Qatar Foundation Annual Research Forum Volume 2013 Issue 1

Immune thrombocytopenic purpura (ITP) is an autoimmune disorder, characterized by dysfunctional cellular immunity including the presence of activated platelet specific autoreactive T cells that recognize and respond to autologous platelet antigens. Autoreactive T cells drive the generation of platelet reactive autoantibodies by B cells as well as T-cytotoxic cell-mediated lysis of platelets. Interleukin-18 (IL-18) is a mediator of T helper type 1 cell responses synergistically with IL-12 that initiate and promote host defense and inflammation. IL-18 has a specific binding protein (IL-18BP) which belongs to the immunoglobulin superfamily. In the present study, serum level and messenger RNA( mRNA) expression of IL-18 as well as IL-18BP mRNA expression were measured in peripheral blood mononuclear cells (PBMNCs) of 100 Egyptian pediatric patients with ITP (70 acute and 30 chronic). In addition to this, we recruited 80 healthy volunteers in order to investigate the possible association between the imbalance of IL-18 and IL-18 BP expressions and the pathogenesis of ITP. IL-18 serum level and mRNA expression were not elevated in cases more than in the control group, but IL-18 mRNA was higher in chronic cases when compared to the acute ones (p = 0.031) and there was a good negative correlation between the platelet count and serum IL-18. IL-18 BP m-RNA was slightly elevated in cases more than in the control group (95% Confidence interval = 1.15-2.01). Our results were not supportive for previous findings of elevated IL18/BP mRNA ratio in ITP patients. This could be referred to the fact that autoimmune diseases are complex genetic disorders, therefore further studies on polymorphisms affecting IL-18 gene expression as well as kinetics of IL-18 expression are required to evaluate the role of interleukin 18 and its binding protein in the pathogenesis of ITP.

Fusarium culmorum is a major fungal pathogen of wheat, causing foot and root rot (FRR) and fusarium head blight (FHB). Yield losses are reported as the grain becomes contaminated by mycotoxins. Among the most bioactive compounds are trichothecenes, sesquiterpene epoxides which are able to inhibit eukaryotic protein synthesis and may cause toxicoses on humans or animals consuming contaminated food or feed. Trichothecenes induce apoptosis and may play an important role in the aggressiveness of phytopathogenic Fusarium species towards plant hosts. The aim of this project is to design, prepare and study new natural and natural-like compounds to be applied in the control of F. culmorum mycotoxin production. Particular attention is paid to the selection and preparation of compounds with selective trichothecene B inhibitory activity compared to compounds showing both mycotoxin inhibitory and fungitoxic activities. The first inhibition experiments were performed using compounds belonging to the family of gallic acid, phenylpropanoids and cinnamic derived acids. In vivo and in vitro test and molecular modeling with computational studies were carried out. A straightforward thin layer chromatography (TLC) method and a quantitative LC-MS analysis were used to identify the presence of B trichothecenes and to evaluate the influence of each compound on different F. culmorum culture extracts. Preliminary results indicate that several molecules are able to inhibit the severity of F. culmorum in planta and its growth as well as trichothecene production in vitro. The level of inhibition of 3AcDON range from 67 to 100% under inducing conditions. Fast and effective methodologies for seed dressing were developed using a natural matrix.

Background: The Middle East and North Africa (MENA) region harbors significant proportions of stunting and wasting coupled to surging rates of non-communicable diseases (NCDs). Recent evidence identified nutrition during the first 1,000 days of life as a common denominator not only for optimal growth and development but also for curbing the risk of NCDs later in life. Collaboration between Qatar and Lebanon was initiated to launch the first mother and child cohort study in the MENA region, examining the effect of maternal and young child nutrition and lifestyle characteristics on birth outcomes and growth patterns. The main outcome of this study is to develop evidence-based country-specific nutrition and lifestyle guidelines for pregnant women and young children to ensure optimal nutrition during the first 1,000 days of life. Methods/Design. This is a prospective three-year cohort study. Pregnant women (n=500) in their 1st trimester will be recruited from healthcare centers in Beirut, Lebanon and Doha, Qatar. Participants will be followed up three times during their pregnancy (once every trimester) and six times after delivery (when the child is 4, 6, 9, 12, 18 and 24 months old). In addition, delivery and birth data will be obtained from hospital records. Data collection will include maternal sociodemographic and lifestyle characteristics, dietary intake, anthropometric measurements, and household food security data. In addition, a blood sample will be obtained from the mother during her 1st trimester. Breastfeeding and complementary feeding practices, dietary intake, as well as the growth patterns of children will also be examined. The development of the nutrition and lifestyle guidelines will follow a multistep process using the Delphi technique. Discussion: The developed guidelines will help promote balanced nutrition and health during the first 1,000 days; constituting the foundation of effective interventions not only to ensure optimal growth and development but also to curb the epidemic of NCDs in the region. This study provides a unique opportunity for further follow up in light of the growing field of nutrition and disease risk.

Development of a Web-based Hybrid Registry for Acute Stroke in Qatar Leopold J. Streletz1,2, Saadat I. Kamran1,2, Mohammad Shahzad1, Reggie Cruze1, Naveed Akhtar1,2, Ahmed Elsotouhy2, Ahmed Khattab3, Damian Jenkinson3, 1Weill Cornell Medical College-Qatar, 2Hamad General Hospital and Hamad Medical Corporation, Doha, Qatar, 3Bournemouth University, Dorset, United Kingdom. Stroke is a worldwide medical problem and is one of the leading causes of death and disability for people over the age of 40. In Qatar, although cardiovascular constitutes a major cause of morbidity and mortality, very few stroke studies have been reported. Current standards of care for stroke patients require medical or surgical interventions within 72 hrs of the initial presentation. This is why our research focuses on acute stroke in order to help develop and improve current models for stroke prediction in Qatar. To achieve this in a systematic way, a disease-specific registry for acute stroke needs to be developed. A disease registry is an ongoing, inclusive listing of all individuals with an identified disease from a defined population. It can be used to monitor long-term trends of disease and can also offer clinical researchers an approach to identify particular subsets of patients for research studies. Our registry will also contain patient management parameters which will serve a more practical hospital function of quality assurance in the Hamad Medical Corporation (HMC) hospitals. The development of this hybrid registry is the focus of this presentation. The lead principal investigator of this research has had a prototype Acute Stroke Database on trial in a medical center in Saudi Arabia that showed great versatility and gave easily accessible data for stroke patient management. With minor modification and appropriate security, it can be made available on-line to hospitals and clinics throughout Qatar and will provide an invaluable tool for monitoring clinical data necessary for stroke patient selection. The database will initially be hospital-based and the population included will be all adult patients admitted with acute stroke or a transient ischemic attack (TIA). The stroke database report form which will initially be used as the basis for the registry has been designed with seven specific sub-sections: Admission, Transportation, Stoke Evaluation, Stroke Management, Stroke Classification, Functional Disability, and Registry Summary. Data sources for the patient will rely heavily upon Emergency Department's records and hospital admission records for the patients. It is hoped that the registry will provide extensive clinical information on all acute stroke patients admitted into the HMC system. Using this information, we hope to be able to determine the trends and the relative frequency of specific disease manifestations in Qatar. We also hope that this information will stimulate other hospitals within the region to examine their management routines and thereby serve as a basis for improvements in patient care across the Middle East. ( NPRP No. 6-565-3-141 Award, Cycle 6, 2013 )

Background: MPNs are clonal haemopoietic disorders that are characterized by excessive proliferation of one or more of blood lineages. MPNs include PV, ET and PMF which are associated by the presence of JAK2 V617F mutation in about 90% of PV and 50% of ET and PMF. The molecular workup of JAK2 & related gene mutations were included in WHO 2008 as one major criterion for the diagnosis of Ph- MPNs. Aim: To genetically characterize MPN patients (pts) in Qatar according to the latest(WHO 2008) criteria using molecular studies for JAK2 V617F mutation, JAK2 exons 12-15 & MPL (S505N & W515 L/K) mutations. Methods: Blood samples were collected from suspected MPN cases & DNA was extracted. Allelic discrimination assays were used to evaluate point mutations causing JAK2 V617F & MPL (W515 L/K) mutations. JAK2 Exon 12 was analyzed using High Resolution Melting Curve (HRM) assay & Sanger Sequencing. In some cases the entire MPL exon 10 & exons 12-15 was studied by RNA extraction followed by cDNA synthesis, amplification & sequencing. Results: 400 patients were classified into PV, ET and PM. Out of 180 PV, 97% of cases were positive for the JAK2 V617F mutation and 3% of cases were negative for other mutations. Out of 200 ET, 48% of cases were positive for JAK2 V617F, one had MPL S505N mutation and 50% of cases were negative for other mutations. Out of 20 PMF, 33% of cases were positive for JAK2 V617F and one unclassified case was characterized by DVT had JAK2 exon 13 mutation (R564L). Conclusion: This study used novel molecular approaches to confirm the diagnosis of MPNs cases in Qatar. The observed patterns of mutations were found to be similar to the international data. In our cohorts of patients, JAK2 V617F mutation was found to be present in almost every patient with PV, nearly 50% of ET patients and less than 50% of PMF patients due to the low number of PMF patients in this study. Our original findings show the presence of MPL S505N mutation in one ET patient which was reported both as an inherited or acquired mutation in very rare cases of ET and R564L mutation in one unclassified MPNs case. An ET patient with MPL S505N progressed to AML. The impact of R564L mutation found in 1 atypical case is still unknown & needs further investigation. We report for the first time the presence of most frequent mutations found in MPNs patients in Qatar. This study is preliminary before further molecular investigations to explore & identify mutations in other candidate genes.

Bipolar Affective Disorders are disorders of mood regulation that affect 1-5% of the population worldwide. The severe mood swings that are the hallmark of this disorder can interfere with the patient's personal life and career and often result in marked distress for the patient and family. While the etiology of the disorder remains somewhat elusive, genetic factors are known to be major contributors. Research in patients of European descent have identified several genes that are strongly associated with bipolar disorder. These genes include CACNA1C, ANK3 and Syne1 genes. However these findings have not always been replicated and it is not known whether these or other genes are also associated with bipolar disorder in populations of other racial/ethnic origin. In an effort to address this issue, we recruited 120 patients with bipolar disorder from different Arab countries. The majority were Qataris. All patients were clinically assessed with the Diagnostic Interview for Genetic Studies (DIGS) that we translated into Arabic and adapted to the local culture. The demographic and clinical characteristics of the patient population will be presented. Compared to patients recruited in other parts of the world, our population sample is unique in at least three different and important ways: 1) there is a high frequency of psychosis among our patients (>60%); 2) co-morbidity with alcohol and/or substance abuse is relatively rare (<20%) and 3) about 30% of patients had a family history of a similar disorder in first degree relatives. DNA extracted from a blood sample was obtained on each patient. The DNA was sent for whole genome sequencing at the Hudson Alpha Institute in Huntsville, Alabama in the USA. The sequencing was completed at a depth of 30X. The genetic variants across the genome through all genes, regulatory regions and intronic genetic sequence were encoded in the data. The total amount of data exceeded 10 Tbytes. We have just started the long and tedious process of data analysis that will be shared. These projects lay the foundation for the establishment here in Doha of a repository of clinical and biological data for patients with bipolar disorders. We hope this work will eventually lead to the establishment of the first Arab Psychogenomic Repository for Bipolar Patients in the Middle East.

