Qatar Foundation Annual Research Conference Proceedings Volume 2014 Issue 1

Background: Undetected repeated foot loading and temperature changes during walking in diabetic patients with peripheral neuropathy significantly increases risk of foot ulceration. Early detection of inflammation due to foot temperature and pressure changes from walking has shown to be a potentially effective strategy in prevention of foot ulcers. Therefore, a clinically feasible assessment of these changes is vital to measure pre-ulcerative inflammation and predict DFUs. The current study is aimed to validate effectiveness of an innovative fiber optics embedded smart textile for simultaneous measurement of plantar pressure and temperature. Methods: The study recruited 21 diabetic patients (Age: 57.8±7.9 years, BMI: 31.6±8.0 kg/m2, VPT: 26.8±15 volt, 68% diagnosed with peripheral neuropathy) at high risk for foot ulcers from Wound and Diabetic Foot Center at Hamad Medical Co. Doha. A series of sensors were juxtaposed on the length of an optical fiber integrated in a comfortable sock (Novinoor LLC, IL) for measuring temperature and pressure changes under anatomical regions of the heel, midfoot, 1st and 5th metatarsal heads, and big toe based on changes in wavelength of light. A thermal image was acquired after five-minute temperature acclimation before walking for validating temperature changes. Participants walked 200 steps to induce thermal stress and follow up thermal image was acquired. Participants also wore F-scan insoles (TekScan®Inc) during walk for pressure validation. Results: All the recruited patients perceived the device as comfortable. A significant correlation was observed between both pressure (r=0.67, p<0.05) and temperature (r=0.55, p<0.05) measurements between the sock and the reference systems under different anatomical regions of interest. Conclusion: This study demonstrates the proof of concept for an innovative smart textile in simultaneous assessment of the key parameters associated with risk of foot ulcer in patients with diabetes. Given the correlation values, additional studies will larger sample size is required to further validate and address whether the technology can predict and better manage diabetic foot ulcers. Funding source: NPRP 4-1026-3-277

Obesity is a growing health concern in Qatar because of the increased risk for type 2 diabetes, hypertension and other vascular disorders. One of the early adverse vascular events in obese individuals is an abnormal endothelial function which might alter the mechanism of vasodilatation. In particular, it is thought that loss of nitric oxide (NO)-mediated vasodilatation might be compensated by dilatation mediated by endothelium-derived hyperpolarizing factor (EDHF) in these individuals. It is however not clear whether such a switich in the contributions of these mediators would depend on the degree of loss of vascular endothelial function. Given that micro vessels in subcutaneous (SC) and omental (OM) fat depots of obese individuals might suffer different degrees of endothelial dysfunction [1], this study investigated whether the roles of NO and EDHF as mediators of vasodilatation of these vessels are altered in morbidly obese Qataris. Small arteries were isolated from SC and OM adipose tissues collected from consented morbidly obese Qatari patients (n=18) undergoing bariatric surgery at Hamad general hospital Doha. The vessels were studied by wire myography. Relaxation curves were generated for actetylcholine (Ach, the classical endothelium-dependent relaxant) in the absence or presence of Nω-Nitro-L-arginine methyl ester (L-NAME, 100 µM, inhibitor of nitric oxide synthase), apamin (0.5 µM) + charybdotoxin (0.1 µM) -combined blocker of EDHF, or BaCl2 (30 µM, blocker of inward rectifier potassium Kir channel ) on initial tone built with noradrenaline (1-5 µM). Curves were also generated for the NO donor and endothelium-independent relaxant, sodium nitroprusside (SNP). The patients had body mass index (BMI) of 46±2 Kg.m-2 and fasting plasma insulin of 17±2 mU/L [Mean±SEM]). Vessels from the SC depot were generally more responsive to Ach compared to OM vessels. Ach curves for both SC and OM vessels were significantly shifted to the right by L-NAME (n=5-7, p<0.05) and more so by apamine+charybdotoxin (n=6-7, p<0.01). The Emax for SC vessels dropped by ̴ 37 % in the presence of L-NAME and by ̴ 64 % in the presence of apamin+charybdptoxin. For OM vessels, the the reductions were ̴ 27 and ̴ 40 % respectively. BaCl2 caused a rightward shift in Ach response in both vessel types (n=4-5, p<0.05) although significant reduction in Emax was only recorded in OM vessels (p<0.05). When Ach and SNP responses were compared for each vessel type, only the OM vessels showed significant endothelial dysfunction (p˂0.01). The results show that eventhough NO still plays a significant part in the endothelium-dependent dilator mechanisms of these vessels from morbidly obese Qataris, EDHF appears to play a greater role, particularly, in the SC vessels. The results also show that the increased role for EDHF is not due to loss of endothelial function since the substantially greater role in SC vessels was observed inspite of the relatively better endothelial function recorded in them compared with OM vessels. Furthermore, Kir channel involvement appears to be depot specific and largely in the OM vessels. 1. Farb MG et al., 2012 Arterioscler Thromb Vasc Biol. 32(2):467-73

