Qatar Foundation Annual Research Forum Volume 2013 Issue 1

AIMS Asymptomatic cardiac disease is present in a large proportion of individuals with generalised cardiovascular disease (CVD). Rural areas in Australia have a lack of health care services with the facilities to undertake a comprehensive community screening project. This study aimed to assess a nurse-led health screening initiative to determine the prevalence and incidence of asymptomatic heart disease using a custom ECG classification system. METHODS 508 people with and without a known history of cardiovascular disease were recruited through the local media and underwent a 12-lead ECG assessment. Using the ECG recordings, individuals were categorised into five classes based on necessity for review and treatment. RESULTS 14% of study participants reported an established history of CVD. 34% of attendees were identified as requiring referral to a general practitioner. These individuals underwent either by-pass surgery, commenced on cardiac medication or were advised on lifestyle changes. However, several more had their referral based on ECG assessment confirmed as appropriate but required no intervention. 4% of referrals were deemed not necessary by general practitioners. CONCLUSIONS The 12-lead ECG classification model as part of nurse-led CVD screening in a rural community, was shown to be a useful guide for referral of individuals to general practitioners for follow up. This model has the potential to improve quality of life by appropriate early referral to primary care practitioners, for follow-up.

Objectives: Underlying coronary artery disease (CAD) is an established risk factor for the development of Atrial Fibrillation (AF). How underlying CAD affects symptoms and outcome of patients presenting with AF remains unknown. The aim of the current study was to evaluate how patients with established CAD as evidenced by a history of old myocardial infarction (OMI) differ in symptoms and outcome when hospitalized with AF in a real-world population. Methods: Retrospective analysis of prospective registry of all patients hospitalized with AF in Qatar from 1991 through 2010 was made. Patients were divided into two groups according to history of OMI on presentation. Clinical characteristics, symptoms of presentation and outcome were analyzed. Results: During the 20-years period, 3850 patients were hospitalized for AF; 417 (10.8%) had OMI on presentation while 3433 (89.2%) had no OMI. OMI patients were 11 years older, had more prevalence of hypertension, diabetes mellitus, dyslipidemia, chronic kidney disease and had lower mean left ventricular ejection fraction on echocardiography (all, P value =0.001). Patients with OMI were significantly less likely to present with palpitations (25.7% versus 47.1%) and more likely to present with shortness of breath (36.9% vs. 26.7%) and chest pain (21.3% vs. 10.5%) compared to non-OMI patients (all, P value =0.001) [table]. The in-hospital mortality rate was significantly higher in patients with OMI (8.6% versus 3.6%; P value =0.001). Conclusions: Our study demonstrates that underlying CAD significantly affects the presentation symptoms and outcome of AF patients.

