bluuebunny/crossref_metadata_2025 huggingface dataset:
A mutation at the H2B histone family [H2BFWT] gene causes a novel X-linked mental retardation with abnormal head shape syndrome
Authors: Chini Vasiliki , Ali Rehab , Khattab Namat , Omran Tawfeq Bin , Al-Sarraj Yasser , Kambouris Marios , El-Shanti Hatem
Published: November 2013

A non-consanguineous Arabic family affected by a putative novel seemingly X-linked disease characterized by mental retardation and abnormal head shape was studied by gene mapping, candidate gene mutation screening and whole X chromosome Exome sequencing of a single affected member to identify the responsible gene defect. Clinical presentation includes mental retardation, hyperactivity, hypotonia, turricephaly (in one affected), dolichocephaly (in the other affected), narrow face, downward slanted palberal fissures, large ears, open mouth appearance, long and slender fingers. Neurologic and metabolic evaluations including urine organic acid, lysosomal enzyme analysis, gaunidinocompound, CDG and Fragile-X syndrome were negative. SNP genotyping with the HumanOmniExpress bead chip [Illumina, USA], analyzed with the GeneMapper software mapped the responsible gene to four possible X-chromosome intervals [p22.33-22.2, p22.2-21.1, p31.1-q22.3, q26.3-28] as the family structure did not allow identification of a single interval with a significant LOD score. Based on the clinical presentation one candidate gene (FGF16) was screened but no pathogenic mutations were identified. Whole Exome target enrichment Next Generation Sequencing for the X chromosome was performed on the ABI SOLiD4 platform for a single affected individual. Three variants were identified within the linkage intervals: AMMECR1 [c.C208T/p.L70F] was excluded as it did not co-segregate with the disease phenotype. A second variant (c.C11T/p.P4L) in the Rab40 GTP-binding protein gene (RAB40AL). Pathogenic mutations within this gene have been associated with Martin-Probst X-linked mental retardation syndrome (MRXSMP) which presents with a different phenotype characterized by hearing loss. The last variant (c.G227A/p.C76Y) at the H2BFWT histone family gene has damaging effects according to PolyPhen and SIFT protein-modeling software, co-segregates to the disease phenotype and is absent in 752 ethnically matched control chromosomes. No known diseases have been associated with mutations in H2BFWT apart from male infertility. Tissue specific H2BFWT expression studies show expression in human fetal brain, making this mutation the likely developmental defect. At present, mutation analyses in additional healthy normal maternal male relatives are underway for the possible exclusion of H2BFWT as the offending gene.
Human hexokinase 2: A key enzyme and promoter of tumor growth
Authors: Mir Nawaz Hussain , Rabeh Wael
Published: November 2013

Malignant tumors metabolize glucose through glycolysis to lactic acid and produce ATP at an accelerated rate when compared to normal cells, a phenotype detected clinically using Positron Emission Tomography (PET). Out of the four available isoforms, Hexokinase 2 (HK2) is the major expressing isoform in cancers specially those that metastasize and kill their human host. In malignant cells, HK2 not only improves the cell's energy supply but also protects cancer cells against apoptosis through direct interaction with the mitochondria and Voltage Dependent Anion Channel 1 (VDAC1). Here we report the 3D crystal structure of the human HK2 in complex with glucose and glucose-6-phosphate, the first enzyme in the glycolytic pathway. The N- and C-terminal domains are catalytically active and linked by a long seven turn a-helix. Each domain contains an active site that is sandwiched between a small and large sub-domain. Cancer patients with high HK2 gene expression level showed a worse prognosis and aggressive character. Therefore, HK2 is an ideal therapeutic target to inhibit cancer proliferation and tumor destruction. Very limited literature describes HK2 and detailed understanding of the HK2 structure and function is needed to characterize its mechanism, to understand its role in cancer metabolism and to develop new drug treatments to slow the rate of cancer proliferation.
Identification of de novo and rare inherited mutations in autism spectrum disorder probands from Qatar by whole genome sequencing.
Authors: El-Shanti Hatem
Published: November 2013

