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Qatar Foundation Annual Research Conference Proceedings Volume 2018 Issue 2
- Conference date: 19-20 Mar 2018
- Location: Qatar National Convention Center (QNCC), Doha, Qatar
- Volume number: 2018
- Published: 15 March 2018
21 - 40 of 82 results
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Antidiabetic and Toxicological studies of ethylacetate and nhexane fractions of Gymnema sylvestre
More LessGymnema sylvestre is a medicinal plant that is used in the folkloric treatment of diabetes mellitus and the management of its complications. This study was aimed at evaluation of antidiabetic and toxicological effects of ethylacetate and n-hexane fractions of Gymnema sylvestre whole plant. Diabetes was induced in Swiss albino rats by single intraperitoneal administration of 110 mg/kg bodyweight of alloxan monohydrate. Rats in their respective groups were orally administered 100, 300 and 600 mg/ kg bodyweight of ethylacetate and n-hexane fractions of the plant daily while the standard drug group received 100 mg/kg bodyweight of metformin. The treatment lasted for fourteen days and on the fifteenth day, animals were anaesthetized and euthanized. Blood samples were collected by carotid puncture for biochemical analysis. In the subchronic toxicological aspect of the study, rats in their respective groups were administered 100, 300, 600 mg/kg bodyweight of the extracts daily for twenty one days and the experiment was terminated on the twenty second day. All the extracts were able to reduce the blood glucose of diabetic rats with 300 mg/kg bodyweight of ethylacetate fraction having higher reduction at 82%. All diabetic rats showed decrease in bodyweight when compared with normoglycemic group. There was significant (p<0.05) reduction in the total cholesterol, triacylglycerol, low density lipoprotein and a concomitant increase in the values of high density lipoprotein in all treated groups when compared with diabetic untreated (negative control).The activity of serum liver enzymes (Ɣ- glutamine transpeptidase, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase) and bilirubin significantly decreased (p<0.05) compared with the diabetic untreated group. Levels of total protein in the treated groups did not differ from the normoglycemic group, while there was a reduction in the concentration of albumin of ethylacetate fraction in a dose dependent manner. All treated groups gave urea and creatinine values that showed no significance differences (p>0.05) with the normoglycemic group. The electrolytes showed significant differences (p<0.05) in all treated groups when compared with the normoglycemic group. There was significant difference (p<0.05) in all the biochemical parameters carried out on the subchronic toxicity test with rats administered ethylacetate and n-hexane fractions of G.sylvestre. The hematological parameters (red blood cell, mean cell volume, mean corpuscular hemoglobin concentration, packed cell volume, hemoglobin) showed no significant difference but a non significant difference in the white blood cell of rats administered with the extract. Therefore, extracts of G. sylvestre might be useful for management of diabetes mellitus and other abnormalities associated with this metabolic disorder
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Generation of a Novel Population of Pancreatic Multipotent Progenitor Cells Expressing NKX61
Authors: Essam Abdelalim, Idil Aigha, Ahmed Elsayed and Bushra MemonDiabetes is a metabolic disease caused by the loss or impaired function of insulin-producing pancreatic β-cells. Different therapeutic strategies aim to restore the endogenous production of insulin rather than the cornerstone insulin injections treatment. Human pluripotent stem cells (hPSCs) have been proposed as an unlimited source for cell-based therapy of diabetes through the directed differentiation into functional pancreatic β cells. Step-wise differentiation protocols based on developmental biology of pancreas, have led to the generation of insulin-producing β cells. However, the majority of the cells produced were poly-hormonal as they expressed other hormones in addition to insulin and have failed to respond when challenged with glucose. The coordinate expression of particular transcription factors (TF) in distinct stages governs the differentiation of hPSCs into insulin β cells. Pancreatic and duodenal homeobox protein (PDX1) is a crucial TF required for pancreas development. On the other hand, homeobox protein NKX6.1 is a potent bi-functional TF that is essential for β cells maturation, proliferation and insulin metabolism. The dual expression of PDX1 and NKX6.1 during multipotent progenitor cell (MPC) stage is vital for guiding the cells towards functional β cells lineage. However, cells expressing PDX1 but lack NKX6.1 expression tend to take the poly-hormonal path. This guided the differentiation protocols to focus on enriching MPC population co-expressing PDX1 and NKX6.1. The aim of this study was to further explore different MPC populations in terms of PDX1/NKX6.1 expression. We used two different differentiation protocols to differentiate hESCs and hiPSCs into MPCs. The mRNA and protein expressions of the generated MPCs were analyzed using immunocytochemistry, RT-PCR, and flow cytometry. Our results showed that hPSCs were successfully differentiated into the conventional (PDX1+/NKX6.1+) and (PDX1+/NKX6.1-) MPC populations. The efficiency of differentiating hPSCs into PDX1+/NKX6.1+ MPCs has varied between the two used protocols. Immunofluorescence staining has unveiled the generation of a novel population that expressed NKX6.1 independently of PDX1 (PDX1-/NKX6.1+) in both hESCs and hiPSCs. This is surprising considering that PDX1 was reported to bind to the promoter of NKX6.1 gene and is needed for NKX6.1 expression. Furthermore, using our optimized protocol, this uncharacterized subset of MPCs was enriched and found to exhibit a pattern of three-dimensional (3D) aggregates that were consistently (PDX1-/NKX6.1+) and surrounded by either (PDX1+/NKX6.1+) or (PDX1+/NKX6.1-) MPCs. To understand and characterize this unique population, we examined the expression of other TFs including endocrine precursors markers Chromogranin A (CHGA) and NKX2.2. CHGA was found to be expressed in the same areas that were positive for NKX6.1 and PDX1. However, the 3D structures that were PDX1-/NKX6.1+ did not co-express CHGA. On the contrary, few cells of these 3D aggregates co-expressed NKX2.2, suggesting that this population may have an undefined role in the development of MPCs into endocrine progenitors. These findings showcase a novel population of NKX6.1 expressing MPCs that did not require PDX1 expression at this stage. Moreover, this population may retain an alternative path towards pancreatic islet cells development that is independent of PDX1. A thorough characterization of this population is needed to explore the regulatory gene network controlling their lineage specification.
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Nonphosphorylated Alphasynuclein at Serine 129: A Potential Biomarker for Parkinson's Disease
More LessAuthor and co-authors’ details: Muneera Fayyad1, Nour Majbour2, Mercy A. Thomas2, N. Vaikath2, and Omar M. A. El-Agnaf1,2 1Life Sciences Division, College of Science and Engineering, Hamad Bin Khalifa University (HBKU), Education City, Qatar Foundation, PO Box 5825, Doha, Qatar 2Neurological Disorders Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, PO Box 5825, Doha, Qatar. Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. It is characterized by a progressive loss of dopaminergic neurons and an accumulation of Lewy Bodies (LBs) and Lewy Neurites (LNs), protein-rich inclusions that deposit in the neurons. These inclusions are mainly composed of alpha-synuclein (α-syn), a small protein with a propensity to aggregate. Evidence from genetic, biochemical, pathological and animal studies suggest that the aggregation of α-syn plays a key role in the pathogenesis of PD and related disorders, termed synucleinopathies. To date, the diagnosis of PD primarily depends on the clinical criteria, however, this approach has its limitations since the neurodegeneration starts several years before symptoms manifest. In other words, the onset of typical motor symptoms is mostly preceded by 50-70% loss of dopaminergic neurons, which explains the irreversibility of the disease at the time of diagnosis. This necessitates the development of reliable biomarkers that would allow early diagnosis of PD at the preclinical stage. Accumulative evidence suggests that the majority of α-syn from LBs in the brains of PD patients is found to be phosphorylated at Serine 129 (pS129-α-syn). It is unknown whether phosphorylation of α-syn promotes or prevents its aggregation and toxicity. Nevertheless, this highlights the importance measuring the levels of pS129-α-syn in biological fluids. We highlighted that CSF oligomeric-/total-α-syn and p-S129-/total-α-syn ratios improved the discrimination between PD and healthy subjects. However, little is known about a the potential diagnostic role for non- phosphorylated α-syn at S129 (npS129-α-syn). Recently, we developed a novel mouse monoclonal antibody (4B1) that is specific for npS129-a-syn (i.e. does not recognize pS129-α-syn). Here we describe the generation of 4B1 using hybridoma technology. The antibody purification was done using Protein-G agarose affinity chromatography, and later characterized using a wide range of biochemical assays. More importantly, we describe the development of the first ELISA assay to reliably quantify concentrations of npS129-α-syn in biological samples. We also assessed the usefulness of our assay using CSF samples from PD patients and age-matched healthy controls. We report that the discrimination power between PD and healthy controls was improved by including npS129-/ t-α-syn ratio. We highlight that the combination of multiple CSF biomarkers, improved the diagnostic accuracy of PD. Such immunoassays would not only aid in the discovery of ideal CSF biomarkers but may also serve as research tools to facilitate a better understanding of the underlying role of α-syn phosphorylation in PD and related disorders. In addition, our efforts to identify biomarkers for PD may reveal molecular species that could serve as therapeutic targets for the development of new disease modifying therapies.