Background & Objectives: Epilepsy is a neurological disorder that is associated with repeated episodes of seizures. In epilepsy, the normal pattern of neural activity is disturbed, causing the patient to experience various symptoms ranging from staring blanking for a few seconds to long periods of vigorous convulsions and unconsciousness. In many patients, the injuries they endure are a direct result of the confusion, loss of muscle control, and unconsciousness caused by the seizure. These injuries include fractures, head injuries, and burns. In an attempt to mitigate such risks, extensive research has been dedicated to developing a device that can detect or predict the onset of seizure episodes. The clinical behavior of an epileptic seizure is preceded and then accompanied by electroencephalographic alterations. As a result, electroencephalography (EEG) is the most common tool to measure these alterations. EEG measures the voltage fluctuations resulting from ionic current flows within the neurons of the brain. Research has demonstrated that epileptic seizures are caused by disturbances in the electrical activity between neurons in the brain. In the healthy brain, neurons fire in an asynchronous manner, relaying messages from one neural network to the other. However, in the epileptic brain, the complex interactions between neuronal networks are characterized by the evolution of synchronization between them. Excessive neuronal synchronization leads to a hyper-synchronous state that triggers the onset of a seizure. Methods: There are many ways to measure the synchrony between two or more continuous time series of brain activity, ranging from linear approaches such as the cross correlation and the spectral coherence function as well as nonlinear measures like mutual information, transfer entropy, Granger causality, or nonlinear interdependence. These measures yield low values for independent time series and high values for correlated time series. In this research, we present a novel patient-specific epileptic seizure onset detector using scalp EEG. The proposed detector employs a novel neural synchronization measure to compute the level of EEG channel synchronization at a particular time instant. Training a support vector machine, in the classification stage of the detector, on the calculated level of neural synchronization from a patient's pre-ictal, ictal, and post-ictal EEG, the detector is able to identify the electrographic onset of an imminent seizure. Results: The proposed detector successfully identifies EEG epochs that are highly synchronized as seizure epochs, while pre-ictal and post-ictal epochs are shown to have a significantly lower level of synchrony. The performance evaluation results of the proposed detector are closely aligned with the electrographic seizure onset time that an expert has visually determined. Conclusion: The quality of life of epileptic patients that suffer from intractable seizures can be enhanced by equipping them with a device that can alert them ahead of time of an imminent seizure. The dramatic increase of synchronization between neuron firing during a seizure is clearly detected using the novel synchronization measure that we propose. The proposed seizure onset detector clearly identifies times of increased neural synchrony and sends an alarm at the earliest abnormal electrographic changes of a patient.