OBJECTIVE : Taenia solium neurocysticercosis (NCC) is the most common parasitic infection of the brain and is a leading cause of epilepsy in the developing world, especially Latin America,India,Africa,and China .It is increasingly being reported in patients suffering from epilepsy . However, its true prevalence and association with adult-onset seizures is largely unknown in the Middle East particularly in Qatar. Our study will demonstrate that NCC is also a major cause of first seizures in an increasingly young population in Qatar. BACKGROUND Awareness of NCC and associated seizures in the developing countries and the increased frequencies of hospital admissions of young Asian patients with first seizures and abnormal brain CT/MRI suggestive of NCC were the main reasons behind this study. METHODS : This is a retrospective and prospective study, based on hospital populations(2010 to present ) .All patients with seizure(s) seen at the emergency department at Hamad Medical Corporation (HMC) ,the largest single governement hospital in the state of Qatar with a capacity of 1600 beds , were reviewed. Among those patients, all individuals suspected of having NCC were admitted for further investigations and treatment. NCC was diagnosed on the basis of the following : CT or MRI (brain) showing cystic lesions with scolex or Lesions suggestive of NCC on CT/MRI and a compatible epidemiological and clinical history. The complementary examinations included an awake EEG, a CT SCAN or MRI of the brain and serum and CSF studies for some. The results of this study were compared to the most recent data reported in the literature. RESULTS: During this period, 120 patients with seizure(s) were seen at the emergency department .Among them , 55 patients (45,8%) were diagnosed as having NCC on the basis of the above criteria. 54 of the NCC patients (98,3%) were males ;Most of them,53 patients(96.5%), expatriate from the Indian Subcontinent.52 patients ( 94,6%) were older than 20years ; 53 patients(96,5%) presented with seizures with 45 patients (81,8%) having their first seizure. 33 patients ,(60%), had partial seizures, the rest secondary generalized or generalized seizures.17 patients presented with headache. Most of the patients(31) showed a viable cyst on CT/MRI .More than half of patients(29) had an abnormal EEG, however relationship between focal EEG changes and cyst location was only found in 13 patients. Most patients were treated with cysticidal therapy and corticosteroids except those patients with calcification lesions on CT/MRI and absence of edema .Non-neurological side effects included abdominal pain ,nausea, and diarrhea in 8 patients. Antiepileptic therapy (AEDs) was used in 50 patients from the onset and avoided in 5 patients with first seizures and tiny lesions on CT/MRI. During the study-period, AEDs were withdrawn in 6 patients.

Metastasis to the peritoneum and lymph node is associated with poor survival in patients with epithelial ovarian cancer (EOC). To better understand EOC metastasis, we carried out exome sequencing, RNA sequencing and copy number variation (CNV) studies on ovary, peritoneum and lymph node tumors from three patients. To analyze single nucleotide polymorphisms (SNPs) from exome and RNA sequencing data, we use the ratio of reference allele reads to the total number of reads as a measure of a site's allele distribution. This approach is more appropriate for analyzing heterogeneous cancer samples than standard SNP calling methods. Analysis of significant SNP, CNV and gene expression shifts across tumor sites and patients reveals a large degree of heterogeneity between patients. The small number of shifting alleles and differentially expressed genes conserved across patients could be interesting genes for further study. In addition, using both the exome and RNA sequencing data, we identify specific alleles that are expressed at significantly higher and lower levels than expected from the genomic allele ratios. These differentially expressed alleles are very interesting candidates for further study as they may indicate tumor selection for particular alleles. Overall, our results indicate a remarkably heterogeneous landscape of ovarian cancer primary tumors and metastasis and suggest that a more patient-specific research and treatment approach is advisable to achieve better patient outcomes.

Ashraf Al-Amoudi1,2 and Achilleas Frangakis3 1Center of Advanced European Studies and Research (caesar), Department of Molecular Sensory Systems, Ludwig-Erhard-Allee 2, 53175 Bonn, Germany, 2German Center of Neurodegenerative Diseases, Ludwig-Erhard-Allee 2, 53175 Bonn, Germany European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany 3Goethe Universität - Institut für Biophysik Max-von-Laue-Str. 1 60438 Frankfurt, Germany Intercellular adhesion junctions are fundamental for the function and development of multi-cellular organisms. They are widely distributed in animal tissues and most abundant in tissues that are subjected to considerable mechanical stress such as heart, skin and muscle. Desmosomes and adherens junctions (AJs) represent major categories of these junctions. The intercellular space of desmosomes and AJs relies on the associations between members of Ca2+- dependent adhesion molecules called cadherins which share high sequence similarity among them.The intracellular region of the junctions form distinct plaque on the cytoplasmic face of the plasma membrane and form complex network of molecular interactions that link the extracellular region of cadherins with the cytoskeleton. Disruption of cadherins or plaques is the hallmark of many blistering and cancer diseases. Recently, the first crystal structure of the full extracellular domains of C-cadherin (a representative of classical cadherins) showed that the cadherin molecules adopt a stable, curved conformation1. In this crystal structure, the neighbouring molecules are oriented in antiparallel and engaged through a mutual exchange of the tryptophan 2 (Trp2) forming a W-like shape. Such Trp2 trans-interactions were supported by mutagenesis data and cell-adhesion assays and are now considered to be physiologically relevant2. Recently, using cryo-electron tomography and quantitative analysis by sub-tomogram averaging, we revealed the molecular organization of desmosomal cadherins and plaque3,4. Our results show two predominant cis- and trans- interactions alternating in a periodic manner similar to the arrangements observed in the linear zipper of the crystal structure of N-cadherins5. In addition, the resulting molecular model explains previous two dimensional images observed with CEMOVIS at various orientations and yields important insights into the assembly of cadherin-based intercellular junction. Our analysis of the desmosomal plaque revealed two-dimensional interconnected quasiperiodic lattice with similar spatial orgnaization of the extracellular region of the desmosome5. We are currently studying the molecular organization of AJs from mouse intestine. Our results indicate highly-organized structure of E-cadherin compatible with the X-ray structure of classical cadherins1. All these results will be presented in the conference. 1. T.J. Boggon, J. Murray, S. Chappuis-Flam ent, E. Wong, B.M. Gumbiner and L. Shapiro, Science. 296 (2002) 1308. 2. S. Troyanovsky, Eur J Cell Biol 84 (2005), 225. 3. A. Al-Amoudi, D. C. Díez, M. Betts, A. S. Frangakis, Nature 450 (2007), 832. 4. A. Al-Amoudi, D. Castaño-Diez, D. P. Devos, R.B. Russell, G.T. Johnson, A. S. Frangakis,Proc. Natl. Acad. Sci. 108 (2011), 6480. 5. L. Shapiro, A.M. Fannon, P.D. Kwong, A. Thompson, M.S. Lehmann,G. Grubel, J.F. Legrand, J. Als-Nielsen, D.R. Colman and W.A. Hendrickson, Nature. 374 (1995) 327.

Objective: To determine the frequencies of abnormal pregnancy outcomes in a cohort of patients in Qatar and to identify clinical and laboratory factors predicting adverse fetal and maternal outcomes with systemic lupus erythematosus in multinational population in Qatar. Study design: Data of 69 pregnancies of 37 systemic lupus erythematosus (SLE) patients from January 2005 to July 2012 in hmc analyzed retrospectively. Lupus activity was assessed based on SLE Disease Activity Index (SLEDAI) criteria. Results: Among 69 pregnancies 35 (50.7%) pregnancies were in Qatari nationals and 34 (49.3%) pregnancies were in Non-Qatari population including Asians and Africans. There were total of 69 pregnancies from 36 patients. Average numbers of pregnancies prior to and after onset of SLE were 3.73±1.8 and 2.72±1.5 respectively. Age at conception (in years) and gestational age at delivery (in weeks) were 34.5±5.4 and 37.4±2.8 respectively. Anti phospholipid antibodies (aPLs), Anti-SSA (Anti Ro) antibody and Anti SSB (Anti La) antibody were present in 18 (26.1%), 23 (33.3%), 13 (18.8%) pregnancies respectively. There were 10 (14.5%) abortions, 5 (5.7%) stillbirths, 1 neonatal death and 54 (78.3%) live births including two twin gestations. Although, not statistically significant, mean gestational age (weeks) was found to be higher in active lupus patients (37.4±1.9vs. 37.2±3.23, p=0.789) and baby weight at birth was found to be low (2.68±0.64 vs. 2.87±0.60, p=0.360) compared to patients on remission. Pregnancy induced hypertension (PIH) (17.4% vs 11.1%), intrauterine growth retardation (IUGR) (36.4% vs 11.8%), preterm delivery ([31.6 % vs 11.8%), still birth (13% Vs 5.6%) and Eclampsia (13% Vs 0%), all were observed to be higher in active lupus patients compared to patients on remission. However thees differences were not statistically significant. Compared with pregnancies without lupus nephritis (n=44), pregnancies with lupus nephritis (n=7) were associated with a higher risk of still birth (28.6% vs. 4.5%, p=0.092), higher rate of eclampsia (28.6% vs. 4.9%, p=0.103), IUGR (42.9% vs. 26.2%, p=0.626), PIH (28.6% vs. 9.8%, p=0.412). The percentage of live births was higher in pregnancies without lupus nephritis compared to pregnancies with lupus nephritis (42/44, 95.5% vs. 5/7, 71.4%, p=0.092), and live births was also significantly higher in pregnancies without eclampsia/preeclampsia compared to pregnancies with eclampsia/preeclampsia (42/42, 100% vs. 2/7, 28.6%, p<0.001), Stillbirth and preterm delivery were found to be higher in pregnancies with protinurea. Among the laboratory parameters, presence of Anti Ro antibody was found to be significantly associated with IUGR (8/18, 44.4% vs. 6/37, 16.2%, p=0.034). One case of neonatal heart block was found in which Anti Ro/La antibody was positive. Low level of C3 was associated with higher rate of stillbirth, IUGR, preterm delivery, and PIH, however, the difference were not statistically significant (p>0.05). Conclusion: SLE in pregnancy in the Qatar population were associated with higher risk adverse pregnancy outcomes. Disease activity during pregnancy, protinurea, lupus nephritis and eclampsia/preeclampsia were all negatively associated with pregnancy outcome such as IUGR, still births and preterm delivery. Laboratory parameters such as presence of Anti Ro/La antibody and low level of C3 were also associated with adverse pregnancy outcomes.

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.