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Screening for Novel Inhibitors of Beta Amyloid Aggregation and Toxicity as a Potential Drug for Alzheimer's Disease
Authors: Sanaa Ali Sharari, Nishant Narayanan, Magdalini Taskou, Kostas Vekrellis and Omar El-AgnafAlzheimer’s disease (AD) is one of the most common neurodegenerative disorders in which the disruption of brain cells causes impairment of cognition. The pathology of AD is still unclear, with different etiologies leading to formation of extracellular senile plaques, intracellular neurofibrillary tangle (NFT) and ultimately neuronal death. However, several investigations showed that the amyloid hypothesis in which the accumulation of the toxic amyloid beta (Aβ) protein in the central nervous system (CNS) is the main pathology of the AD. Currently, there is no proven medication to cure or prevent the disease, however, therapeutic approaches of AD show only relief of symptoms and mostly work on cognitive recovery. Moreover, herbal phenolic compounds grant more effective therapy due to its multifacted action. Based on the previous work targeted the amyloid hypothesis in disease other than AD by using Chinese medicinal compounds, our project is aimed to investigate the activity of Ginsenoside Rb1, Dihydromyricetin and Salvianolic acid on the process of aggregation of Aβ40 and Aβ42. The effect of these compounds on the Aβ aggregation was investigated using different biochemical assays. Our results showed that Salvianolic acid and dihydromyricetin inhibit Aβ40 and Aβ42 fibrilizations. Whereas, Ginsenoside Rbi1 showed no effect on the aggregation process of both amyloids. Overall, these compounds may be considered as starting point for designing new compounds that could be used as drugs for the treatment of AD and related disorders.
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Impact of a Collaborative Pharmaceutical Care Service among Patients with Diabetes in Qatar Petroleum Healthcare Center Dukhan: A Multiple Time Series Study
Authors: Ahmed Awaisu, Sara Abdulrhim, Rana Saleh, Mohamed Abdelazim, Hend Alraey, Ahmed Babiker and Nadir KheirAbstract Background: Diabetes mellitus is a highly prevalent non-communicable disease worldwide. The prevalence of diabetes in Qatar exceeds the prevalence of diabetes in the Middle East and North Africa region and the globe. Similarly, diabetes-related complications and mortality are dramatically increasing worldwide. Poor health outcomes and debilitating consequences can result from inadequate control of diabetes. Previous studies have demonstrated the benefit of pharmaceutical care services on outcomes of diabetes. No studies were done in Qatar regarding this issue. Therefore, the objectives of this study were to: (1) characterize the clinical profile of patients with diabetes attending an ambulatory care clinic at Qatar Petroleum (QP) Medical Center including diabetes-related comorbidities and complications; (2) evaluate the impact of a Comprehensive Pharmaceutical Care Service (CPCS) on glycemic control [glycated hemoglobin A1c (HbA1c) and fasting plasma glucose (FPG)]; (3) evaluate the impact of the CPCS on diabetes comorbidities including lipid profile [low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), triglycerides (TG), and total cholesterol (TC)], systolic blood pressure (SBP), diastolic blood pressure (DBP), and body mass index (BMI) and; (4) classify the drug-related problems (DRPs) identified by pharmacists during the follow-up period. Methods: This was a multiple time series, observational, retrospective, pre-post study among patients attending diabetes clinic at QP Medical Center in Dukhan. Primary clinical outcome measures including HbA1c, FPG, weight, BMI, SBP, DBP, and lipid profile were measured at baseline, 6 months, and 12 months after receiving the CPCS through a retrospective chart review of electronic medical records for the year 2016. The secondary outcome measure, the types of DRPs identified by pharmacists, was collected over the period of 12 months of initiating the CPCS and categorized into a predetermined classification system. Data analyses were performed using IBM SPSS® version 23.0. Primary clinical outcome measures were analyzed inferentially using Repeated Measure ANOVA to determine the impact of the intervention. Sociodemographic characteristics, basic clinical characteristics, baseline and current medications regimens, and types of DRPs identified by pharmacists were analyzed descriptively using frequencies, percentages and means as appropriate. Results: A total of 96 eligible patients with diabetes were included in the study. CPCS significantly improved the following parameters from baseline to 6 and 12 months: HbA1c (8.5%, 7.4%, 7.1%, respectively; P <0.001), FPG (154.1 mg/dL, 115.4 mg/dL, 112.8 mg/dL, respectively; P <0.001), weight (79.9 Kg, 78.3 Kg, 76.9 Kg, respectively; P <0.001), BMI (29.1 Kg/m2, 28.5 Kg/m2, 28.1Kg/m2, respectively; P <0.001), SBP (140.2 mmHg, 129.1 mmHg, 125.3 mmHg, respectively; P <0.001) and DBP (84.7 mmHg, 79.5 mmHg, 76 mmHg, respectively; P <0.001). However, no significant reductions from baseline to 6 and 12 months were observed in LDL-C (2.7 mmol/L, 2.8 mmol/L, 2.7 mmol/L, respectively; P =0.702), HDL-C (1.2 mmol/L, 1.2 mmol/L, 1.3 mmol/L, respectively; P =0.551), TG (1.6 mmol/L, 1.7 mmol/L, 1.7 mmol/L, respectively; P =0.728), and TC (4.3 mmol/L, 4.3 mmol/L, 4.1 mmol/L, respectively; P =0.101). The most prevalent three DRPs identified were lack of understanding of the medication (39.8%), inappropriate dose, form, schedule, route, or method of administration (17.3%), and actual and potential adverse events (14.3%).
Conclusion: The provision of CPCS in a primary healthcare setting in Qatar improves clinical outcomes in patients with diabetes over a 12-month follow-up period. Future studies are needed to determine the long-term outcomes of CPCS.
