significant glucose reduction 30 minutes after glucose challenge. Our data also showed that irisin co-localizes with insulin in pancreatic β-cells in both normal and diabetic animals while it co-localizes with glucagon only in diabetic animals. Moreover, irisin was also detected in skeletal muscle, visceral and subcutaneous adipose tissues. Irisin also reduced triglycerides and increased the level of high density lipoprotein (HDL) and total protein. We also provided evidence that irisin treatment can modulate the tissue level of different peptide hormones such as insulin, glucagon, incretins and leptin. In addition, irisin possesses a potent antioxidant activity and reversed oxidative stress induced by DM. Our in vitro investigations showed that irisin can stimulate the release of insulin from pancreatic β-cells. Irisin could be a potential therapeutic agent in the management of DM

Construction Of Bunds For Oil Storage Tanks

This project is aiming to investigate the current practice of bunds construction for oil storage tanks and provide the most adequate design can be used taking in consideration different criteria and construction aspects. Through this research Analytical hierarchy process were used to analyze the data collected from the current practice in oil and gas industry. In ideal situation constructing earth bund lined with High Density Poly Ethylene will be the best path to take. This research also explains and provides a certain steps that should be followed when building bund for oil storage tank by taking one tank as case study and design bund for it

Assessment of Surface Water Runoff and Groundwater Recharge Using Mathematical Models

In arid and semi-arid regions, surface water resources are scarce and, in most cases, groundwater is the only natural resource of freshwater. Pumping of groundwater often exceeds natural recharge. Therefore, groundwater levels are declining and its quality is deteriorating. Sustainable management of groundwater is thus a key issue and requires implementation of appropriate technologies to augment groundwater resources. Artificial recharge augments the natural movement of surface water into the underground formations using some means of construction whereby surface water from streams or lakes is made to infiltrate into the ground. The UAE is known by its arid conditions and limited renewable freshwater resources. Surface water in UAE is very limited and of a little significance in the water budget of the country. Despite the construction of many desalination plants, groundwater represents a vital natural resource. Although it may not be suitable, in most cases, for drinking, it represents the main source for irrigation. About 85% of the total water consumption in UAE is from groundwater. The sustainability of this precious resource is of prime concern in the UAE. Many dams have been constructed during the last two decades across the main wadis to harvest surface water runoff and recharge groundwater. The importance of this study evolves from the need to assess surface water and groundwater resources in the main wadis which are of vital role in the sustainable development of UAE, specifically, the agricultural development. The study aims at the simulation and quantitative assessment of surface water runoff and the associated groundwater recharge in Wadi Ham, UAE. HEC-HMS and MODFLOW models were used. Due to data limitation, HEC-HMS was applied for the period 1979 to 1989 and MODFLOW was applied for the period from January, 1990 to December, 1993. The study provides a methodology that can be followed in other sites of similar hydrological and hydrogeological conditions. All the data and facilities were provided through a project entitled Assessment of the effectiveness of AI-Bih, AI-Tawiyaen and Ham Dams in groundwater recharge using numerical models . The project was funded by the Ministry of Agriculture and Fisheries. The catchment area and drainage network were delineated based on the available toposheets and remote sensing images using ArcView GIS and AutoCAD softwares. Different wadi tributaries and properties were identified. Comprehensive analyses were conducted to study the variations of rainfall, surface water flow and groundwater levels based on historical records. Several lithologic cross sections were developed to assess the hydrogeology of the area and identify the aquifer geometry. A rainfall/runoff model (HEC-HMS) was used to study the surface runoff process and quantify the total runoff yields. A three-dimensional groundwater flow model (MODFLOW) was used to quantify groundwater recharge and study flow directions and the water balance. The total catchment area to the Wadi Ham Dam is approximately 195 km2. This includes Wadi Ham itself and the catchment of Wadi AI-Farfar system. Rainfall distribution is intermittent and highly scattered. The mean annual rainfall, estimated for 23 years, is 154 mm. Surface water flow is also variable reflecting the intermittent nature of rainfall. Wadi AI-Farfar system has major contribution to the total runoff and accounts for about 40% of the total runoff yield accumulated at the dam site. The Wadi Ham Dam has an effective role in groundwater recharge and its effect is clearly reflected by rise in groundwater levels. The recharge from the dam ranged from 32% to 43% of the dam storage. The flow of seawater to the aquifer is reduced to very low levels during recharge events from the dam while water losses to the sea appear to be very minor. The study suggests some recommendations including continuity of measurements and additional installations of flow gauges and observation wells. The groundwater model developed in this study can be enhanced and its capabilities can be expanded by conducting field inventory of pumping wells, new drillings and pumping tests of longer durations

De novo stone formation in ureteric stump post-nephrectomy

Introduction: The leftover ureteric stump after a simple nephrectomy is rarely symptomatic. Here, we report a unique case of ureteric stump stones that likely developed de novo and patients became symptomatic. Case Report: We report the case of a 53-year-old female, who had benign right nephrectomy for a non-functioning kidney 17 years ago and presented with three years history of recurrent urinary tract infections and right-side abdominal pain. A continuous unenhanced computed tomography scan confirmed the presence of multiple de novo stones in the leftover ureteric stump, which was successfully treated by an open transperitoneal ureteric stumpectomy. She was asymptomatic at 12 months post-operative follow-up. We describe problems of leftover ureteric stumps and the possible pathophysiology of the stones formation in this group of patients. Conclusion: Albeit rare, various symptoms and complications can develop in the leftover stump, including stumpitis, urinary tract infections, and calculi. Therefore, discussion with patients of ureteric stump complications is recommended

Multicriterion approach to the evaluation of irrigation systems performance

PhD ThesisIn recent years the importance and the lack of comprehensive methodologies for measuring the performance of existing irrigation schemes has been widely expressed. The objective of this study is to develop a systematic procedure by which some use can be made of the large quantities of data, already routinely collected in irrigation schemes, for the purpose of their regular seasonal evaluation. Consideration is confined to the performance of the main irrigation system of small-holder, canal-fed irrigation schemes of the developing countries. A generalized conceptual framework has been developed for a methodology by which the performance criteria for any irrigation system can be identified and combined together into a single index which measures the overall performance of the system. Six criteria have been identified as adequate for characterizing the important features of the performance of any irrigation system. These are; adequacy, equity, water losses, water user convenience, cost and durability. New methods for characterizing each of adequacy, equity and water user convenience have been developed and tested using data from the Gezira scheme, Sudan. Characterization of adequacy, equity and water losses involves the development of a soil moisture simulation model and characterization of the water user convenience involves the use of the concept of the fuzzy set theory. Identification of the criteria to be used in evaluating any particular system(s) and evaluating the trade-offs between them requires the participation of the decision-maker in the system(s) to be evaluated. This is achieved through the use of the multi-attribute utility theory. It has been applied with a group of Sudanese officials in order to derive their utility functions. The utility function reflects the decision-maker's strength of preferences over different achievement levels of each objective and his trade-offs between different objectives. The derived utility functions are reported and their usefulness is discussed. The methodology developed provides a useful tool for measuring the performance of irrigation systems, comparing the performance of different systems and assessing improvement in performance resulting from rehabilitation investments.The Ministry of Irrigation, Suda