Background and Introduction—Foodborne illness has been identified as one of the major hindrances to the advancement of health around the world and bacterial pathogens play a major role in this impediment. Although most of the infections are self-limited, different estimates of the cost of illnesses around the world indicate costly episodes with the numbers ranging from $1,600 to $3,000. The global risk of the foodborne pathogens has been exacerbated by globalization of trade and ease of travel around the world. Qatar is where these two factors intersect. Understanding the pathway by which these threats enter the food chain and pose risk to humans will help in developing risk mitigation strategies. In this study we assessed the potential risk of illness from the consumption of mutton contaminated with Escherichia coli O157:H7 in Qatar and identified critical intervention points that would contribute to mitigating its associated risk. Methods—We used the quantitative risk assessment (QRA) methodology using a combination of deterministic and stochastic approaches to address the stated objectives. The QRA approach helps in identifying stages in the production system from farm-to-table that are likely to play roles in mitigating or exacerbating the risk of illness associated with this pathogen (Figure 1). Data on the probability of E. coli O157:H7 in animals, animal products, retail products, and humans were obtained through repeat cross-sectional studies in these populations. Estimates of the adverse health effects were obtained using risk characterization which integrated data on hazard characterization and exposure assessment, including a dose-response model. A Monte Carlo simulation of inputs in the model was performed using the @Risk software (Palisade Software, Newfield, NY, USA) and parameters were obtained using Latin Hypercube sampling. Sensitivity analyses were performed to capture the effect of uncertainty and variability of the different parameters used in the model on the predicted risk of illness. Results—The probability of illness from the consumption of mutton contaminated with E. coli O157:H7 for a healthy female eating at a restaurant range from 7 x 10-3 to 28 x 10-2 depending on the amount of food consumed (Figure 2). However, the risk for the same female eating at home is less (5 x 10-3 to 24 x 10-2). The estimates of illness are three times higher for immune compromised females exposed either at the restaurant or at home. We also evaluated the risk for healthy males exposed at restaurants under similar circumstances and their risk was higher than for females (13 x 10-3 to 44 x 10-2). A similar trend of reduced risk was observed for men exposed at home (9 x 10-3 to 32 x 10-2). The risk of illness due to this pathogen could be significantly reduced for either gender under different scenarios by increasing the roasting of mutton before consumption. Conclusions—This model provides a science-based justification for the awareness about the importance of the probability of adverse health effects due to E. coli O157:H7 in mutton and establishes a scientific foundation for risk managers and public health professionals.

Background: A Canadian study recommends General Practitioners (GP) to use evidence based Clinical Guidelines (CG) when dealing with co-morbid cardiovascular diseases, in particular for the diagnosis and preliminary management of co-morbid Chronic Heart Failure (CHF) and Atrial Fibrillation (AF). Although paper-based Canadian CG exist for the management of CHF and AF, the challenge for physicians is to simultaneously apply multiple independent CG when dealing with patients having cardiovascular co-morbidities. Objective: The objective of this inter-disciplinary research program is to assist physicians in handling co-morbidities through a computerized clinical decision support framework that recommends evidence-based interventions based on the patient&#39;s health profile. We target decision support for the diagnosis and treatment of CHF, AF and co-morbid CHF-AF. Approach: We take a healthcare knowledge management approach to develop a Clinical Decision Support System (CDSS) for handling comorbid diseases. Our solution involves the development of institution-specific CP from a combination of CG, and then generate a CP knowledge model using a semantically-rich formalism—i.e. a CG ontology. The CG ontology semantically defines the clinical concepts in order to establish semantic interoperability between multiple CG. Next, we systematically align the ontologically-modeled CG of different diseases to realize a unified knowledge model that derives the evidence based recommendations for handling both single and co-morbid diseases. Our methodology entails the following steps: (i) knowledge identification to derive specialized disease-specific CG from existing evidence-based sources; (b) knowledge modeling to abstract medical and procedural knowledge from the CG; (c) knowledge representation to computerize the CG in terms of a semantically-rich CG ontology; (d) knowledge alignment to systematically synthesize multiple ontologically-modeled CG to develop a unified ontology-based CG knowledge model representing comorbid diseases; (e) knowledge execution to generate patient-specific recommendations, based on patient data, by reasoning over the aligned CG model; and (f) evaluation of the knowledge model and the recommendations produced in response to a range of clinical scenarios. Results: We present the COMET (Co-morbidity Ontological Modeling &amp; ExecuTion) system to provide clinical decision support for three scenarios: (i) Cardiac Heart Failure (CHF); (ii) Atrial Fibrillation (AF); and (iii) co-morbidity of either AF or CHF. COMET is designed for GP in Nova Scotia and is accessible over the web. Evaluation: A pilot study was conducted to assess how well COMET meets the physician&#39;s needs to manage co-morbid CHF-AF. Conclusion: In conclusion, this project provides a solution for the complex problem of handling co-morbidities in a CDSS. Our solution is based on semantic modeling of disease-specific knowledge which extends the possibility of scaling up to include additional diseases and aligning their knowledge models to handle even further co-morbid situations. Our CG alignment approach helps (a) avoiding duplication of clinical tasks; (b) re-usability of diagnostic results; (c) determine compatibility of different clinical activities; and (d) standardization of care across multiple institutions. We believe that this project achieves knowledge translation whereby we have successfully computerized and translated paper-based CG so that they can now be operationalized at the point-of-care by GP to handle comorbid diseases.

hospital infection due surface contamination becomes very important field of study in recent years. Such contamination can provide a good environment for different microorganisms (i.e. bacteria, viruses, and fungi) to grow and transmit infectious diseases when they come into contact with human body . Recent studies show that surface contamination is accounted for 100,000 deaths in United States alone. Antibacterial coatings has been utilized in many fields such as healthcare, industrial and homes to prevent microorganism's growth and used in sterilization processes. Typically, Semiconductors photocatalysts are used as antibacterial coatings to prevent hospital infections, these materials has ability to interact with light through oxidative process to release radicals to destroy bacteria and viruses. Conventional Metal oxides Semiconductor such as TiO2, ZnO have drawn much attention during the last few years because of their novel photocatalytic activity, availability, stability, strong oxidative capacity, and low cost , . However, due to their wide band gap and high excitation binding energy they only allow absorption in the UV region of solar spectrum. Nanomaterials offered cost-effective solutions for many environmental problems such as waste water treatment, pollution, and anti-bacterial treatment . . It has been known that pure ZnO exhibits low photocatalytic activity due to rapid recombination of photo-activated electrons and holes. It is expected that doping ZnO with metals will improve the photocatalytic activity and disinfection effect. Here report two step synthesis method of Ag/ZnO Nanoparticle heterogeneous Photocatalyst for anti-microbial treatment in hospitals. Our results indicate that Ag/ZnO exhibits high photocatalytic activity and disinfection effect by extending the absorption to the visible range of solar spectrum and prevent the recombination. The nanostructures of the prepared Ag/ZnO particles have been confirmed using UV-VIS absorbance, XRD, and SEM analysis. Antibacterial properties of the Ag/ZnO nanoparticles were investigated by inhibition testing against E. coli using filter sheet. The results, revealed an obvious zone of inhibition around the Ag/ZnO nanoparticles sheet, suggesting the antibacterial property of the Ag/ZnO nanoparticles. The Ag/ZnO system is tested in the presence of visible light and in the dark. The results indicate that Ag/ZnO nanoparticles exhibit antibacterial activity even in the dark. We attributed the photocatalytic activity of the Ag/ZnO Photocatalyst to the Plasmon surface effect of Ag nanoparticles and interaction of Ag with ZnO where Ag nanoparticles act as an electron sink, promoting interfacial charge transfer and reducing charge recombination. Dastjerdi, R., Montazer, M. 2010. A review on the application of inorganic nano-structured materials in the modification of textiles: Focus on anti-microbial properties. Colloids and Surfaces B: Biointerfaces 79: 5-18. Onaizi, S.A., Leong, S.S.J. 2011. Tethering Antimicrobial Peptides. Biotech. Advances 29:67-74. Hoffmann, M. R.; Martin, S. T.; Choi, W.; Bahnemann, D. W. Chem. Rev. 1995, 95,69

Adoptive cell transfer therapy (ACT) holds a highly promising treatment for metastatic melanoma patients. ACT involves the ex vivo expansion of autologous antitumor reactive tumor infiltrating lymphocytes and their reinfusion into lymphodepleted patients, accompanied by IL-2 administration. ACT demonstrates objective clinical responsiveness in 40-50% patients, including 10-21% complete responses. However, the mechanisms underlying the observed inter-individual variability in response to this type of therapy are not well understood. We applied whole genome-wide association study (GWAS) using Illumina OmniQuad 1M SNP bead array and expanded the SNP coverage to 33M by imputation against International HapMap and 1,000 genomes data sets. The analysis was performed in 208 TIL or PBMC samples undergone adoptive therapy or high does IL-2 therapy at the Surgery Branch, NCI. Comparisons between patients experiencing a complete responder (CR, n=30) versus those suffering progression of disease (PD, n=108) excluding the reminder partial responder patients identified 140 independent association SNPs which covers 14 functional known genes at a threshold p-value < 1 x 10-5. Within the chromosomal crossover range (1000Kb); we observed possible association with 405 annotated genes. The strongest signal was rs11587096, rs4506458 on chromosome 1 and rs7894773, rs7070986 at chromosome 10. Several genes at those loci had known immunological function. Those include TLR5, MIA3, TAF1A, DUSP10, DISP1, HHIPL2, MAF177B and EIF3a, FAM45A, SFXN4, GRK5, RGS10, TIAL1, BAG3, INPPF5 AND SEC23IP on chromosome 1 and 10 respectively. In particular, comparisons between patients experiencing a complete response (CR) versus those suffering progression of disease (NR) identified a polymorphism in the region flanking the exon 2 of the G protein-coupled receptor kinase 5 (GRK5) gene as one the most statistically significant polymorphism. GRK5 can exert immunomodulatory function by promoting the desensitization of chemokine receptors, modulating NFkB signaling and promoting the Wnt signaling, a pathway involved in the development of particular CD8+ T lymphocytes. Possible functional impact of the significant SNP on Chr 10 at transcript level was further validated by analyzing encoded gene exons using Fluidigm technology. In conclusion, we have identified different loci associated with clinic outcome by GWAS study suggesting that genetic predisposition is one of the important component determine immune responsiveness.