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Does Weight Loss Through Means of Bariatric Surgery Reduce the Risk of Type 2 Diabetes in Obese Qatari Patient a Retrospective Analysis
Background: The use of bariatric surgeries such as Gastric Bypass and Sleeve Gastrectomy in managing obesity and associated diseases such as type 2 diabetes mellitus (T2DM) has been induced in clinical practice. Weight reduction through means of bariatric surgery has metabolic benefits and may improve the management of T2DM. Objectives: The aim of this study was to investigate if weight loss through bariatric surgery can reduce the risk of T2DM in patients without the onset of T2DM. Study design: A retrospective analysis was conducted on post-bariatric patients at the department of bariatric and metabolic surgery at Hamad General Hospital. Methods: Tow hundred and two eligible pre-diabetic Qatari patients who have undergone bariatric surgery in 2016 and satisfied the inclusion and exclusion criteria of the study were analyzed. Data on Glucose, Insulin and C-peptides levels at baseline and follow-up were extracted in order to compare the change of these variables at baseline, 6 and 10 months follow up before and after 10 months from the date of surgery. Results: Seventy one males with mean age of 32.73 ± 10.37 and one hundred and thirty one females with mean age of 33.90 ± 9.88 were included in the analysis. Change in weight was strongly and positively associated with change in insulin level (0.701, 95% CI: 0.027, 1.347, p = 0.042) also, as weight changes fasting glucose changes (1.993, 95% CI: 0.359, 3.627, p = 0.017). Follow-up period greater than 6 months was not found to be significantly associated with weight loss (2.049, 95% CI: − 2.249, 6.349, p = 0.313). Conclusion: Our study confirms results from international studies that weight loss through bariatric surgery can reduce the risk of developing Type 2 Diabetes Qatari obese patients. The results of the study suggest that post-surgery periods can be detrimental to the fate of fasting glucose and insulin levels and therefore compliance maybe of great importance to ensure success and sustainability of weight loss and diabetes prevention. Larger samples size and longer follow-up period is required to confirm these findings.
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Utilization of Date Pits in the Production of Functional Chocolates
Authors: Syed Zamzam, Eisha Rajab Nafiea, Huda Ahmed Al-hadhromi and Fida Anamangadan AliBackground: World production of dates was almost 9 million tons by 2010, with almost 960 thousand tons of date pits being discarded. This huge amount of waste has shown to be a rich source of carbohydrate, fiber, protein, fat, antioxidant, phenolic, and minerals like potassium, phosphorus, and magnesium. Not only is it an excellent source of nutrients, but has also shown to have health benefits such as reducing the side effects of certain therapeutic drugs, and otherfunctional uses, like used as a coffee substitute for a caffeine free drink. Like date pits, chocolate is a natural functional food which has shown to have a favorable effect on human health especially on the cardiovascular disease and it is one of the most consumed food among all age groups.Objectives: The main objective of this study is utilize date pits as an additive to chocolate and produce improved functional food product and evaluate its sensory features.Method: Commercial date pit powder, dark chocolate, and milk chocolate was purchased from local Qatari markets. The commercial powder was further grinded using a regular household blender and sieved into 300 and 150 μm using electronic sieve. The developed products had varying percentage of date pit powder: chocolate ratio (1:9, 3:7, 5:5 and 7:3). The chocolate products cross-section was observed under microscope, sensory analysis for 8 attributes and thenutrient content for each product was done using USDA food composition tables and food label of the commercial date pits purchased from Deyma.Results: Dark and milk chocolate with 150 μm date pits, (1:9) ratio had the highest homogeneity under the microscope. The quality test for functional chocolates of 1:9 and 3:7 ratio made with 150 μm rated as very good but 5:5 and 7:3 required lots of improvement. Sensory evaluation and hedonic test showed that dark chocolates made with 150 μm date pits was the most liked products. Finally, the calories and the fat content decreased as the date pits concentration increased.
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GameBased NonWeight Bearing Exercise to Improve Postural Balance in Diabetic Patients Underjoining Hemodialysis
Authors: He Zhou, Rania Ibrahim, Abdullah Hamad, Talal Talal, Fadwa Al-Ali and Bijan NajafiBackground: Poor balance, falls, and foot problems are serious detriments for the diabetic patients due to the obesity and diabetic foot ulcer. In addition, for the diabetic patients undergoing hemodialysis (HD) treatment, the HD process often leaves them too fatigued to engage in any physical activity or daily exercise, further deteriorating their motor functions and increasing risk of falling. Exercise would be effective for this population. However, due to the time availability, post-dialysis fatigue, as well as limitation of transportation to exercise facility, the conventional exercise for this population is impractical. Objective: We are developing an interactive foot and ankle exercise game that can be played during HD sessions to improve foot region blood flow, as well as reduce foot problems. In this study, we examined the feasibility and effectiveness of this innovative wearable sensor based non-weight bearing exercise (Exergame) to improve postural balance in diabetic patients undergoing HD treatment. Methods: Sixty diabetic subjects receiving HD treatment were recruited and randomized into an intervention group (IG: n = 29, age = 63.3 ± 7.9 years, BMI = 31.2 ± 6.5 kg/m2, female = 41%) and a control group (CG: n = 31, age = 66.5 ± 10.7 years, BMI = 32.3 ± 8.2 kg/m2, female = 55%). Both groups underwent a 4-week ankle and foot exercise program (30 minutes per session, two sessions per week) during HD process. The IG received exercise via the Exergame program, which uses wearable sensors attached on subject's feet. The subject's 3-dementional ankle and foot movements were visualized in real-time on a computer screen placed in front of him/her. The subject performed some game-like tasks by moving and rotating the foot and ankle. The difficulty level of the task was gradually increased depending on ability of the subject (like a game) from a simple flexion-extension movement to more complex movements including medial-lateral movement with different range of motion. The CG received traditional foot and ankle exercise without any technology. Postural balance was assessed in the semi-tandem test. Balance tests were performed at baseline and conclusion of the program, under both eyes-open and eyes-closed conditions. Balance parameters included ankle sway and hip sway in anterior-posterior (AP) direction (degree), medial-lateral (ML) direction (degree), as well as in area (degree2). Results: All IG subjects achieved to complete all exercise tasks indicating the feasibility of the Exergame platform. No adverse event or difficulty were reported indicating practicality of the exercise program. None subject in the IG was dropped out during the 4-week exercise program. Low dropout rate may indicate acceptability of the proposed Exergame platform. Under eyes-open condition, the IG had significant ankle sway reduction in the AP direction (Cohens’ d effect size = 0.55, p = 0.037), when comparing with the CG. At conclusion, the AP direction ankle sway reduced 18% in the IG, while in the CG it increased 58%. More significant improvements of postural balance were observed under eyes-closed condition. When comparing with the CG, the IG had significant ankle and hip sway reductions in both AP and ML directions, as well as in area (p < 0.050). The highest effect size contrasting changes between the IG and CG was also observed for ankle sway in ML direction (Cohens’ d effect size = 0.76, p = 0.005). Conclusions: This study demonstrated feasibility, acceptability, and effectiveness of an innovative Exergame program to improve postural balance in diabetic patients undergoing HD treatment. The key innovation of the proposed intervention is its practicality to be done during HD process, which could address the limitations of prior exercise interventions in HD patients, for example the low adherence of therapeutic exercise.