بعد ان قمنا بتفسير جديد لطيف التوحد وعمل طريقة جديدة لعلاج طيف التوحد الغير جيني وهي العلاج عن طريق برمجة العقل والمشروحة في البحث الأول وهي باختصار وهي فرضية أن عقل الطفل عندما يولد يكون عقله محمل ببرنامج مكتسب من الجينات وضعه الخالق سبحانه وتعالى نصه انتبه الى ما هو مكرر انتبه الى المثيرات البصرية والسمعية ولكي يعمل هذا البرنامج يجب التفاعل مع الطفل لتحفيز عقل الطفل وخلاياه العصبية في حالة أن الطفل تم إهماله في الشهور الأولى أو أن الدماغ لم يحفز فيصبح اقل نشاطا في السنوات اللاحقة قمنا بوضع أسئلة لأهالي أطفال التوحد واتضح من إجابة الأسئلة من أهالي أطفال التوحد أن 80 في المية من الأطفال تعرضوا لإهمال غير مقصود بتركهم أمام قنوات الأطفال في العام الأول لفترة طويلة فيصبح الطفل يستقبل فقط يحدث كسل في التفكير بالكلام ويضعف الكلام حيث اكتساب اللغة تنتج من التفاعل مع الآخرين وليس من مشاهدة التلفزيون وتضعف حاسة اللمس والشم ويقل التفاعل في هذه اللحظة يتوقف العمر العقلي وللأسف قد يلاحظ أحد الوالدين أن الطفل تغير ولا يرد ولكن يستمروا في الخطأ - ويقولون أن الطفل صغير ويستمروا في إهمال الطفل بدون قصد ويوفروا له القناة إلى أن يبلغ الطفل عامان ويذهبون للطبيب ويقول لهم إن انتظروا إلى أن يبلغ الطفل عامه الثالث وهذا من اكبر الأخطاء حيث يجب أن يتم ملاحظة الطفل في العام الأول إذا لم يكن طبيعيا وتطوره البصري والذهني والسمعي والحسي غير طبيعي علينا بمعرفة السبب - وهو التلفزيون إذا كان طبيعي في أول 6 اشهر لانتا إذا تأخرنا وكان عمر الطفل العقلي متوقفا في العام الأول والعمر الزمني للطفل 3 سنوات فسوف يكون تعويض الفارق بين العمرين سيأخذ وقتا أطول وهو ما يثبت صحة افتراضية حدوث خلل في البرنامج التشغيلي لعقل الطفل *** التوصية منع الاطفال اقل من عامين لمشاهدة التلفزيون نهائيا وخاصة في العام الأول التفاعل مع الطفل قدر الإمكان بالصوت والحركة والابتسامة واللمس * . وجدت بحث في النت انه بعد تشغيل التلفزيون ب 30 ثانية تقوم الأجزاء المسؤولة عن التركيز في عقل الطفل بالانغلاق كذلك بحكم دراستي أن الصوت القادم من التلفزيون لا يشمل فقط الصوت المسموع ولكنه يشمل ما تحت السمعي من ترددات صغيرة وهي اقل من 20 ذبذبة في الثانية واعتقد إنها هي الأخطر لتلف خلايا الدماغ لدى الأطفال عند التعرض لها لمدة طويلة هذه الموجات التحت سمعية تستخدم في طرد الحيوانات وتستخدم في الطب للعلاج ولكنها لفترة زمنية قصيرة - مثل علاج الأوعية الدموية بالموجات تحت سمعية - ومنها ما يسبب إدمان لبعض الترددات مثل الرجل الذي يشعر بالراحة عند سماعه مقرئه المفضل أو مطربه المفضل ولان معظم قنوات الاطفال تعمل على تكرار الأغاني فلذلك يميل الطفل إليها ويحدث شبه إدمان لترددات الأغاني لذلك تجد الطفل لاستجيب لنداء والده ولكنه بمجرد تشغيل قناة ينجز باليها الطفل بسرعة حتى لو كان في غرفة أخرى ** توجد بعض رسائل الاهالي والتي معظمها تثبت ان الطفل تعرض لاهمال غير مقصود بتركه امام قنوات الاطفال وخاصة مع وجود خادمة لا تتكلم لغة الطفل وقد تكون الأم مشغولة بالعمل او بالحمل في اهم اشهر يحتاجها الطفل للتفاعل والتطور ويتضح أن قنوات الاطفال سبب رئيسي لزيادة معدل طيف التوحد

Grape leaves are widely consumed in Palestine, and many Mediterranean countries. This food item is considered as a delicacy in many cultures, and most consumers consider it as also a healthy food. Accordingly, we started two years ago a study to assess the nutritional quality of leaves collected from two grape varieties, namely Shami and Baituni, which were collected from two regions, namely Dahria (considered as an arid region) and Beit Umar (considered as temperate region). Leaves were collected during spring time in three replicates and directly grinded to powder in liquid nitrogen. To assess the nutritional quality, leaf extract were tested as anticancer agent, and tested further for the total antioxidants potential. Moreover, leaf extracts were subjected to detailed analysis for active compounds using GC-MS and LC-MS. Results show that leaves from Shami grapes clearly inhibited the proliferation of lung cancer cells. Concerning the influence of cultivation area, Shami leaves from the temperate region (Beit Umar) proved to be more effective that those collected from Dahria (the arid region). In addition, leaves from Baituni grapes proved to be ineffective against lung cancer. In contrast, the GC-MS analyses of primary metabolites show that leaves of both grape varieties, which were collected from the arid region, contain higher levels of a large set of compounds including alanine, valine, isoleucine, proline, serine, threonine, uracil, sorbose, malitol, quercetin, and maltotriose. This dramatic increase in these compounds may be attributed to osmotic adjustment of plants to cope with drought stress prevailed in that region compared to the temperate region. The analyses for secondary metabolites and total antioxidants potential are closed and will be represented, in connection with changes in primary metabolites and anticancer activity of grape leave extracts. In conclusion, results clearly show that consumption of grape leaves is very healthy, and its consumption may contribute to Mediterranean diet by preventing the occurrence of severe diseases. Moreover, detailed analyses using GC-MS, and LC-MS may reveal the active compounds behind the health-promoting impact of grape leaves. Further purification of these compounds may allow for future usage of leaf extract of Shami grapes as natural pharmaceuticals.