Oxygen is essential for the survival of all aerobic organisms but it is also, paradoxically, a toxic, mutagenic gas. Molecular oxygen is highly reactive and its partial reduction generates reactive oxygen species (ROS). Under normal physiological conditions, ROS are produced in low amounts as a result of active aerobic metabolism and have an important role as signaling molecules. At higher concentrations, ROS are cytotoxic and damage macromolecules. Proteins are major targets of ROS, resulting in a change in the structure and/or function of the oxidized proteins. Dietary antioxidants have been shown to modulate the extent of protein oxidation in plasma. However, the significance of dietary antioxidants in preventing vital oxidative changes of proteins still remains unknown.Therefore, in the present work we have evaluated the antioxidant significance of cucumber and zucchini extracts in the prevention of oxidative modification of proteins in human keratinocytes. Vegetables were collected from the farm in Qatar and their juice was extracted by a heavy-duty juicer, with a stone mill-like screw, using a low speed of 80 RPMs resulting in minimal heat build up and oxidation of samples. Copper sulphate, a well known inducer of lipid peroxidation, was used to alter redox homeostasis in human keratinocytes. Cells were treated with copper sulphate (LD22.5) and vegetable extracts were used to prevent oxidative damage of proteins. After 24 hours, the ability of extracts to inhibit copper induced cell death was evaluated by MTT assay and the proteins were isolated for redox proteomics analysis. Proteins were then separated by 1-D gel electrophoresis, digested with trypsin and peptides were detected by Orbitrap LC-MS/MS. Afterwards, the MS/MS data were searched using Proteome Discoverer 1.4 against Homo sapiens database incorporating the comprehensive workflow that included several dynamic modifications of peptides, like N-terminal carboxymethyl, C-terminal oxidation and terminal independant oxidation and trioxidation of peptides. The results obtained showed that cucumber and zucchini extracts were able to inhibit copper induced cell death, LD0 and LD12 respectively. Furthermore, the results obtained revealed several peptide modifications that were inhibited by the vegetable extracts and associated with inhibition of copper induced cell death. Finally, future identification and quantification of redox-based changes within the proteome both in redox signaling and under oxidative stress conditions and their inhibition by dietary antioxidants represents new and exciting field that will have a significant impact on a number of pathophysiological conditions and aging

Although prostate cancer can be clinically managed in its early phases, the inability to control the more aggressive late-stage disease has prompted the search for novel therapies. We hypothesize that strategies targeting polyamine homeostasis may be effective against prostate cancer. The prostate has the highest level of polyamine biosynthesis of any tissue, and it is the only tissue in which polyamines are purposely synthesized for export. In particular, large amounts of polyamines are excreted by the prostate into semen. Thus, we reasoned that polyamine homeostasis may be altered in the prostate relative to other tissues and that tumors derived from this gland may exhibit atypical regulatory responses in order to synthesize large amounts of polyamines in this tissue. Intracellular levels of polyamines are homeostatically maintained by effector systems controlling the biosynthesis, uptake and export of these molecules. By acetylating polyamines, the enzyme spermidine/spermine N1-acetyltransferase (SSAT) controls polyamine inactivation and export. Specifically, SSAT catalyzes the transfer of acetyl groups from acetyl-coenzyme A (acetyl-CoA) onto intracellular polyamines and thereby marks them for export and/or catabolism, which reduces their positive charge, blocks biological activity, promotes degradation, and facilitates excretion. We showed that in prostate tumors, overexpression of SSAT leads to futile metabolic cycling (polyamine flux). Furthermore, our and others studies have shown that overexpression of SSAT in transgenic mice (SSAT-tg) increased energy expenditure, which produced a polyamine-based cycle, reduced the levels of acetyl-CoA, increased glycolytic enzyme expression and decreased lactate production. These proof of principle studies provided evidence for linking the polyamine flux to the Warburg effect. Additional studies in prostate tumor cell lines have shown that the polyamine flux increases the glucose uptake, thereby creating the possibility of improved positron emission tomography (PET) with 18-fluorodeoxyglucose (FDG) because this imaging is not currently possible in prostate cancers. To further study the effect of polyamine flux on tumor growth in vivo, our transgenic mice were crossed with TRAMP mice (TRansgenic Adenocarcinoma of Mouse Prostate) to produce a bigenic mouse line (TRAMP/SSAT). These mice showed an increased in polyamine flux and importantly a reduction in prostate tumor burden. This novel approach for treating cancer by targeting a key regulator of cancer metabolism may provide a better, more efficient treatment for prostate cancer and improved PET imaging.