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Exergame: A Gamelike Exercise to Improve Motor Functions and Physical Activities in Diabetic Patients Undergoing Hemodialysis
Authors: He Zhou, Rania Ibrahim, Abdullah Hamad, Talal Talal, Fadwa Al-Ali and Bijan NajafiBackground: Balance, mobility, falls, and foot problems are serious detriments for the diabetic patients undergoing hemodialysis (HD) treatment. In addition, the HD process often leaves them too fatigued to engage in any physical activity or daily exercise, further deteriorating their motor functions. Exercise would be effective for this population. However, due to the time availability, post-dialysis fatigue, as well as limitation of transportation to exercise facility, the conventional exercise is impractical. Objective: We are developing an interactive foot and ankle exercise game that can be played during HD sessions to improve mobility and balance, as well as reduce foot problems. In this study, we examined the feasibility and effectiveness of this innovative wearable sensor based non-weight bearing exercise (Exergame) to improve daily physical activity in diabetic patients undergoing HD treatment. Methods: Thirty-three diabetic subjects receiving HD treatment were recruited and randomized into an intervention group (IG: n = 15, age = 62.2 ± 7.6 years, BMI = 29.1 ± 6.1 kg/m2) and a control group (CG: n = 18, age = 66.6 ± 8.7 years, BMI = 32.5 ± 9.0 kg/m2). Both groups underwent a 4-week ankle and foot exercise program (30 minutes per session, two sessions per week) during HD process. The IG received exercise via the Exergame program, which uses wearable sensors attached on subject's feet. The subject's 3-dementional ankle and foot movements were visualized in real-time on a computer screen placed in front of him/her. The subject played some game-like tasks by moving and rotating the foot and ankle. The difficulty level of the task was gradually increased depends on ability of the subject (like a game) from a simple flexion-extension movement to more complex movements including medial-lateral movement with different range of motion. The CG received traditional foot and ankle exercise without technology. Daily physical activity data was assessed for 48 hours (day and night) at baseline and post 4-week exercise, using a validated wearable sensor (PAMSysTM). Daily physical activity was quantified by duration spent in each main posture (i.e. lying, sitting, standing, and walking) and activities (e.g. postural transition, sedentary behavior, etc). Results: All IG subjects achieved to complete all exercise tasks indicating the feasibility of the Exergame platform. No adverse event or difficulty were reported indicating practicality of the exercise program. None subject in the IG was dropped out during the 4-week exercise program. Low dropout rate may indicate acceptability of the proposed Exergame platform. At the end of intervention, subjects in the IG were more active than subjects in the CG. In summary, the IG performed 53% more posture transitions to walking (Cohen's d effect size = 0.5) and 39% more posture transitions between sitting and walking (d = 0.5), when compared to the CG. Subjects in the IG also had significant less sedentary behavior than subjects in the CG. In summary, subjects in the IG spent 5% less time on sitting and lying (p = 0.049, d = 0.7), as well as 47% more time on standing and walking (p = 0.049, d = 0.7), when compared to subjects in the CG. Conclusions: This study demonstrated feasibility, acceptability, and effectiveness of an innovative Exergame program to improve daily physical activity in diabetic patients undergoing HD treatment. The key innovation of the proposed intervention is its practicality to be done during HD process, which could address the limitations of prior exercise interventions in HD patients, for example the low adherence of therapeutic exercise. Further studies should be addressed to confirm the observation with larger sample sizes.
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The epigenetic response to disease and environmental challenges: a deep multiomics phenotyping view
More LessEpigenetic regulation of human cellular functions allows temporal adaptation to changes in health, lifestyle and environment. Complex diseases and exposure to environmental challenges may lead to adjustments of the expression of certain enzymes, transporters, and metabolic regulator genes (1). The response to such challenges by adjustment of gene expression may be reflected through changes in the DNA methylome (2). A recent metabolomics epigenome wide association study showed that the methylation states of certain DNA cytosine-guanine (CpG) pairs are strongly associated with blood metabolite levels (3). Interestingly these metabolomics associated CpG sites are also associated with a related complex trait falling in one of two major groups, the first being disease driven i.e. diabetes and/or obesity that also associate with liver function or blood pressure, and the second being environmentally driven i.e. smoking. We performed deep molecular phenotyping covering approximately 4000 traits in blood, urine and salivary samples from a diverse population of 359 individuals from the Qatar Metabolomics Study of Diabetes (QMDiab), using array-based DNA genotyping and methylomics, NMR based lipidomics, mass-spectrometry based metabolomics, aptamer based blood-circulating proteomics, and total plasma protein N- and IgG-glycomics. We confirmed the established smoking and diabetes associations in QMDiab and identified novel multi-omics associations at these sites. In particular, we identified deep molecular phenotypes that are characteristic for the TXNIP-diabetes and the AHRR-smoking associations, including diabetes and smoking associated metabolites such as 1,5-anhydroglucitol (1,5-AG) and o-cresol sulfate respectively, diabetes and smoking associated proteins such as Sex hormone-binding globulin (SHBG) and Polymeric immunoglobulin receptor (PIGR) respectively, and diabetes and smoking associated glycans. We also replicated some of the novel associations, particularly the proteomics and glycomics associations, in two independent studies (KORA and TwinsUK). These observations show an interesting overlap between DNA methylation and pathways relevant to complex disorders and environmental challenges. We also addressed the direction of that involvement in this study. Motivated by a recent obesity Mendelian randomization study (4) that showed a causal effect of adiposity on the methylation levels of multiple CpG sites near obesity-related genes, we used Mendelian randomization to test the direction of association between the metabolite and methylation levels of selected obesity associated CpG sites in KORA. In line with that study, we also found a causal effect of metabolite levels on methylation of the given CpG sites, i.e. glycerophospholipid PC(O-36:5), glycine, and a very low density lipoprotein A (VLDL-A) on the methylation of the DHCR24, MYO5C, and CPT1A loci, respectively. The overlap of disease- and lifestyle-associated CpG sites with metabolite-associated CpG sites suggests that the organismal adjustment to disease or environmental challenges can be captured by measuring relevant intermediate molecular phenotypes (multi-omics) (5). Taken together, this study supports the hypothesis that multi-omics-associated CpG methylation can serve as a functional readout of the organism's response to the challenges induced by disease or environmental stress, serve as novel functional diagnostic and prognostic biomarkers, and indicate potential targets for therapeutic intervention.
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Development of Novel Diagnostic and Therapeutic Tools for Parkinson's Diseases and Related Disorders
Authors: Nour Majbour, Muneera Fayyad, Mercy Thomas, Nishant Vaikath and Omar El-AgnafParkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease. The biggest roadblock we are facing for the cure of PD is the lack of reliable biomarkers for the disease diagnosis or progression. This is a problem, not only from a clinical standpoint, but also because it affects the integrity of clinical trials and epidemiological research. Thus, the development of simple diagnostic tests to aid the clinical diagnosis of PD and other neurodegenerative diseases is of great importance. PD is characterized with a long preclinical phase that might serve as a window for early therapeutic intervention once disease-modifying therapies are available, however, the lack of reliable biomarkers for PD diagnosis and progression represents a major obstacle to achievement of this goal. One of the most prominent pathological features of most neurodegenerative diseases is the deposition of specific protein aggregates in neuronal or glia cells. In PD, such deposits are named Lewy bodies (LBs) and Lewy neuritis (LNs), the pathological hallmarks of PD, in which α-syn is the main constituent. α-Syn is 140 amino acid, a pre-synaptic neuronal protein and its aggregation and dysfunction is linked to a number of neurodegenerative disorders, named Synucleinopathies. PD, dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) all fall under the umbrella of Synucleinopathies. The aggregation of α-syn starts long before the onset of the clinical symptoms and continues to spread throughout the brain as the disease progresses, making these aggregates strong candidates for biomarkers development. α-Syn is subjected to several post-translational modifications (PTMs) such as phosphorylation, oxidation, nitrosylation, truncation and ubiquitination. However, whether these PTMs act to enhance or halt α-syn neurotoxicity remains poorly understood. Biochemical examination of LBs revealed the presence of full-length α-syn as well as different species of truncated α-syn. Truncated α-syn was found in the brains of patients as well as the brains of healthy subjects, suggesting that α-syn truncation takes place even under normal physiological conditions. A marked difference, however, in the amount of truncated α-syn in synucleinopathies’ patients was noted compared to control subjects. Truncated α-syn was also found to be abundant in the brains of PD and DLB patients, suggesting that truncated α-syn may play a normal physiological role as well as a pathological one. Our group has succeeded to develop several highly specific antibodies that were explored for diagnostic and therapeutic purposes. Here in this project, we describe the characterization and applications of our novel conformation-specific mouse monoclonal antibodies against different truncations of α-syn as diagnostic and therapeutic tools for synucleinopathies. The specificity and sensitivity of our antibodies were thoroughly assessed by an array of biochemical methods including slot blotting, western blotting, ELISA and immunohistochemical analysis in parallel with commercially available antibodies. Next, we explored the potential of these novel tools in biological samples (brain tissues and biofluids) from patients with different synucleinopathies. Our antibodies exhibited a specificity towards different conformations of α-syn that none of their commercial peers did. Our novel antibodies also stained a pathology in human brain tissues that was not captured by gold standard antibodies for Immunostaining of α-syn pathologies. Our antibodies are not only valuable for the discovery of ideal biomarkers but also for a better understanding of the underlying pathophysiological process in PD and related disorders.