Developmental disabilities (DDs) are a diverse group of physical and mental impairments. Subjects with DDs almost suffer long lasting deficiencies in normal developmental milestones. Etiologies of DDs might look different in communities with high rate of consanguineous marriages, which increase the likelihood of hereditary monogenetic disorders, particularly the autosomal recessive (AR) ones. This study focuses on rare heritable disorders affecting either the normal movements or normal brain growth, in addition to other interesting monogenetic disorders. The study excludes common known causes of DDs as Down or fragile X syndromes or others. This study is aiming both to assess the contribution of rare AR heritable disorders to the burden of DDs in our population. And to better understanding of the clinical profile and molecular basis of DDs, particularly those evolved in consanguineous families. Early identification of the causative mechanism will not only delineate the management strategy and provide family recurrence risk but also it will help to outline primary preventive measures and introduce actions on how people with DDs can improve the quality of their lives. Patients and methods: A total of 62 families [308 individuals] were enrolled in three approved research grants, two NPRPs and a WCMCQ-Research BMRP, addressing: Hereditary Spastic Paraplegias (HSPs) as a group of movement disorders (ascertained in the period between 10/2012-July/2013], Teebi' monogenetic diseases in Qatari [2012-2013], and congenital brain malformation (CBM) [2011-2013] disorders. Patients were referred mostly from Pediatric Neurology, and also from genetic, physiotherapy, and adult Neurology departments of HMC, the largest referral hospital in Qatar. Genomics, bioinformatics and molecular biology studies were carried out at WCMCQ labs. Results: We identified 26 HSPs families [111 individuals], 14 families [75 individuals] with Teebi-monogenetic disorders, and 22 families [122 individuals] with congenital brain malformation. Demographic data: Patients' nationalities were: Qatari [~31%, 100%, &54% in HSP, Teebi' monogenetic, and CBM, respectively], Egyptian [~19% and 9% in HSP and CBM, respectively], Palestinian [~15% for HSPs], Omani [~ 11% &~ 5% in HSPs & CBM], and other nationalities [23% and ~32% in HSP & CBM, respectively]. Consanguineous marriages were in 20 HSP [77%], 14 Teebi' [100%], and 17 CBM [77%] families. Clinically: HSPs patients were subcategorize as AR-complex phenotype [~77% of HSP families], in which presentations of seizures, mental involvements, ataxia, extrapyramidal manifestation, optic atrophy or others were invariably associated, Autosomal dominant [15%] and X-linked [~8%]. Teebi' families were subcategorized as nine families [~64%] with neurologic disorders {hereditary neuropathy "pain insensitivity", vanishing white matter, dystonia, and seizure syndromes} and five independent families, each presents [~7%] with a neuromuscular, an autoimmune, a rare muscle disease, developmental delay with behavioral abnormalities, and mitochondrial disorder. CBM families showed variable forms of cortical and central brain malformation, calcification and migration defects. Genomic data: ten HSPs, twelve Teebi', and nine CBM, families were subjected to Whole Genome Sequence (WGS). Data are currently under bioinformatics and molecular biology studies. Plans are in place to WGS other families. Conclusion: Presented research can be enriched and integrated into the national health management and patients care systems.

Three patients from two related and consanguineous sibships of Pakistani ethnic origin are affected by a recognizable pattern of multiple congenital anomalies. The clinical picture includes increased inner canthal distance, hypoplastic upper lid with ptosis, blepharophemosis, maxillary hypoplasia, facial asymmetry, cleft lip/palate, high arched palate, irregular dentition, low set ears and low posterior hairline, mild scoliosis and decreased carrying angle of elbow. The apparent clinical characteristics overlap, but do not identify solely, with the individual Malpuech, Michels, Mingarelli or Carnevale syndromes, or what has been collectively referred to as the 3MC syndrome; hence, the referral to the phenotype as Multiple Congenital Anomaly syndrome. The family was studied by homozygosity mapping, and Whole Exome Sequencing of a single affected individual performed on ABI SOLiD4. A novel homozygous mutation [c.G542A] affecting the evolutionary conserved residue p.C181Y was identified at 3q27 in the MASP1 encoding a mannose-associated serine protease 1. The variant was confirmed by Sanger sequencing, segregates with the phenotype in the family and is predicted to be damaging by PolyPhen and SIFT. MASP1 functions as a component of the lectin pathway of complement activation. Mutations in the MASP1 gene and another gene (COLEC11) involved in the same pathway have been associated with human craniofacial malformation indicating an impending role for complement pathway elements in vital developmental processes during embryogenesis. The identified autosomal recessive variant extends further support to this hypothesis.