Background: Early and rapid onset of obesity in the Qatari population, consequent to expansion primarily of abdominal adipose tissue, is closely associated with inflammation and insulin resistance. Recent interest has focused on microRNA (miRNA), both as biomarkers and mediators, of disease and therefore potentially therapeutic targets. MiRNAs are stable, non-coding species involved in the post-transcriptional regulation of gene expression. Aims: This study investigated the expression of a panel of miRNAs associated with inflammation and insulin resistance in peripheral blood cells of subjects with a range of adiposities and insulin sensitivities. The effect of surgical weight loss on these miRNAs was also investigated in a subset of patients. Method: Non-diabetic Qatari subjects were recruited from patients awaiting weight reduction surgery and from a normal population. Anthropometric measures were recorded. Fasting blood samples were obtained from all subjects, and in a subset after surgical weight loss, for determination of lipids, glucose, insulin and adipokines. miRNA from peripheral blood cells was used to assess their expression using an inflammatory array. Subjects were grouped by body mass index and insulin sensitivity. Results: Three comparisons were carried out: 1. Normal/over-weight (N/OW) versus obese (Ob), 2. Insulin Sensitive (IS) versus Insulin Resistant (IR), and, 3. Before (BWL) and after weight loss (AWL). Despite being matched for age (M 29.5±9.8 vs F 30.1±6.5 years), and BMI (M:36.1±12.9 vs 36.6±10.0 kg/m2) the males had higher systolic and diastolic blood pressure and mean arterial pressure, while levels of both leptin and adiponectin were higher in females. The N/OW, compared to the Ob group, had lower levels of systolic blood pressure, higher HDL-cholesterol, lower leptin, interleukin-6 and higher adiponectin levels. The IS group compared to the IR, matched for BMI, age and plasma glucose, had lower insulin and HOMA index of insulin resistance, as well as leptin and adiponectin. Weight loss was accompanied by a significant reduction in BMI (BWL:41.6±8.6 vs AWL 34.7±8.7 kg/m2), leptin, insulin and HOMA-IR. Three miRNA were significantly different between the different body weight groups. Conversely, 12 miRNA changed significantly when IS were compared to the IR. Weight loss also produced changes in the expression of ten miR species. Conclusion: It is apparent that significant differences in expression of the miR species occur along with changes in metabolic and inflammatory parameters in the different body weight groups, which are further enhanced both synergistically and independently by insulin resistance. Some, but not all, of the metabolic and inflammatory lesions that accompany obesity and insulin resistance appear to be ameliorated by weight loss. The target genes of these miRNAs are currently being investigated to assign possible functionality.

Obesity has increased at an alarming rate over the past three decades. It is likely caused by increased caloric intake combined with genetic predisposing factors and is a major risk factor for type 2 diabetes (T2D). Obesity is linked to chronic inflammation, which was proposed as a cause for insulin resistance and T2D. The obese state creates a microenvironment within the adipose tissue that is susceptible to accumulation of reactive oxygen species (ROS). Accumulated ROS leads to DNA damage and activation of DNA damage response. When DNA is severely damaged and can't be repaired, the cell undergoes senescence, an irreversible cell cycle arrest. Senescence has been linked to aging illnesses and even to obesity with accumulation of senescent pre-adipocytes. A major player in detecting and defending against oxidative stress is PARP-1. PARP-1 activation has been shown to be associated to melanoma senescence, inflammation, obesity and diabetes. The role of PARP-1 in ROS-induced senescence and inflammation of pre-adipocytes has not yet been investigated. Therefore, to study PARP-1 function in pre-adipocytes senescence, we generated and characterized an in vitro experimental model for cellular senescence in primary human and mice pre-adipocytes using hydrogen peroxide (H2O2) as a source of ROS. Our preliminary data shows PARP-1 induction in ROS-treated pre-adipocytes. We are currently using this senescence model to characterize the function of PARP-1 by using gene-silencing approaches.

Obesity is an established risk factor for hypertension. About 1 billion adults are overweight globally and numbers appear to be increasing. Stimulating endogenous activation of brown adipose tissue (BAT) mass that has unprecedented metabolic capacity can combat obesity, reverse insulin resistance and reduce comorbidities. Renalase is a recently discovered flavin adenine dinucleotide (FAD)-dependent oxidase, predominantly secreted into the circulation from the kidney and regulates catecholamine degradation and metabolism. Renalase gene is also present in heart muscle, skeletal muscle and liver cells in humans, and in mouse testicles. Four isoforms of renalase gene has been identified in humans (hRenalase1 to hRenalase4), however only hRenalase1 is detected in human blood suggesting that hRenalase2 to 4 may have alternative function. Unlike the classical amine oxidases which are expressed intracellularly, renalase is present intracellularly and is also secreted into the circulation. Circulating renalase appears to mirror sympathetic tone, a brief increase in catecholamines results in significant up-regulation of renalase synthesis, secretion and activity. Catecholamines are principle activators of BAT thermogenesis and angiogenesis both in rodents and humans. Characterization studies in renalase‐knockout mice shows that these mice have about 25% reduced body weight compared to control, increased circulating catecholamines, are hypertensive, and have cardiovascular defects. Renalase‐knockout mice have activated sympathetic system and possibly have increased BAT activity as a result of elevated catecholamine's in the circulation. Our findings in adipose tissue demonstrate that the renalase gene and protein is expressed in both white and brown adipose tissue depots. Expression of renalase increases in BAT of mice during non-shivering thermogenesis and in diet-induced obese mice. The expression of renalase gene, protein and secretion are significantly higher in differentiated mature brown and white adipocytes compared to preadipocytes. Stimulation of mature brown adipocytes with norepinephrine, the main catecholamine released during cold induced non-shivering thermogenesis in vivo, results in significant increase in renalase expression suggesting the importance of renalase in non-shivering thermogenesis. In white adipocytes, renalase expression is up-regulated in response to treatment with obesity linked adipokines, specifically, leptin and insulin. We report renalase as a novel adipokine expressed and secreted from both BAT and WAT. From our preliminary findings and observations in renalase knockout mice having increased sympathetic activity and circulating catecholamines, we hypothesise "renalase regulates BAT development, thermogenesis and metabolism". Therefore further studies are needed in renalase knockout mice to understand the role of renalase in adipose tissue metabolism which could provide us clues on its role in obesity and insulin resistance. Understanding the mechanisms of renalase action may provide translational data that underpins future treatment in obesity associated cardio-metabolic complications.

Calcium is a ubiquitous signaling molecule involved in various cellular processes, including fertilization, muscle contraction or synaptic transmission. There are two major sources for Ca2+: the extracellular media and intracellular Ca2+ stores, particularly the endoplasmic reticulum (ER). When intracellular stores are depleted, a signal is transmitted from a Ca2+ sensor protein that localizes to the ER membrane (STIM) to the plasma membrane to trigger the opening of the Ca2+ channel Orai. This mechanism, known as store-operated calcium entry (SOCE) activates multiple physiological processes and provides Ca2+ to the SERCA pump to refill the ER stores. To avoid unspecific Ca2+ diffusion in the cytosol, SOCE is a highly localized signal, spatially restricted to dense domains (clusters) created by protein-protein interactions between STIM and Orai. Ca2+-sensitive effectors that respond rapidly to Ca2+ influx through SOCE are therefore in the immediate vicinity of the cluster. We here describe a novel mechanism that expands this Ca2+ signaling microdomain through functional coupling of SOCE, SERCA and the IP3 receptor, to allow efficient activation of Ca2+-activated Chloride channels (CACC) localized away from SOCE clusters. When intracellular Ca2+ stores were emptied using ionomycin, a small CACC activation by SOCE was observed. Conversely, when the stores were depleted following injection of IP3 there was a significantly larger CACC activation (2.5 ± 0.5 nA, n=14 vs 0.08 ± 0.02 nA, n=20). Surprisingly the size of the SOCE current was similar in both conditions, indicating that similar levels of Ca2+ influx lead to different CACC activation. The same mechanism could also be induced when IP3 production was stimulated by lysophosphatidic acid (LPA) and we did show that the cell membrane depolarization induced by LPA required SOCE activation, indicating a physiological function of the process in regulating membrane potential. Ca2+ injection experiments ruled out any increase in the CACC sensitivity to Ca2+, while imaging intracellular Ca2+ levels reflected the amplitude of the Cl- currents Analysis of the localization of the Xenopus CACC (TMEM16a) and of the ER calcium sensor STIM1 indicated that they did not co-localize but rather have a tendency to exclude each other following store depletion. Simultaneous expression of STIM1, Orai1 and SERCA2b tagged with fluorescent markers indicated that the three proteins co-localized in clusters at the plasma membrane following store depletion, creating a very restricted cytoplasmic volume where Ca2+ is increased prior to its pumping into the ER lumen. Finally, GFP-tagged IP3 receptors were not found to be enriched in the clusters. Our results show functional coupling between SOCE, SERCA and IP3 receptors to effectively activate CACCs in response to agonist induced store depletion. Here, Ca2+ entering the cell through SOCE is rapidly taken up into the ER by SERCAs and released through open IP3 receptors close to its target, the CACC. This mechanism extends the function of SOCE to the activation of channels that or not located in the immediate vicinity of the extracellular Ca2+ source without requiring large intracellular calcium events to target distant Ca2+ sensitive elements.

Title: Preliminary Results and Clinical Relevance of Next Generation Sequencing in Hypertrophic Cardiomyopathy Patients in Qatar. Kholoud Al-Shafai 1, Despina Sanoudou 1,2, Paul Barton 3 , Lama Shuayb 1 , Emmeleia Nana 2 , Pothitos Pitychoutis 2 , Rachel Buchan 3 , Roddy Walsh 3 , Stuart Cook 3, Magdi Yacoub 1,3, Mohammed Alhashemi 4 1 Qatar Cardiovascular Research Center (QCRC), Qatar Foundation, Doha, Qatar, 2 Department of Pharmacology, Medical School, University of Athens ,Greece, 3National Heart & Lung Institute, Imperial College London, London, UK. 4Cardiac OPD and Rehabilitation, Heart Hospital, Doha, Qatar. Hypertrophic cardiomyopathy (HCM) is the most common inherited heart muscle disease with a prevalence of 1 in 500 in the general population. HCM exhibits a remarkable clinical and genetic heterogeneity, with over 30 genes being implicated so far. However, the full spectrum of genes and mutations leading to HCM remains to be discovered to help the understanding of genotype-phenotype relationship and its clinical implications. Next generation sequencing (NGS) technologies are powerful tools to study these issues. Here, we utilized NGS technologies to sequence the exomes of over 170 genes including all known HCM genes. Preliminary results of seventeen HCM patients recruited at the Heart Hospital-Qatar is presented, with particular reference to the clinical implications of NGS in early disease detection, diagnosis and disease management. Different previously known HCM disease-causing genetic variants were detected, within sarcomeric genes including TNNI3, MYBPC3, MYL3 and MYH7. Patients carrying those variants were offered genetic counseling and advised for clinical and genetic screening of relatives, leading to the early detection of HCM in a 13 years old boy, coupled with efforts to detect genotype-positive phenotype-negative relatives. Of particular interest are genetic variants found within PRKAG2, NEXN that have not been previously described in HCM and need to be further assessed and screened in relatives. In addition, two genetic variants were detected in SOS1 and RAF1 that were previously related to Noonan Syndrome leading to the diagnosis of Noonan syndrome variants in these patients with cardiac hypertrophy associated phenotype. This is an ongoing program which is expected to yield further valuable information which could influence the management in these patients.