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The Cellular Interplay Between CD44 and Na+/H+ Exchanger1 in Cardiac Remodeling
Authors: Fatima Mraiche, Muna Suleiman, Nabeel Abdulrahman and Jensa JosephBackground: Extracellular matrix (ECM) remodeling is a characteristic feature of cardiac remodeling which, if left untreated, progresses to heart failure. Cardiac fibroblasts, the major cellular component of the myocardium, are responsible for maintaining the ECM integrity. Upon cardiac injury, such as myocardial infarction (MI), pressure or volume overload, cardiac fibroblasts transdifferentiate into cardiac myofibroblasts. Cardiac myofibroblasts are capable, of secreting proinflammatory cytokines and collagen; initiating tissue repair mechanisms (i.e., cardiac fibrosis). Hyaluronan (HA), a major component of the ECM, which is synthesized by hyaluronan synthase enzyme-2 (HAS-2), was shown to contribute in ECM remodeling and myocardial fibrosis by interacting with its cell surface receptor; CD44. CD44 is a transmembrane glycoprotein involved in multiple physiological and pathological conditions. Na+/H+ exchanger isoform-1 (NHE-1) a cardiac specific intracellular pH regulator, which is triggered by neurohormonal stimulation of Angiotensin II (ANG II), phenylephrine (PE), endothelin-1 (ET-1) or inflammatory mediators has also been implicated in cardiac remodeling. A previous study has shown that HA-CD44 interaction enhanced ECM remodeling in a non-cardiac model through activation of NHE-1 and hyaluronidase-2 (HYAL-2), a low pH-dependent enzyme which degrades hyaluronan polymers into lower molecular weight fragments. Yet, the link between NHE-1 and CD44 interaction in cardiac setting has not been addressed.Methods: CD44 expression was measured by qPCR and immunohistochemistry in transgenic mice expressing cardiac specific NHE-1. In vitro, normal human ventricular cardiac fibroblasts (NHCF-V) were treated with either 0.1 or 1 μM ANG II for 6, 24 or 48 hours to induce myofibroblast phenotype. Cell lysates and culture media were collected and analyzed by immunoblotting. Standard CD44 (CD44s), soluble CD44 (solCD44), unmodified CD44, HYAL-2 and HAS-2 protein expression were measured following ANG II treatment.Results: mRNA expression and immunohistochemistry data demonstrated that CD44 expressions were significantly elevated in heart tissues from transgenic mice expressing cardiac specific NHE-1 compared to wild type. Immunoblotting analysis of NHCF-V cell lysates showed a significant increase of CD44s protein expression, appearing at 75 KDa, following 0.1 μM ANG II treatment for 24 hours (131.14 ± 3.18 % ANG II vs. 100% control; P ≤ 0.01). CD44s protein expression did not show a change at 6-hour or 48-hour time point. Unmodified CD44, appearing at 37 kDa, HAYL-2 and HAS-2 protein expressions did not change following stimulation with various concentrations of ANG II at various time points. However, a trend towards increase was observed with solCD44 protein expression, appearing at 75 kDa, in NHCF-V conditioned media (CM) following 24-hour treatment with both 0.1 and 1 μM ANG II. A similar trend was observed with HYAL-2 protein expression in NHCF-V CM following 24-hour treatment with 1 μM ANG II, whereas there was no observed protein expression for HAS-2 and the unmodified form of CD44. Conclusion: ANG II, a well-established stimulator of NHE-1, is able stimulate the CD44s in NHCF-V cell lysates. Similarly, a trend towards increase of solCD44 expression was demonstrated in NHCF-V CM when treated with ANG II. This maybe due to the expression of CD44 in the extracellular space. HYAL-2 protein was also expressed in NHCF-V CM, while no change was detected in cell lysates. The protein and gene expressions of CD44, HYAL-2 and HAS-2 in the presence and absence of a NHE-1 inhibitor and ANG II type 1 receptor (AT-1) inhibitor remain unknown and need to be addressed to further understand the cellular interplay of NHE1 and CD44 in cardiac remodeling. It is of a significant importance to identify the signaling pathways leading to CD44 activation for better understanding of etiologies behind cardiac remodeling; and to find new potential targets that would suppress or regress the progression to myocardial dysfunction and heart failure.
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Engineering antibodies for diagnostic and therapeutic approaches in neurodegenerative diseases
By Ahmad NajjarEngineering antibodies for diagnostic and therapeutic approaches in neurodegenerative diseasesA. Najjar1, N.N. Vaikath2, I, Hmila2, Nour Majbour2, O. El-Agnaf11Life Sciences Division, College of Science and Engineering, Hamad Bin Khalifa University (HBKU), Education City, Qatar Foundation, PO Box 5825, Doha, Qatar2Neurological Disorders Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, PO Box 5825, Doha, Qatar.Neurodegenerative diseases affect millions of people worldwide, with Parkinson’s disease (PD) ranked as the second most common age-related neurodegenerative disorder affecting over 1 million people in the United States alone. Common neurodegenerative diseases such as PD, Dementia with Lewy Bodies (DLB) and Multiple System Atrophy (MSA) are characterised by progressive deposition of α-synuclein (α-syn) protein within inclusions referred to as Lewy bodies and glial cytoplasmic inclusions respectively. This has led to classifying these diseases under the umbrella term Synucleinopathies due to the pathological accumulation of this protein. The various diseases vary in where the protein is deposited and which regions in the brain become affected.α-Syn is a relatively small protein constituting 140 amino acid residues having an unfolded native state. α-Syn aggregation occurs in a stepwise manner where monomers lead to transient oligomers, which ultimately lead to proto and mature fibrils within neurons. Such accumulation seems to target dopaminergic neurons located in the substantia nigra pars compacta. Current treatment such as Deep Brain Stimulation (DBS) and L-dopa (the precursor for dopamine) does not focus on slowing disease progression; rather it focuses on symptomatic relief.Amongst the various approaches attempting to tackle the pathological features of synucleinopathies, immunotherapy holds much promise. α-Syn antibodies could potentially block processes leading to the pathogenesis of such neurodegenerative diseases. The limitation of such antibodies is their inefficiency in crossing the Blood-Brain Barrier. The aim of our project focuses on using a fusion protein engineered to include the FAB region of an existing antibody, which is confirmation specific to α-syn pathology. This single-chain-fragment-variable is designed to have increased BBB penetration by virtue of its smaller size and its conjugation with a carrier. It is envisaged that with enhanced penetration there will be superior brain targeting results compared to conventional α-syn antibodies. Upon expression and purification of α-syn and various designs of the fusion protein, the two proteins will be extensively characterized by means of Dot Blots, ELISA assays and affinity experiments. Neuronal cell lines and primary neurons from rat or mice will be employed to test our fusion protein in vitro. This will ultimately be done using immunocytochemistry techniques. For in-vivo experiments, the fusion protein will be tested on transgenic mice overexpressing α-syn.The outcomes of this project are threefold. If successful, the fusion protein could be useful in passive immunization of Synucleinopathies, finding its use as a clinical diagnostic tool for such diseases. Further manipulation of the fusion protein, namely attachment of a Fluoro-radiolabelled isotope can be used for imaging using positron emission tomography (PET). This would allow for its use in medical imaging to track α-syn pathology in PD, DLB and MSA patients.