Insulin resistance and beta cell dysfunction are core defects in type 2 diabetes (T2DM). Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) are intermediate states in the transition in glucose tolerance from normal to T2DM, both of which are associated with increased conversion rate to T2DM. Understanding the metabolic abnormalities that lead to the development of IFG and IGT will help develop strategies to prevent the development of T2DM. in the present study, we have examined the metabolic abnormalities responsible for the development of IFG and IGT in Arab individuals. 43 subjects with NGT (n=17), isolated IFG (N=17) and isolated IGT (n=9) received 75-gram OGTT and plasma glucose, insulin and C-peptide concentrations were measured at baseline and every 15 minutes for 3 hours after the glucose drink. Insulin secretion was measured with the incremental area under the plasma insulin and C-peptide concentration curves and insulin sensitivity was measured with the Matsuda Index. Beta cell function was measured with the Disposition Index as the product of insulin secretion and insulin sensitivity indices. IGT subjects manifested severe insulin resistance compared to IFG and NGT subjects. The Matsuda Index was 3.7±0.4, 7.2±1.0 and 8.4±1.1, respectively (p<0.01 for IGT versus both IFG and NGT). Beta cell function measured with the Disposition Index from 0-180 minutes was markedly reduced in IGT subjects compared to IFG and NGT individuals, 6.5±1.2, 34.0±5.6 and 32.9±4.9, respectively, (p<0.05 for IGT versus IFG and NGT. However, insulin secretion during the first 30 minutes during the OGTT was reduced in both IFG and IGT compared to NGT, 68.1±8.1, 52.6±7.4, and 100.7±10.9, respectively, (p<0.01 for both IFG and IGT. Collectively, these results indicate that similar to other ethnic groups, distinct metabolic defect characterize IFG and IGT in Arabic individuals Acknowledgment: We would like to thank Sanaa Mansy and Evette Rofaeil for their excellent care of the study participants. Supported by Qatar Foundation grant NPRP 4-247-3-076 to MAG and MZ

Qatar experience in Standard Breast Cancer Screening Authers: Dr Salha Bujassoum ,Dr Hekmet Bugrein , Dr Reena ALaSSAM , Dr Mufid Elmistiri Abstract Qatar has one of the highest age-adjusted breast cancer incidences in the Arab world. Although this is much lower than the incidence in the West. Breast cancer incidence in Qatar was 45 per 100,000 in 2003-2007.These higher incidence rates in Qatar are mainly due to the growing population. The prevalent age group, between both Qatari and non-Qatari patients, was 40-50 years old. This suggests that the age-specific incidence of breast cancer in Qatari women is shifting more to a pattern usually not seen in Western nations where median age at diagnosis is 61 years of age, moreover the diagnosis is often at advanced stages of breast cancer. These factors, together with reconfirmed evidence of mortality benefit from breast cancer screening trials, led to establishment the first hospital based mammographic breast cancer screening program in Qatar. It uses a distributed model of mammography service. The program accepts eligible asymptomatic women at age between 45 - 69 years and was launched in 2008. It adopted international standards of breast screening practice and breast cancer detection. Methods A retrospective study was conducted to describe the breast cancer screening program in Qatar and to overview the detection rates, positive predictive values and sensitivity and specificity of mammogram. Results Total number of screened women was 4264 with an increasing participation, year by year. Out of these, Qatari patient's accounts for 1145, and non Qatari for 3119. The age group of breast cancer detected cases from screening program (43-51). Total breast biopsies were 82 core, of which 45 were positive of breast carcinomas, (37) invasive ductal carcinoma, (8) noninvasive ductal carcinoma. The Invasive cancer detection rate was 8.2 % The positive predictive value (PPV) was 46%. Sensitivity value has improved from 51% in 2008 to 70% in 2012 as well as specificity value that has increased from 77% in 2008 to 83% in 2012. Conclusion Public acceptance of the breast cancer screening program in Qatar gradually increased and detection rates were acceptable in this part of the world. We have a unique population of multinationals that merits tailored screening tools.