The interest in smart body‐centric wireless networks (BCWNs) for healthcare applications is increasing as clinical acceptance of wireless technology is growing; they potentially combine ease of use with greater independence to the patient. BCWNs are emerging for in‐patient and out‐patient monitoring of ECGs, pulse oximeter, blood pressure, insulin pumps and blood glucose. Coupled with the use of location‐based systems, BCWNs can be applied to ensure the well‐being and safety of aged people in different scenarios with continuous monitoring and tracking. Particularly, Wearable electrocardiogram (W-ECG) recorders are increasingly in use for long-term care for patients with chronic disease, assistive technology for the elderly, risk management for people in rehabilitation, lifestyle monitoring, pre-and post-chirurgical monitoring, and heart anomalies early detection [1]. Devices currently available in the market can typically provide an activity-aware, 2 channels, 3-channels ECG or a 5-channels ECG [2]. However, the systems mentioned are limited in the quality of ECG singles received due to the restrictions on the number of electrodes used. A 12-channels ECG would give a more detailed look at the heart&#39;s three areas (anterior, lateral, inferior), and changes in certain segments of the ECG in the related leads for each area suggest the area of concern. Thus, this work addresses the demand of a wireless activity-aware 12-channels ECG to replace inconvenient wires. Available off-the-shelf programmable sensors is initially applied to test the functionality of the algorithms and also to identify the required components aiding in reducing size and cost. A key point of the successful deployment is a long-term test trial performed within a partnered cardiologist institution, to verify ECGs data against obtained with data from standardized devices. Eliminating wires attached to the patient that usually strap the patient and limit his/her movement and activities would make a patient more comfortable while wearing the ECG system and therefore allow continuous monitoring over a longer period of time. Moreover, the compensation of ECG noise due to the body movement enables the patient to wear the W-ECG while during normal life activities. In this way, a long-term evaluation monitoring the heart activities after a surgery, enabling an early detection of several heart-related diseases or predict heart activity failures can be performed without the patient repeatedly having to visit the doctor or being in bed, with a dramatic improvement of quality of life. Fig. 1 shows measured average power consumption against margins for multi-hop (MH) and single-hop (SH) networks in W-ECG monitoring applications tested on real subject. References: [1] J. Sriram, M. Shin, T. Choudhury, D. Kotz, &quot;Activity-aware ECG-based patient authentication for remote health monitoring&quot;, ICMI-MLMI &#39;09 Proceedings of the 2009 international conference on Multimodal interfaces, Pages 297-304. [2] Shuo Xiao; Dhamdhere, A.; Sivaraman, V.; Burdett, A.; , &quot;Transmission Power Control in Body Area Sensor Networks for Healthcare Monitoring,&quot; Selected Areas in Communications, IEEE Journal on , vol.27, no.1, pp.37-48, January 2009

Background: Developing effective public health policies and strategies for interventions necessitate an assessment of the structure, dynamics, disease rates and causes of death in a population. Lately, Qatar has undertaken development resurgence in health and economy that resulted in improving the standard of health services leading to enhanced life expectancy as was evident in the entire Qatari population (i.e., Qatari nationals and non-Qatari residents). No study has attempted to examine the influence of improving the health services on the homogenous, stable population of Qatari nationals. Objective: The present study examines the population structure and dynamics and the related changes in the cause-specific mortality rates and disease prevalence in the Qatari nationals. Methods: This is a retrospective, analytic descriptive analysis covering a period of 5 years (2007-2011) and utilizes a range of data sources from the State of Qatar including the population structure, disease-related mortality rates, and the prevalence of a range of chronic and infectious diseases. Factors reflecting population dynamics such as crude death (CDR), crude birth (CBR), total fertility (TFR) and infant mortality (IMR) rates were also calculated. Results: The Qatari nationals is an expansive population with an annual growth rate of ~4% and a stable M:F ratio. The CDR declined by 15% within the study period whereas the CBR was almost stable. The total disease-specific death rate, however, was decreased in the Qatari nationals by 23% due to the decline in mortality rates attributed to diseases of the blood and immune system (43%), nervous system (44%) and cardiovascular system (41%). There was a high prevalence of a range of chronic diseases whereas very low frequencies of the infectious diseases within the study population. Conclusion: Public health strategies, approaches and programs, developed to reduce diseases burden and the related death, should be tailored to target the population of Qatari nationals since this population exhibits characteristics that vary from the entire Qatari population.

Background: The incidence of Colorectal Cancer (CRC) peaks in the sixth and seventh decade of life and its precursor lesions a decade earlier in average risk population. American College of physicians (ACP) recent guidelines suggests CRC screening at 50 years of age and older in average risk persons to detect and treat colorectal cancer precursor lesions and early cancers. Objective: To delineate the incidence of Colorectal Cancer (CRC) and Cancer Precursor Lesions (CPL) in the 30 - 49 years age group in symptomatic and asymptomatic average risk population of Doha, Qatar. Method: Lower gastrointestinal endoscopies are routinely done in Qatar for diagnosis and treatment for patients presenting with lower abdominal pain, bleeding or worsening constipation. A retrospective collection of data was done to know the incidence of CRC and CPL among all the patients reporting to our hospital with above mentioned symptoms. Based on the results of this data, a cut off age was calculated with highest sensitivity and specificity for detection of CPL. A CRC screening program was then initiated among asymptomatic subjects with positive immunological fecal occult blood (iFOBT) and age > 40 years were invited for screening colonoscopy. Incidence of CPL (colorectal adenomas) and CRC was calculated prospectively in the average risk asymptomatic population among various age groups. Data regarding the incidence of CRC and CPL among symptomatic and asymptomatic (screened) population was compared. Results: A total of 1489 lower gastrointestinal endoscopies were done in symptomatic patients over a one year period. The mean age was 47.5 years, 935 were males with 71.3 % being expatriates. Overall, among the symptomatic people, CPL were detected in 14.5 % (n= 216) and CRC in 5.6 % (n= 84).Of these, CPL and CRC was detected in 22.6 % (n= 49) and 34 % (n=29) respectively in the age group of 30-49 years. Among the asymptomatic 1242 people who participated in the CRC screening keeping a cut-off age of > 40 years, 57 people (4.6%) were found to be positive for occult blood in stool. Of them, seven and five patients were detected to have CPL and CRC respectively between the age group of 40-74 years. In the 30-49 years age group, CPL was detected in 14.3 % (n=1) but without any CRC. Table 1. Conclusion: One-third of cancers (34%) and one-fifth of cancer precursor lesions (22 %) are detected in the 30-49 years age group in symptomatic patients in Qatar. Among the young (fourth decade of life) asymptomatic subjects, the incidence of cancer precursor lesion remains similar to symptomatic patients but without any obvious cancer. Hence, it is recommended that young symptomatic patients should undergo lower endoscopy early to detect cancer and cancer precursors. Larger studies are required in the asymptomatic subjects of 40-49 years age group to estimate the incidence of pre-cancerous lesions that might benefit from CRC screening.

In recent years a specialist interest has developed worldwide in Advanced Wound Management for difficult to heal chronic wounds. This is timely given the increasing number of elderly in the population and the growing burden of diabetes, obesity and cardiovascular disease that all contribute to an increase in hard to heal wounds. Further progress in Advanced Wound Management will require an improvement in personalised medicine for the patient and in particular an improvement in the availability of diagnostic tests and parameters that fulfil clinical need in wound management decisions. At the current time in wound care there is little available in near patient testing for clinical diagnostics. This research project focuses on a number of metrics for wound condition and wound healing: wound moisture, wound fluid pH, and wound matrix metalloproteinases (MMP) enzyme activity. To observe these important markers a state of the art sensor for wound moisture monitor is being deployed in clinical studies and new sensors are currently in development for both pH and MMP-9 enzyme level. Moisture levels in wounds can determine how well a wound heals and in addition it is possible to make decisions on the need for dressing changes based upon moisture readings taken from inside the dressing. The pH of a wound can affect many different phases of the healing process such as oxygen levels, cell proliferation, protease enzyme activity and bacterial growth. If the pH level of a wound can be effectively monitored then it can act as a biological marker to aid in diagnostics and in establishing the optimum conditions for healing. The pH electrode has not been successfully adapted into smaller and alternate packaging because the membrane that forms the selective part of the electrode, being made of silicon glass, is fragile, thus limiting manufacture, sterilisation and practical application. A disposable sensor has been produced through a screen printing method with an ion-selective membrane. The sensor is able to detect the pH in an operational range in the pH 3.5-10 with as little 10µL of fluid. MMPs are involved in every phase of wound healing. If the balance of the MMPs is upset within a wound it can upset the cellular processes preventing healing and eventually causing further damage to the wound. In chronic wounds the amount of MMP-9 activity has been found to be 30 times more than in acute wounds. By measuring the MMP-9 level of a wound the clinician will be able to choose treatment appropriately to return the MMP level to optimum healing conditions. The project has developed an assay for measuring MMP-9 at physiologically relevant levels between 0.01-100ng/ml. These sensors will enable the wound healing markers of moisture, pH and MMP enzyme activity to be studied and profiled in Hamad Medical Corporation which will further the understanding of these markers and their relationship in the complex healing process involved in chronic wound healing.

Background and Objectives-Salmonella enterica is one of the most commonly reported causes of bacterial foodborne illness around the world. Many factors, including food of animal sources, play a role in the predominance of certain serovars. The occurrence of S. enterica serovars varies between different geographical regions and data on their occurrence in Qatar is lacking. Knowledge on the occurrence of zoonotic serovars and associated factors will help to design cost-effective risk mitigation strategies. This risk of salmonellosis has been exacerbated by the ease of travel around the world, increase in world trade of food and animal items, and continued migration of people. Qatar is one of the countries where the factors that exacerbate the risk of foodborne diseases intersect. We carried out a combination of epidemiologic and molecular studies to investigate the distribution of S. enterica serovars in this highly diverse population, and to identify the factors that play a role in the predominance of a particular serovar. Methods-We carried out a repeat cross-sectional study in which human and non-human samples were collected and Salmonella spp. were detected using a combination of bacterial enrichment and real-time PCR. Salmonella isolates were analysed using the Multi-locus sequence typing (MLST) scheme and assigned accordingly by their eBURST groups (eBGs). We used the minimal spanning tree (MST) analysis to investigate the relationship among the isolates from different sources. Data on putative risk factors were collected and analysed for significance of association with particular serovars. Results-We identified 27 different sequence types (STs) and the most common were ST11 (29.5%) and ST19 (11.5%). Among the 27 STs, seven were novel (ST1695, ST1696, ST1697, ST1698, ST1699, ST1702, and ST1703). The STs related to serovar Enteritidis were ST-11, ST1695, and ST-1702; to Typhimurium were ST-15, ST-19, and ST-568; and to Newport were ST-31, ST-808, and ST-1698. Three of them were revealed to be common serovars in this study. In the MST analysis, three major clusters were presented in the overall population: Enteritidis, Newport and Typhimurium. Furthermore, it also revealed the possibility of transmission of strains between human and animal sources according to the lineages of STs. It was more likely to detect serovar Enteritidis in Qataris and serovar Typhimurium in non-Qataris in this study population. Conclusions—A diverse set of serovars were identified among the samples which could be due to the large scale of emigration and importation of animal feed and products in Qatar. Overall, our data also reveals the possibility of transmission of Salmonella isolates between human and animals; however, a detailed analysis of larger sample over a longer period of time using whole genome sequencing (WGS) could help to shed more light on the dynamics of transmission between these populations.