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Generation and Charactarization of Mouse Monoclonal Antibodies Against Phosphorylated Alphasynuclein at Serine 129
More LessGeneration and Charactarization of Mouse Monoclonal Antibodies Against Phosphorylated Alpha-synuclein at Serine 129. Author and co-authors> details: Heba Al- Tarawneh1, Muneera Fayyad2, Nishant Vaikath3, Nour Majbour3, and Omar M. A. El-Agnaf2,3 1Weill Cornell Medical College in Qatar, Education City, Qatar. 2Life Sciences Division, College of Science and Engineering, Hamad Bin Khalifa University (HBKU), Education City, Qatar Foundation, PO Box 5825, Doha, Qatar 3Neurological Disorders Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, PO Box 5825, Doha, Qatar. Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer>s disease and one of the leading causes of disability worldwide. It manifests itself through several clinical symptoms, with the most prominent being motor impairment, resting tremors, rigidity and bradykinesia. PD is mainly characterized by a progressive degeneration of dopaminergic neurons in a region within the midbrain known as the Substantia Nigra. The major pathological hallmark of Parkinson’s disease is the appearance of proteinaceous inclusions known as Lewy bodies (LBs) and Lewy neurites (LNs). These depositions are largely composed of a small 140-amino acid protein called alpha synuclein (α-syn). In fact, aggregation of α-syn has been implicated in a number of neurodegenerative diseases, collectively termed synucleinopathies. These include PD, Dementia with Lewy bodies and multiple system atrophy. Given the central role of α-syn in PD and related disorders, extensive efforts have been devoted in investigating the mechanisms that may regulate the aggregation and toxicity of this protein. In the last decade, an increasing number of studies has indicated that while only a small fraction of α-syn (<4%) is phosphorylated in healthy brains, the majority of α-syn within LBs was found to be phosphorylated at Serine 129 (>90%), raising the possibility that phosphorylation may play an active role in α-syn aggregation. However, findings are contradictory and this hypothesis remains unclear. To date, there are no diagnostic tools that enable early detection of PD. The only Confirmed diagnosis is based on clinical criteria, which are preceded by a prolonged phase of neurodegeneration and an irreversible loss of dopaminergic neurons. This has driven several studies to explore α-syn as a candidate biomarker for PD. Given the strong association of pS129-α-syn with LB pathology, measuring levels of pS129-α-syn in biological samples could serve as a potential biomarker for diagnosis of PD. In this study, we describe the generation and characterization of three mouse monoclonal antibodies (5B9, 6H5, and 9G1) that are specific for pS129 α-syn. These were generated using hybridoma technology and purified by protein-G agarose chromatography. Using a wide range of biochemical assays, we demonstrated the specificity of our new antibodies to pS129 α-syn. This highlights that our highly specific antibodies represent excellent research tools to investigate the role of α-syn phosphorylation in LB pathology. Moreover, our antibodies can be used to develop different quantitative and qualitative immunoassays. Also our antibodies can help answer whether phosphorylation at S129 suppresses or enhances α-syn aggregation and toxicity, which is crucial for the understanding of synucleinopathies pathogenesis and thus the development of new disease-modifying therapies for PD and related disorders.
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Projecting the Burden of Type 2 Diabetes Mellitus in Qatar: Analytical Insights
Authors: Susanne F. Awad, Martin O'Flaherty, Julia Critchley and Laith J. Abu-RaddadBackground: Extracellular matrix (ECM) remodeling is a characteristic feature of cardiac remodeling which, if left untreated, progresses to heart failure. Cardiac fibroblasts, the major cellular component of the myocardium, are responsible for maintaining the ECM integrity. Upon cardiac injury, such as myocardial infarction (MI), pressure or volume overload, cardiac fibroblasts transdifferentiate into cardiac myofibroblasts. Cardiac myofibroblasts are capable, of secreting proinflammatory cytokines and collagen; initiating tissue repair mechanisms (i.e., cardiac fibrosis). Hyaluronan (HA), a major component of the ECM, which is synthesized by hyaluronan synthase enzyme-2 (HAS-2), was shown to contribute in ECM remodeling and myocardial fibrosis by interacting with its cell surface receptor; CD44. CD44 is a transmembrane glycoprotein involved in multiple physiological and pathological conditions. Na+/H+ exchanger isoform-1 (NHE-1) a cardiac specific intracellular pH regulator, which is triggered by neurohormonal stimulation of Angiotensin II (ANG II), phenylephrine (PE), endothelin-1 (ET-1) or inflammatory mediators has also been implicated in cardiac remodeling. A previous study has shown that HA-CD44 interaction enhanced ECM remodeling in a non-cardiac model through activation of NHE-1 and hyaluronidase-2 (HYAL-2), a low pH-dependent enzyme which degrades hyaluronan polymers into lower molecular weight fragments. Yet, the link between NHE-1 and CD44 interaction in cardiac setting has not been addressed.Methods: CD44 expression was measured by qPCR and immunohistochemistry in transgenic mice expressing cardiac specific NHE-1. In vitro, normal human ventricular cardiac fibroblasts (NHCF-V) were treated with either 0.1 or 1 μM ANG II for 6, 24 or 48 hours to induce myofibroblast phenotype. Cell lysates and culture media were collected and analyzed by immunoblotting. Standard CD44 (CD44s), soluble CD44 (solCD44), unmodified CD44, HYAL-2 and HAS-2 protein expression were measured following ANG II treatment.Results: mRNA expression and immunohistochemistry data demonstrated that CD44 expressions were significantly elevated in heart tissues from transgenic mice expressing cardiac specific NHE-1 compared to wild type. Immunoblotting analysis of NHCF-V cell lysates showed a significant increase of CD44s protein expression, appearing at 75 KDa, following 0.1 μM ANG II treatment for 24 hours (131.14 ± 3.18 % ANG II vs. 100% control; P ≤ 0.01). CD44s protein expression did not show a change at 6-hour or 48-hour time point. Unmodified CD44, appearing at 37 kDa, HAYL-2 and HAS-2 protein expressions did not change following stimulation with various concentrations of ANG II at various time points. However, a trend towards increase was observed with solCD44 protein expression, appearing at 75 kDa, in NHCF-V conditioned media (CM) following 24-hour treatment with both 0.1 and 1 μM ANG II. A similar trend was observed with HYAL-2 protein expression in NHCF-V CM following 24-hour treatment with 1 μM ANG II, whereas there was no observed protein expression for HAS-2 and the unmodified form of CD44. Conclusion: ANG II, a well-established stimulator of NHE-1, is able stimulate the CD44s in NHCF-V cell lysates. Similarly, a trend towards increase of solCD44 expression was demonstrated in NHCF-V CM when treated with ANG II. This maybe due to the expression of CD44 in the extracellular space. HYAL-2 protein was also expressed in NHCF-V CM, while no change was detected in cell lysates. The protein and gene expressions of CD44, HYAL-2 and HAS-2 in the presence and absence of a NHE-1 inhibitor and ANG II type 1 receptor (AT-1) inhibitor remain unknown and need to be addressed to further understand the cellular interplay of NHE1 and CD44 in cardiac remodeling. It is of a significant importance to identify the signaling pathways leading to CD44 activation for better understanding of etiologies behind cardiac remodeling; and to find new potential targets that would suppress or regress the progression to myocardial dysfunction and heart failure.