Background: Features of diabetic retinopathy (DR) include leukocyte adhesion, hyperpermeability and retinal neovascularization (RNV). Our previous studies demonstrated that reactive oxygen species (ROS) derived from the NADPH oxidase activity play crucial role in the pathogenesis of retinal vascular injury during DR. Recently we also demonstrated that upregulation of 12/15 lipoxygenase (12/15-LOX) and its lipid metabolites, 12- and 15-HETEs during DR contributes to RNV via disrupting the delicate balance in the levels of vascular endothelial growth factor and pigment epithelium derived factor (VEGF/PEDF). The goal of our study is to investigate whether 12/15-LOX also contributes to retinal inflammation during DR via activation of NADPH oxidase, endoplasmic reticulum (ER) stress response, and VEGF-receptor2 (KDR). Methods: We used cultured human retinal endothelial cells (HRECs) to test the effect of 12/15-LOX derived lipid metabolites on barrier function, leukostasis and tube formation. The amount of HETEs product of 12/15-LOX in the vitreous of patients with or without DR was measured by LC/MS. HETEs were also tested in the retinas of diabetic mice and in mice with oxygen-induced retinopathy (OIR). The direct effect of 12- and 15-HETE on HREC barrier was examined in the presence or absence of NADPH oxidase inhibitors diphenylene iodonium (DPI) and apocynin using FITC-dextran flux assay and electrical cell-substrate impedance sensing (ECIS). The impact of HETEs on leukocyte/endothelial cell interaction and tube formation was also tested. Production of reactive oxygen species in response to HETEs treatment was measured by dihydroethedium (DHE) and dichlorofluorescein (DCF) reactions. Western blotting (WB) was used to evaluate the changes in the protein levels of the catalytic subunit of the NADPH oxidase (NOX2), ER stress proteins, phospho-VEGF-R2 and the protein tyrosine phosphatase (SHP1). In vivo studies were performed using a mouse model of type 1 diabetes, the akita mice (Ins2Akita) treated with or without the 12/15-LOX inhibitor baicalein (75 mg/kg in drinking water) for ~10 weeks. This was followed by analysis of ROS, HETEs, leukostasis and inflammatory mediators. Multiplex Immunoassay was used to measure the levels of inflammatory mediators such as the adhesion molecules (ICAM-1 and VCAM-1) and IL-6. Results: Our experiments showed significant increase in the REC permeability and reduction in the transcellular electrical resistance (TER) by 12- and 15- HETEs compared to the control suggesting pro-permeability role of 12/15-LOX. Leukocyte adhesion and tube formation were also increased by 12- and 15-HETEs. This was associated with significant increases in ROS generation, levels of NOX2, ER stress response proteins and p-VEGF-R2.There was also a significant decrease in the levels of p-SHP1. These effects of HETEs were prevented by NADPH oxidase or VEGF-R2 inhibitors. In vivo studies demonstrated significant abrogation of the retinal HETEs, adhesion molecules (ICAM-1 and VCAM-1), IL6, ROS generation and NOX2 expression in diabetic mice treated with baicalein. Furthermore, the number of adherent leukocytes was reduced in 12/15-LOX-deficient and baicalein-treated mice. Conclusion: 12/15-LOX contributes to DR via NADPH oxidase-dependent mechanism which involves activation of ER stress response and VEGF-R2. Thus, 12/15-LOX is a potential therapeutic target to prevent the development of vascular dysfunction during DR.

BACKGROUND AND OBJECTIVE: Knee surgeries for total knee replacement or Anterior Cruciate Ligament (ACL) repair involve the use of intraoperative computer-assisted navigation techniques for guiding surgical tools during the procedure. In clinical practice, a digital map of the knee is created for navigation from images acquired preoperatively. High hard-tissue contrast makes CT the preferred imaging modality. However certain knee surgeries, such as ACL repair, require segmentation of soft-tissue structures for navigation. As opposed to CT, MRI has soft-tissue contrast. Considering this advantage, we investigate the applicability of MRI for segmenting both hard-tissue as well as soft-tissue structures in ACL repair surgery. METHODS: MR images (3D-DESS protocol; Pixel Size = 0.46x0.46mm²; FoV = 150x150mm²; slice thickness = 3mm; inter-slice distance = 3mm) of the knee at four flexion positions (30°, 45°, 90°, Full-Extension) were collected using Siemens Espree scanner on eight healthy volunteers. Two experts manually delineated the MR images using OsiriX software. The delineated boundaries of the hard-tissues (Tibia, Femur, and Patella) and soft-tissue (ACL) were used to create respective binary masks which were then combined into a single mask for each tissue type using STAPLE algorithm. The output was fed to Marching-Cube algorithm followed by Laplacian smoothing filter to generate triangular meshes of the knee structures. These 3D meshes can be used as a digital map to ease the navigation (Figure 1). RESULTS: The binary mask overlap between experts (Table 1) is used to measure the reproducibility of the segmentation and hence the confidence in generating 3D models for navigation. The high overlap for hard-tissues shows that MRI is relevant to segment them. The lower overlap for soft-tissues shows a perfectible segmentation, but still sufficient to show that their segmentation is achievable using MRI. CONCLUSIONS: This work is a first step towards using preoperative MRI segmentations for surgical navigation in knee surgeries showing it can provide not only hard- but also soft-tissue information as compared to CT.