Background and objectives-Foodborne illness has been determined to be one of the major limitations to the advancement of world health and with the ease of travel around the world and the increase in trade of food and animal products, the risk has been exacerbated in recent years. It has been proclaimed as one of the high priority issues in the Qatar National Food Security Master Plan. Different estimates of burden of disease consistently indicate a high cost per episode, irrespective of the country where the study is conducted. The mechanism by which foodborne pathogens cause disease is complex and the cytolethal distending toxin (CDT) has been identified as one of the virulence factors that contributes to gastroenteritis. The CDT is a trimeric subunit toxin produced by gram-negative bacteria that causes cell-cycle arrest and causes affected cells to die by apoptosis. In an effort to understand the mechanisms by which foodborne pathogens put humans at risk of chronic gastroenteritis sequelae, this study investigated the occurrence of the CDT among Salmonella spp., Escherichia coli serogroups and Campylobacter spp. isolates recovered from animals and humans in Qatar. Methods—Samples collected from animals and humans were screened for the presence of these three foodborne pathogens using a combination of bacterial enrichment and molecular detection. Positive samples were further examined for the presence of the CDT gene and its three subunits (cdtA, cdtB, cdtC) using a polymerase chain reaction (PCR) approach. Results—To date the cdtB gene was detected in C. jejuni and C. coli isolates from animals at a rate of 70 and 89%, respectively. The cdtC gene was detected in 72% of the C. jejuni animal samples examined to date. Only cdtB was detected in Salmonella spp. and E. coli spp. isolates from animals and at a much lower rate. Both cdtB and cdtC were detected at a higher rate among C. jejuni and C. coli recovered from human cases enrolled in this study (Figure 1). Conclusions—The high prevalence of the CDT genes among Campylobacter isolates in both animal samples and human clinical cases suggests a possible critical role for the toxin in the pathogenesis of the diseases caused by these pathogens. By virtue of its toxicity, CDT has been incriminated in the risk of chronic gastroenteritis sequelae, including Inflammatory Bowel Disease and is likely to play role in the risk of this disease among human population in Qatar.

There are obvious and well known links between air quality and acute respiratory illnesses that are common in Qatar and other Middle Eastern countries. For example, recent studies have documented a number of respiratory problems associated with inhalation of dust during dry, windy periods. In Qatar, exposure to dust and sand are anecdotally associated with a variety of respiratory issues including asthma and chronic obstructive pulmonary disease (COPD). These illnesses may be brought about by physical damage caused by the particles themselves, or by microorganisms that can be associated with these particles. In this study we will examine the relationship between different climatic variables, daily airborne particulate matter, and hospital admissions for respiratory problems over an eight month period to establish possible relationships. The results of the study will shed light on the importance of weather phenomena, particularly windy conditions, in impacting respiratory health in Qatar. These data are particularly important as respiratory problems are expected to increase as climate change results in hotter, drier conditions over the next few decades.

Abstract (342 words) Background: The scale and nature of hepatitis C virus (HCV) disease burden in Qatar is poorly known. In addition to establishing the level of infection among the Qatari population, characterizing HCV disease burden is of particular relevance as Qatar has a large expatriate population some of whom are from countries with substantial HCV prevalence. Objective: To investigate the epidemiology of HCV in Qatar among Qataris and expatriate resident populations. Methods: We conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Sources of data included PubMed and Embase databases. Our analysis included all primary studies reporting HCV prevalence or incidence measures in Qatar. Extracted measures were then classified and analyzed on the basis of the study population's risk of acquiring HCV. Meta-analyses were conducted incorporating inverse variance weighting and using a random-effects model to pool summary estimates of HCV prevalence, among general population groups, for Qataris and the population as a whole. Results: We identified seven studies providing a total of 23 measures on HCV prevalence and none on incidence in Qatar. HCV prevalence in the general population was 0.51% (95% confidence interval (CI): 0.43-0.59) among Qataris, and 1.01% (95% CI: 0.43-1.82) overall. Among blood donors the prevalence ranged from 0.3-11.2% depending on country of origin. The highest prevalence was reported among Egyptian migrants followed, though by a large margin, by Pakistani migrants. Among high risk populations, HCV prevalence was as high as 44.6% in hemodialysis patients, 25.8% among cirrhosis patients, and 9.0% among lichen planus patients. Conclusions: National-level HCV prevalence in Qatar is comparable to that in developed countries, but higher prevalence is found in specific expatriate populations reflecting the higher prevalence in the countries of origin. The high prevalence found among high risk groups possibly dates back to exposures that occurred prior to the enforcement of stringent infection control and blood screening protocols, implemented in the 1990s after the virus discovery. Since HCV prevalence is rather low, HCV prevention policy in Qatar should focus mainly on prevention and infection control in clinical settings.

Dilated Cardiomyopathy (DCM) is a leading cause for heart failure characterized by an enlarged ventricular cavity causing systolic dysfunction. Although a multifactorial disease, DCM has been attributed to gene mutations in approximately 30-50% of cases. However, the full spectrum of the genetic basis of DCM remains elusive. QCRC-IGC is a Doha-centered intercontinental consortium comprising teams from Egypt, Greece, UK, Italy and the USA. It aims at discovering novel gene variants implicated in DCM pathogenesis and/or progression, through the establishment of a multinational DCM patient cohort and the genetic investigation of over 170 genes (including all DCM genes) using the cutting-edge technology of Next Generation Sequencing (NGS). Herein we present the genetic screening of sixteen DCM patients (5 sporadic and 11 familial), as confirmed by echocardiography and/or MRI, who did not have a history of alcoholism or coronary angiography findings. Over 1,600 variants were detected in each patient, the vast majority of which represent well documented benign polymorphisms. Forty variants had never been reported before, involving the genes: TTN, SYNE1, MYH6, ALMS1, SDHA, MYPN, LAMA2, TPM1, PLEC, FOXD4, ILK, SGCB and DSP. TTN mutations are being detected in 27% of DCM cases. Of particular interest is the polymorphism observed in the gene DSP, as it was detected in two affected sisters of the same family, it represents the only common potentially pathogenic variant shared between them, and it is bioinformatically predicted to lead to a dysfunctional protein product. Importantly, other mutations in DSP have been previously associated with DCM as well as ARVC. Significant findings of immediate research and ultimately diagnostic/prognostic value are beginning to emerge. Additionally, the discovery of novel pathogenic mutations would unveil promising new therapeutic targets. QCRC is currently intensifying the patient recruitment process at the clinical level, while focusing on the molecular characterization of the emerging novel variants using in silico modeling, induced pluripotent stem cells, and systems biology approaches.

Abstract- Developing visual prosthesis in human cortex or on retina has gained some importance over years. However, visual prosthesis in thalamic region targeting lateral geniculate nucleus (LGN) has few advantages though. This paper proposes a simulation model for deep brain visual prosthesis that will harness the capacity of the residual central visual neurons. This prosthesis creates percepts, substituting an engineered prosthetic for the image capture and early visual processing properties of the LGN neurons that we plan to drive artificially. Introduction- Glaucoma is an incurable neurodegenerative disorder leading to permanent blindness. Glaucoma accounts for blindness in 4-5 million of the world's people and is unusually prevalent in Eastern Arabia. In Qatar, glaucoma is said to account for 40% of its cases of blindness and 16% of people above age 40 are affected by this disease. Restoration of visual function in glaucoma by stem cell therapy or genetic engineering could provide a quite good solution, but the likelihood of these approaches providing a cure for glaucoma in the near term is tenuous. A neuroprosthetic approach offers the most likely short-term treatment for glaucoma-induced blindness. This paper describes early progress made towards designing a visual prosthesis to treat blindness through glaucoma. In glaucoma, there is evidence that the LGN undergoes degenerative changes in human patients [1]. Obviously, LGN degeneration during glaucoma needs to be factored into the design of the electrode array. Design and Concept- The proposed design of the visual prosthetic requires many components (Fig 1). The electrodes are positioned in the dorsal layers of the LGN and all other components located outside the body. Images are captured and adjusted for position of gaze and processed by spatiotemporal filters to provide signals that can be used to drive LGN neurons similar to their natural drive. These signals drive the electrode array with a pattern of stimulation pulses. Electrical stimulation circuitry provides charge-balanced current pulses to the electrodes to activate LGN neurons. Results- An array of electrodes distributed across a semi-elliptical shaped flat surface that interfaces with the top three LGN layers (layers 6-4) is designed. The flat semi-elliptical shaped head, resembling the tip of a knife, facilitates easy penetration through the soft brain tissue. To match LGN dimensions, the head would be 2.5 mm wide, 2 mm deep and 50 µm thick. Fig 2 shows the proposed design with 184 hemispherical shape electrodes placed on either side of the lead with diameters of 50 µm and center to center spacing of 200 µm. The hemispherical shape of electrodes avoids concentration of current density at one place since it does not have any corners or edges. Thus these electrodes deliver uniform current density around the electrode minimizing the electrode and tissue damage. The electrodes are placed in a triangular array to maximize packing density and maintain equal distance between neighboring electrodes. Reference- [1] Gupta, N. et al., 2009. Atrophy of the lateral geniculate nucleus in human glaucoma detected by magnetic resonance imaging. The British journal of ophthalmology, 93(1), pp.56-60.

Design of a new Wavelet-based preprocessing stage for improved time-frequency detection of fetal movements Dr. Taoufik Ben Jabeur and Pr. Boualem Boashash Department of Electrical Engineering, Qatar University Background: Improving Newborn Health Outcomes can be achieved by monitoring Fetal Movement (FetMov) activity which relates directly to the fetus well-being. Several methods exist to record these Fetal movement (FetMov) signals including active (Ultrasounds) and passive ways (accelerometer). Ultrasound is an accurate measurement but expensive and intrusive; for these reasons, capturing FetMov through accelerometer sensors is a preferred option as it is low cost and nonintrusive. In this approach, different sensors are placed on the abdomen of the pregnant woman. Each sensor produces a FetMov signal. The recorded FetMov signals have been shown to be noisy and non-stationary signals containing several artifacts. Thus, a pre-processing stage is required to reduce the noise and eliminate the artifacts. Objectives: This work aims at designing a new pre-processing stage for improving FetMov detection by applying Wavelet de-noising algorithm followed by a threshold given by Kurtosis parameter. Methods: The new method is based on a Wavelet de-noising algorithm followed by a high pass filter to reduce some artifacts. A threshold given by Kurtosis parameter is used in the elimination of the artifacts. Results and conclusion: Simulation results show that the proposed pre-processing stage allows to reduce the noise and to eliminate more than 70% of the artifacts. Few artifacts are still present in the FetMov signals. As the FetMov signal is non-stationary, we use a Time Frequency Matched filter detector (TFMF) based on QTFDs to detect FetMov from these artifacts. The proposed preprocessing stage combined with TFMF detector improves significantly the performance of the detection of the FetMov signal leading to possible improvements in health outcomes for the fetus. Keywords: Fetal movement; Wavelet; Time frequency Matched Filter; Quadratic Time Frequency Distribution.