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Nutritional Value of Kid's Meal offered by International Fast Food Restaurants in Qatar
More LessBackground The nutritional content of kid's meal in Qatar has often been overlooked. In our efforts to reach out to children of Qatar, their nutritional intake could be a nice place to start. The objectives of this study are to assess nutritional value of kid's meal offered by some international fast food restaurants in Qatar and to determine density of international fast food restaurant offering kid's meal by municipality areas. Methods We selected 6 international fast food restaurants that offer kid's meals and the density of these restaurants by kids' population aged 1-9 years old in Qatar. The selected fast food restaurants were McDonald's, Burger king, KFC, Hardee's, Papa john's, and DQ Grill & Chill. We assessed the number of branches of the restaurants using phone applications zomato and talabat. These applications allow the user to know the location and the numbers of branches in different municipality areas. We used also the official restaurants websites to collect data of the nutrient content of kids' meals offered by the 6-international restaurant in Qatar. Moreover, we used GPS to make sure of the location and the number of these restaurants. The entire restaurant offered 4 combinations of kid's meals except Papa John's offered 4 meals. We selected from each restaurant chain 25% of the total branches available in Qatar. During our visit, we asked for nutrition fact table of meals offered for kid's. Only McDonald's provide nutrition fact with meals for all customers. The other restaurants provide it only on websites or management department. We calculated the density by dividing the number of international fast food over the total children population aged 1-9 years old multiplying by 1000. SPSS and ANOVA (at p < 0.05) were used to analysis data. Results McDonald»s has the highest number of outlets which represent 41 out of 133 international fast food outlets offering kids meals and the DQ grill and chill had the lowest number of outlet which represent 5 out of 133. The average nutrients content of 23 kid»s meal offered by international fast food restaurants in Qatar was 653.30 ± 31.5 calories for calories contents, 21.61 ± 10.24 g for protein content, 28.32 ± 9.07 g for fat content, 84.57 ± 19.22 g for CHO content, 4.40 ± 2.79 g for fiber content and 968 ± 372.31 mg for sodium content. The percentage of covering the RDA calories recommendation of children aged 1-9 years old by 23 kid»s meals offered by six international fast food in Qatar was 47.8 ± 0.02% for calories, 134.6 ± 0.13% for protein, 58.9 ± 0.04% for fat, 63.6 ± 0.03% for CHO, 20.2 ± 0.03% for fiber and 91.4 ± 0.08% for sodium. In general, international fast food kid's meals are rich in carbohydrates, fat, protein, sodium and low in fiber. Conclusion Nowadays children are eating foods prepared outside the home more frequently than ever; improving the nutritional quality of food items offered at fast-food restaurants can contribute to important gains in population health. In this study, we found that fast food meals are nutritionally inadequate and its regular consumption is associated with excess intake of calories, fat, sodium, protein, carbohydrate, and low fiber intake.
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Reducing Heart Failure Admissions through Improved Care Systems and Processes
More LessHeart failure (HF) is a complex chronic condition that can result from any cardiac disorder that impairs the ventricle's ability to fill with or eject blood. The American Heart Association predicts that there will be about 10 million HF patients in the US by 2037, with total hospitalization costs exceeding $70 billion. This represents a considerable burden to hospitals nationwide, including the Massachusetts General Hospital (MGH) – a leading medical center that has long grappled with patient overcrowding and capacity constraints. This research project covers an extensive mapping of the HF care pathway at MGH, followed by the results of a detailed retrospective analysis of the general behavior of HF patients admitted to MGH. We notice that the majority of HF admissions originate as self-referrals via the Emergency Department (ED) and take place on weekdays, between the hours of 9am and 6pm. Moreover, we find that about 57% of hospitalized HF patients often have no scheduled follow-up appointments with their providers in the two weeks leading up to their admissions and, similarly, about 43% have no scheduled appointments in the eight weeks post hospital discharge. These represent two critical time periods in the events of acute heart failure decompensation. In an effort to prioritize targeted outpatient care, we propose a predictive model which aims to identify patients at greatest risk of a first hospital admission following encounters with their primary care providers and/or cardiologists in any given year. We perform logit-linear regressions on multiple prior first admissions and use predictors that, among others, include clinical risk factors, socioeconomic features and histories of prior medications. Some of the model's most significant predictors, as identified by the Akaike information criterion (AIC), include patient's age, marital status, ability to speak English, estimated average income, previous administration of loop diuretics, and the total number of medications prescribed or administered. To assess the quality of our predictions, we turn to the receiver operating characteristic (ROC) and its resulting average area under the curve (AUC) of 0.712. As the team continues to focus on developing interventions that offer better care to HF patients, the value of our model lies in its ability to prioritize patient needs for outpatient care and monitoring, and to guide the allocation of limited care resources.
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Implementation and feasibility study of a tailored health education bot in Telegram for mothers of children with obesity and overweight
Authors: Luis Fernandez-Luque, Abdelkader Lattab, Santiago Hors and MOHAMED AhmednaINTRODUCTION Obesity is one of the major health risk factors behind the rise of non-communicable conditions. Understanding the factors influencing obesity is very complex since there are many variables that can affect the health behaviors leading to it. Nowadays, multiple data sources can be used to study health behaviors, such as wearable sensors for physical activity and sleep, social media, mobile and health data. In this poster we describe a system which uses an off-the-shelf messaging app coupled with a recommender system to provide tailored health recommendations in arabic and/or english to mothers with overweight children in Qatar. This is part of the ICAN project. The ICAN project was funded by the Qatar National Research Fund (a member of Qatar Foundation) under project number NPRP X- 036- 3–013 (Adapted Cognitive Behavioral Approach to Addressing Overweight and Obesity among Qatari Youth). Childhood obesity is a growing epidemic, and with technological advancements, new tools can be used to monitor and analyze lifestyle factors leading to obesity, which in turn can help in timely health behavior modifications. In this paper we describe developed Telegram bot coupled with a recommender system to send educational messages using health recommendations. This bot allows automatic sending of messages that can be answered by the user. The answers can be ratings in a 1 to 5 star scale, or plain text, depending on the message. In a trial held in Qatar, an educational intervention for mothers using Telegram was carried out for a twelve-week period, which overlapped with the holy month of Ramadan and the school summer break. The goal was to keep the mothers motivated to actively work towards keeping their children healthy. Our nutritional advice took into account the religious month of Ramadan. METHODOLOGY We defined a pool of motivational messages for the mothers associated to different topics and challenges regarding the nutrition and physical activity of their children. The messages were created in English and Arabic language. A total of 24 keywords were defined. These keywords linked each message to features that define it (i.e. deals about vegetables, fats, religious quotes regarding healthy eating, healthy recipes, etc). A special set of 9 messages were specifically designed to be sent when users start the intervention. The answers to these messages define the initial user profile. Once an initial user profile is known, the user will start receiving messages on a weekly basis, one tailored message per week up to a maximum of 77 messages. Users can rate the messages based on their perceived usefulness. This feedback is stored in the user profile - user-keyword vector - so that the following messages that she receives contain keywords - message-keyword vector- that were included in previously rated messages. A total of 38 mothers, with children between 9 and 12 years old, joined the program to receive tailored messages across the entire summer based on their personal preferences. After each week, the system asked them whether they had completed the challenge, and their opinion about their difficulty, and usefulness. RESULTS During the 4 months of the intervention, about 500 messages were sent to the participants. The participants had a total of 94 challenges included in the messages that they could promise to accomplish. Of these, 11 challenges were totally completed, 42 challenges were almost completed, and 7 challenges had been given up by the mothers after they initially promised to do them. The data also shows that over 59 messages, only 17 were found easy to do, however 39 challenges were found ‘just fine’ to do. Over 59 challenges, 47 messages were found useful by mothers. CONCLUSIONS In this study we have tested the feasibility of a recommender system tailoring health messages delivered by an off-the-shelf messaging app as Telegram, and we consider the results show that the system achieved to rise some motivation from mothers to give a healthy diet to their children. However, further work is needed to assess how we can increase the engagement so that more of the proposed challenges are accepted, and completed, and also if to compare with groups of mothers that do not have the app in a formal randomized control trial.