The application of DNA-based methods for inferring ethnicity to investigate criminal cases has been well documented in recent literature. Based on self claimed ethnicity, numerous human diseases and the efficacy of therapeutic drugs have been linked to ethnic backgrounds. These racially-related diseases and drug responders included, but not limited to, cardiovascular disorders, sickle cell anemia, breast cancer, prostate cancer and responders to the therapeutic agent BiDil (hydralazine hydrochloride and isosorbide dinitrate) for treating congestive heart failures. Surprisingly, for all these cases no DNA based ethnicity method was used to verify the observed link between the ethnic origin and the risk for the specific medical ailment. The most probable cause is lack of a test that has the capacity to separate between the disease-causing genes and the markers for assessing ethnicity in genomic DNA. To this end, a logarithmic method was developed and validated utilizing the disease free STR genetic markers, which have demonstrated their suitability to separate between the two entities. The developed software system is currently used by our laboratory under the commercial name "Ethnitest" for inferring ethnic composition in racially admixture- individuals. The assay demonstrated low error rates and can accommodate more than ten population groups with distinct and proportional likelihood probabilities. Among self-claimed African American, Caucasian, Asian and Hispanic American populations, the assay demonstrated that 20%, 35%, 55% and 95% of these cases, respectively, are consistently admixtures. Upon further investigations, self-claimed Hispanic populations from three different geographical regions (North, Central and South America) showed that they are invariably all admixtures. As expected, the major constituents of these admixtures were found to be Native Americans and Europeans. In contrast, self-claimed Africans showed minimal admixtures among West African populations. However, East African populations showed different admixtures with African, Asian and Middle Eastern as the dominant ethnicities. As expected, the composition of the North Africans revealed that it was mostly dominated by European and Middle Eastern. Among staged prostate cancer DNA samples from self-claimed African American, the Ethnitest showed only 50% to perhaps have an origin in the African American population. The impact of these assessments on disease disparity and personalized medicine will be discussed. Furthermore, the limitations in the application of SNP and gender based ethnicity assays on disease disparity will also be discussed.

Background and objective The Middle East and North Africa (MENA) is home to the world's largest producer of opioids, as well as to major drug trade routes. Over 80% of the global supply of heroin is produced in Afghanistan, and over 75% of this is trafficked through Iran and Pakistan. The increased availability and purity of inexpensive heroin in MENA appears to have led to a subsequent rise in injecting drug use. The objective of this sub-study was to estimate the proportion and number of people who inject drugs (PWID) in MENA, as part of a larger study of HIV epidemiology among PWID in this region. Methods This was a systematic review of literature following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Sources of data included PubMed, Embase, regional databases, conference abstracts, as well as a large body of country-level reports. A generic "drug use" search of these databases was performed. Data on PWID population size estimates in the 23 MENA countries were extracted from relevant studies. Estimates were weighted by adult population size. When more than one such estimate was available per country, we used their mean. Adult population size was extracted from the United Nations World Population Database. Results After screening 4,985 citations, we extracted 121 and 105 measures on the number and proportion of PWID, respectively. We estimated that there are 0.6-1 million PWID in MENA. Pakistan, Iran, and Egypt have the largest number, with an average of about 210,000, 180,000 and 89,000 PWID, respectively. The weighted mean prevalence of injecting drug use was estimated at 0.23 per 100 adults (range 0.03-0.50%), and was highest in Iran (0.43%). Studies of sub-national populations showed geographical heterogeneity in the proportion of PWID. Data on the prevalence of female PWID were scarce. Overall, the mean proportion of females among PWID in included studies was 3.6% (range: 0-35%). Conclusion The mean prevalence of injecting drug use in MENA (23 in every 1000 adults) is comparable with global figures which range from 0.06% in South Asia to 1.50% in Eastern Europe. The prevalence of injecting drug use varied between MENA countries, being higher in the eastern part of the region; and appeared to be heavily concentrated among men. With recent evidence suggesting emerging HIV epidemics among PWID in several MENA countries, these findings take on additional importance. There is an urgent need to scale up harm reduction services for the nearly one million individuals who form this vulnerable population group in MENA.