ABSTRACT Background and Objective HIV and herpes simplex virus type-2 (HSV-2) are sexually transmitted infections, with HSV-2 being nearly 10 times as infectious as HIV. HSV-2 prevalence has been established as an objective biomarker and a proxy measure of sexual risk behavior. HIV epidemics appear to be emerging in the Middle East and North Africa (MENA) region, but the time course and future size of these epidemics are still unknown. We assessed HIV epidemic potential across regions using the association between HSV-2 and HIV prevalence, and based on a global systematic review of HIV and HSV-2 prevalence and meta-analyses. Methods Sources of data were PubMed and Embase databases, and country-level reports. Data on the prevalence of HIV (PHIV) and of HSV-2 (PHSV2) in the same population were extracted from eligible studies. Our analysis included all population groups except adolescents and injecting drug users, where the dominant mode of HIV transmission was not sexual. Studies with sample sizes of less than 50 were excluded. Odds ratios were calculated as (PHSV2/ (1- PHSV2)) / (PHIV/ (1- PHIV)), and relative risks as (PHSV2/ PHIV). Meta-analyses were conducted incorporating the inverse variance method and using a random-effects model to pool summary estimates of odds ratios and relative risks in different geographical regions. Results The meta-analysis included 662 study measures with a total population of 590,220 individuals from 67 countries. The pooled odds ratio of HSV-2 prevalence relative to HIV prevalence was low in Sub-Saharan Africa, Asia, and North America/West Europe, 6.0 (95% CI 5.5-6.5), 10.4 (95% CI 9.2- 11.8), and 13.0 (95% CI 9.9- 17.8), respectively. We found high odds ratios in East Europe 73.6 (95% CI 32.8-165.5), MENA 38.0 (95% CI 15.2-95.0), and Latin America 30.4 (95% CI 22.4-41.4). The pooled estimates of relative risks followed the same pattern as the odds ratios across all regions. Discussion The small odds ratios in sub-Saharan Africa, Asia, and North America/West Europe suggest established HIV epidemics that have likely reached saturation. Meanwhile, the large odds ratios in MENA, East Europe, and Latin America, suggest emerging HIV epidemics that have not yet reached their epidemic potential. These results corroborate recent data about the trend of HIV epidemics in these regions. The findings are of concern for MENA as they suggest that the HIV epidemics are likely to grow within this decade and the next one. HIV response in MENA needs to be expanded through bio-behavioral surveillance, voluntary counseling, testing, and treatment services, and focus on HIV prevention.

Health-related quality of life (HRQoL) measures are important indicators of perceived physical and mental health and are affected by changes in health status, demographic characteristics, culture, and ethnicity. Although recent studies have reported on HRQoL in midlife women in the US, most notably the Study of Women's Health Across the Nation (SWAN), there has been little research conducted on quality of life issues experienced by midlife women in the Middle East. Qatar has a high prevalence of obesity, a known risk factor for many chronic diseases, including osteoarthritis (OA) and rheumatoid arthritis (RA), which adversely influences HRQoL. This study has the following goals: To compare HRQoL among midlife Arab women living in Qatar to that of women in the US, (2) to report the prevalence of osteoarthritis (OA), rheumatoid arthritis (RA), and symptoms of aches and stiffness in joints, (3) to examine the impact of OA and RA on HRQoL, and (4) to compare arthritis prevalence and HRQoL of Qatari women to that of non-Qatari Arab women living in Qatar. This is a cross-sectional study of 841 women aged 40-60 recruited from nine primary health centers. Height and weight were assessed by physical examination and body mass index (BMI) was calculated as weight (in kilograms) divided by the square of height (in meters). Face-to-face interviews included demographic questions as well as questions about whether women suffered from any of a list of medical conditions, including OA and RA. The SF-36 was used to assess HRQoL and eight subscales were computed. A higher score designates a more favorable health status. Overall, women in Qatar had significantly lower mean scores than women in the SWAN for bodily pain (53.0 vs 68.9, p=0.0001) and for vitality (49.6 vs. 54.8, p=0.0001). BMI = 35 was found in 41.4% of women. OA and RA were reported by 4.8% and 4.3% of women, respectively, yet 71.6% reported being bothered by aches or stiffness in joints within the past two weeks. Half of women reported that these symptoms were either quite bothersome or intense. Women who reported having OA or RA had significantly lower scores on physical function (p<0.0001 and p=0.0002, respectively). Those with RA also had significantly reduced functioning for role physical (p=0.001). There was a trend toward lower scores among women with RA on bodily pain, vitality, and social functioning and among women with OA on bodily pain compared to women not reporting arthritis. Qatari nationals had a significantly higher prevalence of OA compared to non-Qatari women (7.4% among Qatari nationals vs. 2.6% among non-Qatari women, p=0.001). Women of Qatari nationality reported lower mean scores on physical function than non-Qatari women (73.3 vs. 80.0, p<0.0001). Midlife women in Qatar reported more bodily pain and reduced vitality than women in the SWAN, which may be the result of joint pain. The high prevalence of obesity may be predisposing women in Qatar to arthritis, which appears to be underdiagnosed given the high prevalence and intensity of joint aches and stiffness. National surveillance of the population is warranted.

All muscles involve the interaction between two sets of filamentous proteins, actin and myosin, that leads to muscle contraction and force production mediated by the hydrolysis of ATP (Adenosine triphosphate). Actin filament structure is understood to high resolution, but myosin filament structure is much less well defined. The myosin filaments are formed from complicated arrangements of myosin molecules and accessory proteins. Myosin molecules are hexameric polypeptide chains, each consisting of two myosin heavy chains (MHC) and four myosin light chains (MLC). Accessory proteins are the myosin binding protein C (MyBP-C) and Titin. We have previously resolved the three-dimensional (3D) structure of myosin filaments in normal human heart muscles (AL-Khayat et al., Proc. Natl. Acad. Sci., USA, 110, 318-323). Mutations in cardiac muscle myosin (MHC or MLC) and its associated proteins (MyBP-C or Titin) are known to be associated with a number of myopathies (e.g. familial hypertrophic cardiomyopathy and dilated cardiomyopathy) which change the proteins involved in producing and regulating heart muscle contraction. In order to understand the effect of myosin-associated heart disease, it is important to understand the 3D structure of myosin filaments in both the normal as well as in the diseased human heart muscles. The aim of this project is to study and compare the arrangement of the myosin molecules and the accessory proteins in the human heart muscle myosin filaments and how these arrangements change in diseased human heart muscles, suffering from either hypertrophic or dilated cardiomyopathies. A laboratory method to isolate myosin filaments from normal undiseased human cardiac muscle that preserves the highly ordered pseudo-helical structure of the myosin filaments has already been developed. This led, for the first time, to the detailed analysis of the 3D structure of myosin filaments from normal human heart muscles by utilizing the experimental technique of transmission electron microscopy (EM) as well as the computational single particle image analysis, 3D reconstruction and structural interpretation. Knowledge of this 3D structure serves as the starting point from which myosin filaments isolated from human cardiomyopathic samples, with known mutations in either myosin or its associated proteins, will be studied later in detail. The 3D structure of mutated myosin filaments will be resolved by a state of the art Electron Microscopy Facility at QCRC which is now underway. This will have both the highest spatial and time resolution for collecting EM images. A laboratory method will also be developed to isolate myosin filaments from human cardiomyopathic samples, which will be examined by EM and single particle image analysis so that to determine the overall 3D structure of myosin filaments in diseased heart muscles. By direct comparison to the known 3D structure of myosin filaments from normal undiseased human cardiac muscle, this would eventually permit the structural effects of known myosin filaments-associated mutations to be investigated in detail as well as to relate structure-to-function-to the overall disease process. Detailed understanding of the disease process would then allow us to design possible.

Background: EEG signal are widely used for detecting abnormalities such as seizures in newborn babies. EEG signals have non-stationary characteristic, therefore time frequency distributions (TFDs) are a preferred tool for their analysis. The classification performance of most time-frequency (t-f) methods is restricted by the resolution limitation of TFDs. Objective: The main objective of this research is to propose a new time-frequency pattern recognition technique that improves the performance of earlier methods by defining a new high resolution data adaptive time-frequency distribution. Methods: The key steps of the proposed t-f pattern recognition scheme are 1. Transformation of an EEG signal in the t-f domain by using a high resolution TFD. 2. Estimation of the instantaneous frequency (IF) and instantaneous amplitude (IA) of signal components. 3. Extraction of statistical features such as mean, variance, skewness and kurtosis from the estimated IF and IA. 4. Training of a support vector machines using extracted features. The accurate estimation of the IF and IA of signal components is a key step of the proposed t-f pattern recognition technique. Estimation of the IF and IA of signal components depends on the ability of a TFD to resolve closely spaced signal component. In order to overcome the resolution limitation of existing TFDs, we define a new high resolution data adaptive TFD that adapts the direction of its smoothing kernel at each point in the t-f plane based on the direction of energy concentration in the t-f plane. The proposed adaptive TFD out performs other standard methods of t-f analysis in terms of its resolution and instantaneous frequency estimation capabilities. Results: The proposed t-f pattern recognition methodology is applied to detect seizure activity in newborn EEG signals. The classification performance of widely used TFDs such as the extended modified B-distribution, compact support kernel, spectrogram, and proposed adaptive TFD is compared using the leave-one out cross-validation technique. The proposed TFD outperforms other TFDs as well as earlier methods of seizure detection by achieving the total accuracy of 97.5%. Conclusions: A new time-frequency pattern recognition technique for the classification of EEG signals is presented. Results indicate that the performance of the time frequency pattern recognition techniques is sensitive to the resolution performance of TFDs as high resolution TFDs have achieved better classification results.