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Development and characterization of monoclonal antibodies for Parkinson's Diseases and Related Disorders
More LessDevelopment and characterization of monoclonal antibodies for Parkinson’s Diseases and Related Disorders Najlaa Al-Thani1, Nour Majbour2, Muneera Fayyad3, N. Vaikath2, and Omar M. A. El-Agnaf2,3 1 Carnegie Mellon University in Qatar 2Neurological Disorders Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, PO Box 5825, Doha, Qatar. 3Life Sciences Division, College of Science and Engineering, Hamad Bin Khalifa University (HBKU), Education City, Qatar Foundation, PO Box 5825, Doha, Qatar Neurodegenerative diseases are the leading cause for disability in the world and one of the biggest burdens on our societies. Parkinson's Disease (PD) is the second most common neurodegenerative disease after Alzheimer's Disease (AD). PD is a chronic, progressive and irreversible disorder. The social and economic burden imposed by PD is significantly increasing as populations age. PD was first described by James Parkinson, an English physician, in his assay “Shaking Palsy” over 100 years ago. Although in less than a year PD will enter its next century, many aspects of the disease remain to be elucidated. PD can be sporadic or inherited, and in both cases it is accompanied by degeneration of dopaminergic neurons in the SN. Lewy bodies (LBs) and Lewy nurites (LNs) are the main pathological features of PD, where alpha-synuclein (α-syn) is the main component. α-Syn is a pre-synaptic neuronal protein and its aggregation and dysfunction is linked to a number of neurodegenerative disorders named as “synucleinopathies”. Synucleinopathies mainly refer to PD, dementia with Lewy bodies and multiple system atrophy. α-Syn is 140 amino-acid protein that is highly abundant in the brain and can also be found in red blood cells, plasma, cerebrospinal fluid (CSF) and saliva. The protein is natively unfolded, however, accumulating evidence indicate that enhanced oligomerization and aggregation of α-syn is associated with increased toxicity. Extensive efforts have been put into the elucidation of the mechanisms responsible for the polymerization and aggregation of α-syn. α-Syn undergoes several post-translational modifications such as phosphorylation, truncation or ubiquitination. A better understanding of the role of α-syn post-translational modifications will help to elucidate the exact role of α-syn in the pathogenesis of PD, paving the way to develop new diagnostic and therapeutic strategies for synucleinopathies. Truncated α-syn was found to be abundant in the brains of PD and DLB patients, suggesting that truncated α-syn may play a normal physiological role as well as a pathological one. C-terminal truncated α-syn as it exhibited a higher propensity to fibrilize in comparison with WT full length α-syn. In vitro studies that truncated α-syn specifically C-terminal residues 109-140 promoted aggregation presumably through nucleation formation. Antibodies that recognize both full length and c-terminally truncated a-synuclein are available, however, to study the role of c-terminally truncated a-synuclein in PD, specific antibodies are needed. In this project, we have generated and thoroughly characterized monoclonal antibodies against c-terminally truncated α-syn at Asn122. Following the selection of the stable clones, only the clones of IgG antibody were selected. All the clones were passaged multiple times to identify stable clones and subjected to single cell cloning to achieve monoclonality. The selected clones were cultured on a larger scale, mass culture, and the culture supernatant was then purified using Protein G affinity purification. The mAbs were highly selective for 122 α-syn, and didn't cross-react with 140 α-syn. The specificity and sensitivity of these antibodies were assessed by an array of biochemical methods including slot-blotting, western blotting, ELISA and immunohistochemical analysis. The potential of our antibodies can be explored as diagnostic or therapeutic tools for PD and related disorders.
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Development and Exploration of a Novel Personalized Cancer Vaccine Based on Virus-Like Particles (VLPs) by Incorporating Melanoma Specific T-cell Epitopes
Authors: Mona Omar Mohsen and Martin F. BachmannCancer Immunotherapy has significantly advanced cancer treatment modalities. However, therapeutic cancer vaccine aiming at reactivating anergic or dormant T cells has so far shown modest immune responses. VLPs have made notable strides in the last three decades in vaccine development field, mainly as prophylactic vaccines against VPV and HBV. The current project aims to design and build a multi-step platform for developing personalized therapeutic melanoma VLP-vaccine by integrating immunopeptidomics and exome sequencing approaches using melanoma patient-specific T-cell epitopes. To obtain a proof of concept in murine models, we have performed immunopeptidomics and exome sequencing for B16F10 melanoma cell line. The central goal of this platform (combining immunopeptidomics and exome sequencing) is to integrate the obtained data to develop a pipeline enabling the identification of mutated peptides which would constitute a promising cancer target for vaccine development. Our preliminary data of immunopeptidomics (alone) has shown large number of peptides which we have then prioritize and filter using bio-informatics and via probing with tumorinfiltrating lymphocytes (TILs). Peptides from immunopeptidomics were assessed for number of physical characteristics, such as their length and MHC-class I affinity as well as biological characteristics, such as being melanocyte specific, oncogenic or mutated. One of the key candidate was PMEL (gp100), a 100kDa type I transmembrane protein expressed in pigmented cells of skin and eye (tissue-specificity). A second promising candidate was MTC-1, an anti-oncogene that plays role in cell cycle regulation. If constitutively expressed, MTC-1 increases CDK4/6 kinases in breast cancer and promotes angiogenesis by inhibiting apoptosis. Furthermore, the selected peptides were synthesized and used to stimulate TILs to search for pre-existing immunity. TILs were labelled with CFSE and stimulated with the respective peptides (PMEL, MTC-1, no peptide or a mixture) and proliferation was assessed by determining CFSE dilution of CD8+ T-cells. Both peptides and -in particular the peptide mix- induced proliferation of T-cells, indicating that the transplanted tumor spontaneously induced T-cells against the respective epitopes. In the next step, we have prepared the vaccine using the bio-orthogonal copper-free click chemistry to couple the peptides of interest. Bio-orthogonal copper free click chemistry coupling method has shown efficacy, specificity and safety in our previous experiments. Bacteriophage Qb-VLPs were used and loaded with type-B CpGs which are known to be one of the most potent adjuvants in mice. The prepared vaccine cocktail was tested in C57BL/6 mice bearing B16F10 melanoma tumors with/without checkpoint inhibitors. Our preliminary results have shown significant regression in tumor size as well as significant production of IFN-g. We have also carried out extra analysis to characterize myeloid cells in the tumor microenvironment for each group to assess the effect of vaccination on myeloid cells in the tumor. The results indicated a notable decrease in TAMs characterized by (CD11b+/F4/80+ cells) in the group treated with vaccine+anti-PD1. This multi-step process can later be translated into the clinics and can be applied to other types of solid tumors. We are in the process of integrating exome sequencing data with immunopeptidomics aiming to identify mutated antigens which will increase the efficacy of the developed vaccine.
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