The eye is the clearest and most accessible organ to observe anatomical and physiological characteristics of microvessels, the smallest blood vessels of the circulatory system. The microcirculatory bed of the retina shares similar anatomical and physiological characteristics with the cerebral and coronary circulations. Therefore, subtle changes in the retinal blood vessels can mirror early cardio- and cerebrovascular events long before their clinical manifestation (e.g. hypertension). Retinal images contain information to develop quantitative diagnostic algorithms for morphology, physiology, and pathology. Analysis of retinal images allows quantification of many vascular features: the Central Retinal Arteriolar and Venular Equivalents (CRAE & CRVE), morphological features (branching, tortuosity and geometric pattern of the vascular bed), but also small changes in the diameter of microvessels in response to disease or external factors. Particularly CREA and CRVE have been associated with hypertension, coronary heart disease, stroke, and type II diabetes as well as with acute responses to environmental (e.g. air pollution exposure) and lifestyle (e.g. smoking and physical inactivity) risk factors. We demonstrated in a longitudinal panel study with 52 healthy individuals aged 22 to 62 years that short-term changes in particulate air pollution (PM10-concentrations ranging from 9.16 µg/m³ to 126.58 µg/m³) caused a significant narrowing of the CRAE by 0.69 µm (95% CI= -1.13 µm to -0.26 µg; p = 0.0032) on the day following peak exposure. This narrowing was equivalent to 1.5 years of aging. The associations were independent of individual characteristics such as gender, age and BMI. The results indicate that microcirculatory blood vessels can be affected by short-term changes in air pollution, and may contribute to the development or aggravation of cardiovascular disease, perhaps even induce events. To allow for a more automated analysis of retinal images, we developed stand-alone software which results in a faster, objective, and more precise grading of large numbers of images. VITO embeds this tool in a data portal, which includes batch processing and quality control. We are exploring if handheld retinal cameras can replace heavier and more expensive tabletop cameras. If these instruments are interchangeable, then we can work towards a truly mobile health solution. The unobtrusive nature of retinal imaging has high potential for facilitating long-term, recurrent monitoring of the population in epidemiological settings, in line with the P4-Medicine paradigm (Preventive, Personalized, Participatory & Predictive). Also for specific vulnerable subpopulations such as elderly, pregnant women, and school children, the non-invasiveness and ease of routine allows for wide deployment in large-scale, even population-wide longitudinal studies. Retinal imaging can also contribute to evidence-based population health programs. It addresses several pressing health challenges in Qatar and Belgium (cardiovascular diseases, obesity and diabetes); identifies risk factors and their effect in vulnerable groups (e.g. the potential adverse health effects of exposure to indoor and/or outdoor air quality) and provides a non-invasive and personalized method to follow-up the effect of disease prevention and healthy behavior campaigns. VITO is actively seeking for partners and projects in this research area.

A gradual shift from GHz to THz range in the past few years has celebrated the invention of many new technologies in the field of communications, computers, electronics and medicine. Nano-networks are the new era technologies defined as electronic components and their interconnection within a single chip on a nano-scale [1]. The concept of Network on Chip (NoC) is exploited on a scale ranging from micrometers to nanometers. This term is also referred to as the network-like interconnection of nano-materials such as carbon nanotubes arrays [2,3]. The research done in the past has broadly explained the same concept of nano-networking with different terminologies and slightly varying definitions depending on the mechanisms of networking and communication. In this study, the main focus is on propagation investigation at THz frequencies in human tissues, such as blood, fat, and skin, which is conducted with the aim to fix the early paradigms for a pioneering investigation in this field. The path loss values obtained from numerical simulation have been compared to an analytical model in order to verify the feasibility of the numerical analysis which can be subsequently extended in order to take into account more realistic parameters such as the antenna, or inhomogeneity of the materials. The study also explores the methods and techniques to characterize biological medium necessary for Nano-network communication. Time Domain Spectroscopy has immensely contributed in the field of medical imaging, analysis of protein and other biomolecules, finger print analysis of chemicals and food quality control [4]. The aim is to utilise this technique to study the dielectric properties of various biological samples. Subsequent sections of the chapter will discuss various biological entities such as skin & its layers, blood, hydration shell and sweat ducts. As one begins to understand the human body anatomy from wireless communication perspective, one can realizes its overall complexity and random nature. The main objective of this work is the potentiality of nano-scale EM communication exploiting the THz regime of the electromagnetic spectrum. The nano-scale EM communication becomes an obvious choice due to the fact that molecular information for a human body is indeed sensitive in the THz regime. Additionally, this part of the spectrum is much safer to interact at a cellular scale that its counterparts in the microwave or gigahertz range. The proposed in-vivo body nano-networks ensures their stability without disturbing the harmony of in-built molecular structure of the body. Moreover, in most of the cases medicine fails to understand the root cause of the problem but once a monitoring network is established, one can extract various unknowns and treat them effectively.