Background. Ovarian cancer is the second leading cause of cancer-related death in women worldwide. Despite optimal cytoreduction and adequate adjuvant therapy, initial tumor response is often followed by relapse. Targeted therapies have been evaluated in ovarian cancer to overcome resistant disease. Among them anti-angiogenic therapies inhibit new blood vessel growth, induce endothelial cell apoptosis, and block the incorporation of haematopoietic and endothelial progenitor cells into new blood vessels. Despite in-vitro and in vivo successes anti-vascular therapy with bevacizumab targeting VEGF has limited efficacy in ovarian cancer. Anti-angiogenic treatment increases hypoxia, and might lead to tumor rebound and drug resistance. The precise molecular mechanisms underlying clinical resistance to anti-VEGF therapies are not well understood. But it became clear that the multiple changes in the stroma may determine the treatments outcome, Hypothesis. We hypothesized that abnormalities in the tumor endothelium may contribute to treatment resistance and produce and promote a residual microscopic disease and resistance to bevacizumab. Methods. We showed that Akt pathway is activated in vitro and in vivo in ovarian cancer endothelium. We used Akt-activated endothelial cells (E4+EC) that replicate tumor endothelium biology, and their control, HUVEC to investigate the anti-angiogenic activity of bevacizumab by angiogenesis and migration assays. We conducted XTT assay to examine the effect of bevacizumab on proliferation of VEGF producing human ovarian cancer cell lines. Expression of FGF-2, phospho-AKT was assessed by western blotting and flow cytometry. Finally, using a feeder-free matrigel and spheroid models of ovarian cancer we examined the effect of bevacizumab on residual disease. Results. Our study describes a comprehensive observational and functional investigation on the pivotal role played by the endothelium in the resistance to bevacizumab. We showed that the cross-talk between ovarian cancer cells and the endothelium activate PI3k/Akt. According to our findings, activated ECs expressing higher amount of VEGF-A tend to be less susceptible to the inhibitory effect of bevacizumab. Bevacizumab had no effect on the proliferation of Akt-activated EC, but significantly inhibited angiogenesis and delayed wound healing in HUVEC. We were able to show most primary ovarian cancer cells and ovarian cancer cells cultures secrete a large quantity of FGF-2 and showed that FGF-2 is able to revert the effect of bevacizumab on HUVEC. Our data suggest that an FGF-2/FGFR mediates a cross-talk between cancer and endothelium and is inviolved in an angicrine switch. We demonstrate the role of Akt-activated EC in supporting expansion and self-renewal of OCC in a residual disease context. Conclusion. We used the E4+ECs as a surrogate for tumor associated endothelium. We showed that an FGF-2/PI3K-AKT autocrine loop is required in ECs to perturb bevacizumab treatment. In summary, our study point out the role of an activated endothelium in the constitution of the residual disease and resistance to bevacizumab.

Both diabetes and cancer are prevalent diseases whose incidence is increasing worldwide and especially in countries that are undergoing rapid industrialization (i.e. Golf Countries). Lifestyle risk factors including diet, physical activity and obesity play a pivotal role in the etiology of both diseases. Epidemiological studies provide strong evidence that subjects with diabetes are at significantly higher risk of developing many forms of cancer and especially solid tumors. In addition to pancreatic and breast cancer, the incidence of colorectal cancer is increased in diabetes. A person with diabetes has a 38% higher risk of developing colon cancer compared to other people. Male diabetes patients were found to have a 20% higher risk of developing rectal cancer. While diabetes and especially type 2 diabetes and cancer share many risk factors, the biological links between the two diseases are poorly characterized. We have evidence that in human epithelial colorectal cancerous cells, either high glucose, insulin or their combination inactivates adenine monophosphate kinase (AMPK), induces the loss of function of the tumor suppressor gene, tuberous sclerosis complex 2, encoding tuberin, activates the mTOR/S6Kinase pathway and enhances the generation of mutagnic DNA, 8-oxodG. We also show that AMPK inactivation upregulates Nox1, which in turn inactivate tuberin and mTOR. These observations were associated with increased cellular proliferation, migration and fibronectin accumulation. Treatment of the cells with metformin, a potent AMPK activator or with rapamycin, an mTORC1 inhibitor, decreases the rate of cellular proliferation and migration and reverse the biochemical changes seen in cancerous cells treated with high glucose, insulin or their combination. In rodent models of diabetes, we find that loss of function of tuberin is associated with loss of function and mutations of OGG1 gene and accumulation of significant amounts of 8-oxodG and activation of the mTOR/S6Kinase pathway. These observations are paralleled by an increase in the levels of ROS production through an NADPH dependent mechanism. These observations indicate a critical role for AMPK, tuberin and mTOR in diabetes progression. These same observations were found in animal models that develop spontaneous colorectal cancer, APC mice. Activation of AMPK or blockage of mTORC1 pathways in the APC mice decreases ROS production, reverse OGG1 mutation and 8-oxo-dG accumulation in the colon and decrease tumor development. Our Findings may suggest that activation of AMPK, blockage of mTORC1 or inhibition of the NADPH oxidases pathways represent potential targets to reduce or to inhibit the onset and the progression of colorectal cancer in diabetes.

Prostate cancer (PC) is the second leading cause of cancer related death in men in several countries and is the most common cancer in men in Qatar according to recent statistics of the years 2010 and 2011. Understanding the molecular mechanisms underlying the development of PC progression is critical for developing novel therapies. Neuroendocrine (NE) differentiation of PC cells is an oncogenic process that has been reported as a mechanism contributing to hormone refractory PC progression. NE cells are found in most prostate adenocarcinoma that are significantly enriched as disease progresses, and are extremely resistant to apoptosis caused by androgen ablation therapy, therapeutic drugs or radiation. However, the mechanism of resistance to apoptosis of these cells is not clearly understood resulting in major impediment in PC treatments. The current study aims to initially identify the optimal conditions to induce NE phenotype in PC cells in vitro and to identify the molecules or pathways responsible for resistance to apoptosis in NE cells of prostate adenocarcinoma. Since NE cells are also quiescent as cancer stem cells (CSC), we investigated the relation between NE cells and CSC. Using the expression of NE-specific markers such as Chromogranin A and Neuron specific Enolase (NSE) an optimal method for the differentiation of PC cells to NE cells was identified and used to generate a repertoire of NE-induced PC cells for genome-wide analysis. Our analysis identified differential regulation of pro-apoptotic and anti-apoptotic molecules in NE cells accounting for resistance to apoptosis. We also show that the NE repertoire is highly enriched in CSC as demonstrated by sphere formation method. The identification of key molecules involved in resistance to apoptosis is critical for the development of novel therapeutic drugs that can interfere with NE differentiation and thus PC progression.

Background: Egypt has by far the highest national-level hepatitis C virus (HCV) prevalence in the world, with more than 14% of the general population infected with the virus. The drivers of such epidemic are still not completely identified, with previous parenteral antischistosomal therapy (PAT) campaigns conducted throughout Egypt proposed as the major contributor of the high HCV prevalence. In an effort to clarify specific drivers of the HCV epidemic in Egypt, and to identify priority populations for HCV prevention interventions, we conducted a comprehensive statistical analysis and mapping of the spatial distribution of HCV infection across Egypt. Methods: We conducted statistical analysis of the world's largest cross-sectional study of HCV conducted by the Demographic and Health Survey in Egypt (EDHS) in 2008 including demographic, health, and HCV biomarker information for a sample of over 11,000 individuals aged 15-49 years. We also identified and compared spatial clusters with high numbers of HCV infections using Kulldorff spatial scan test. The test locates areas with higher numbers of HCV infections than expected under spatial randomness. For each identified cluster, a likelihood ratio test was computed. A P-value was determined through Monte Carlo simulations to evaluate the statistical significance of each cluster. Results: The analysis of the EDHS data indicated that only 9.1% of the population aged 15-59 was exposed to PAT; from this fraction, 28.6% are infected with HCV. These values suggest that PAT might be responsible for only about 8% of the total HCV infections in Egypt. Moreover, ever had a blood transfusion, ever had a dental treatment, and ever had a surgery significantly increased the odds of testing positive for HCV by 54%, 45%, and 28%, respectively. Our results also indicated substantial geographical clustering of HCV infections in Egypt. We identified settings with high HCV prevalence distributed in six geographical clusters located at the interface between the governorates of Beni Suef and Minya, Faiyum, Dakahlia, Kafr el-Sheikh, Monufia, and Minya. Conclusion: The small fraction of the population with previous exposure to PAT suggests that other modes of transmission fueled the HCV epidemic, and could be playing an essential role in the current spread of the HCV infection in Egypt. Our study provides direct evidence for strong geographic clustering of HCV infection in Egypt and locates priority geographic areas for spatially targeted interventions.

Abstract Objective: To compare the efficacy and safety of 5%, 3%, and 0.9% saline solution for treating acute bronchiolitis in the prehospital setting. Study design: This was a double-blind trial including consecutive infants aged <18 months treated in an urban urgent care setting. A total of 165 patients were randomized to receive nebulized 5%, 3%, or 0.9% (normal) saline with epinephrine every 4 hours. The primary efficacy outcome was bronchiolitis severity score improvement at 48 hours (c2 analysis). Scores and oxygen saturation immediately before and after each treatment were recorded to assess safety. Results: A total of 187 previously healthy infants (median age, 3.1 months) diagnosed with bronchiolitis were enrolled. Positivity for respiratory syncytial virus was similar in the 3 treatment groups (mean, 56%). At 48 hours, the mean severity score for the 5% saline group was 3.69 _ 1.09, and that for the 0.9% saline group was 4.12 _ 1.11 (P = .04; difference, 0.43, 95% confidence interval for the difference, 0.02-0.88). The mean severity score for the 3% saline group was intermediate at 4.00 _ 1.22. Revisit rates after discharge were similar in the 3 treatment groups. No adverse reactions or other safety concerns were identified. Conclusions: Nebulization with 5% hypertonic saline is safe, can be widely generalizable, and may be superior to current treatment for early outpatient treatment of bronchiolitis.

Introduction Colorectal cancer (CRC) is increasing in incidence in several Asian countries but screening programs are lacking. In Qatar, ,we embarked on a pilot study for Colo-Rectal Cancer (CRC) screening based at 3 primary health centers among subjects with average risk for colorectal cancer. Aim To devise a national screening program for the early detection of colonic cancer among persons at average risk for Colorectal cancer (CRC) ,based on the outcome of our pilot study Methods All subjects aged 40-74 years at average risk for CRC ie that is individuals without history of polyps or documented cancer or inflammatory bowel disease in the past and absent family history are included. They are subjected to screening by immunochemical fecal occult blood testing at the primary health centers. Subjects positive for stool occult blood undergo total colonoscopy at the tertiary care hospital. Cancers and polyps picked up are documented and subjected to appropriate investigations and therapy Results A total number of 1242 healthy subjects at average risk for CRC, between ages of 40-74 years underwent stool occult blood testing by immunochemical fecal occult test. 57 (4.5%)were found to be positive and referred for colonoscopy. Of the 57 eligible persons, invited for colonoscopy, 32(56.4%) underwent the procedure , of whom 7 had polyps and 5 patients had cancer or advanced adenoma. Conclusions Cancers and adenomatous polyps which are treatable and curable can be successfully picked up by primary care level screening programs. Relevance, feasibility and cost effectiveness of such screening programs in Middle East has to be confirmed by community based programmatic screening studies in our region