Autism spectrum disorder (ASD) is a clinically and etiologically heterogeneous condition with high prevalence amongst all world populations. Due to the life long morbidity, ASD poses a profound world-wide public health challenge. Despite its obviously high heritability, a genetic cause is only identified in a small fraction of patients due to its complex etiologic heterogeneity. Recently, whole genome sequencing (WGS) emerged as a powerful tool for variant discovery due to its comprehensive and uniform coverage and is expected to be beneficial for studying ASD. We used WGS to examine 20 families with ASD, mainly from Qatar, as well as from a few other Arabic countries, to detect de novo or rare inherited genetic variants predicted to be of pathogenic significance. All probands were diagnosed with ASD by at least an ADI-R (Autism Diagnostic Interview-revised) evaluation, in addition to other screening or confirmatory tools and were recruited from the Shafallah Center for Children with Special Needs. Due to the nature of the ascertainment source, all probands had associated intellectual impairment. In all probands known causes of ASD were excluded, fragile X syndrome by PCR and Southern blott, Rett syndrome (for females) by Sanger resequencing and MLPA and Copy Number Variations (CNV) by SNP genotyping on an Illumina 1M-Duo SNP chips. Among all probands, we identified deleterious de novo mutations in six (30%) families and inherited X-linked in two families (10%). We did not identify any inherited autosomal dominant mutations, but identified putative inherited autosomal recessive varations in three families (15%). The deleterious de novo variants were found in five previously unrecognized autosomal genes, and in one known autosomal ASD gene. The inherted X-linked variations were found in ASD risk genes. We are interested in deeper examination of the putative variations with autosomal recessive pattern of inheritance, since the parents of 60% of the probands are consanguineous. The deeper examination will employ the study of knock-out and knock-in mouse models and different in silico and in vitro protein modeling studies. These results so far suggest that WGS of a trio coupled with thorough bioinformatic analyses provide a powerful diagnostic tool in ASD. It is also a potent methodology for gene discovery in ASD, which may provide the basis for genetic testing for early diagnosis and early targeted intervention with a final goal of better outcome.
Antibacterial, antitumor and antioxidant of bioactive compounds extracted from secondary metabolites of the fungus Rhizoctonia solani Kuhn
Authors: Muhsin Tawfik
Published: November 2013

Abstract The aim of this study is to examine the bioactive compounds from secondary metabolites of the fungus Rhizoctonia solani against some selected strains of pathogenic bacteria. The fungus grown in a fermented culture and the filtrate was extracted in different chemical solvents. The fungal crude extract was used to examine the bioactivity against six strains of bacteria using disc diffusion method. The results showed that the fungal extract exhibited highest growth inhibition against E. coli (34 mm inhibition zone) and S. aureus (38 mm). The minimal inhibitory concentration (MIC) values were 12.5 ug/ml and 6.5 ug/ml against E. coli and S. aureus, respectively. The fungal crude extract did not show any toxicity against human red blood. A comparison between bioactivity of the fungal extract with five commercial drugs against the tested bacteria showed that the fungal extract exhibited a significant bacterial growth inhibition than the commercial drugs. Meantime, the fungal extract showed an antitumor bioactivity by using tumor cell-line of Hep2 at low concentration (0.05 mg/ml). Also the fungal extract revealed an antioxidant action by using Fe II reduction test. Chemical analysis by using FT-IR, HNMR, and GC-Mass techniques indicated that the fungal extract composed of two main chemical compounds; Malonic acid, 2, 4-dimethyl-3-yl ethyl ester with a chemical formula C12H22O4 and Molecular weight of 230 kd and Pentanedioic,2-oxo-dimethyl ester with a chemical formula C7H10O5 and molecular weight of 174 kd. It can be concluded that the fungus R. solani possesses a potential bioactive compounds as a promising agents in medical therapy.
Symptomatic treatment approach does not appear to be effective in controlling Chlamydia trachomatis transmission
Authors: Omori Ryosuke
Published: November 2013

[Background] Chlamydia trachomatis (CT) is one of the most common bacterial sexually transmitted infections (STIs) worldwide, and is a major cause of pelvic inflammatory disease, infertility, and ectopic pregnancy. A recent study has found larger than expected prevalence of CT in Qatar, with a prevalence of about 5% among women attending primary health-care centers. The driver of such higher than expected prevalence is not clear. We examined whether the lack of screening programs for CT could contribute to explaining this level of prevalence. [Method] We constructed a mathematical model to examine the public health impact of different CT treatment approaches. The model was parameterized by the prevalence of CT in Qatar along with state of the art empirical evidence of CT natural history and transmission. The population was divided into different risk and age groups, and a mixing matrix was introduced to describe the mixing between these groups. The impact of treatment was assessed at endemic equilibrium. Univariate sensitivity analyses were conducted. [Results] Nearly 63% of CT infections in the population were asymptomatic. A symptomatic treatment approach, where 90% of symptomatic cases were treated, reduced CT prevalence by only 6.5%. An opportunistic screening program, where 20% of the population was screened annually for CT, reduced the prevalence by 36%. Routine screening program, where 50% of the population was screened annually for CT, reduced the prevalence by 93%. The large impact of screening on CT transmission was driven not only by the diagnosis of asymptomatic infections and treating them, but also by reducing effectively the duration of the infectious period during which infected persons can transmit the infection to other individuals. [Discussion] Our results suggest that a key contributor to the higher than expected prevalence of CT in Qatar, is the non-availability of CT-specific screening programs to detect and treat asymptomatic CT infection, such as those available in West Europe and North America. Current programs that focus on treatment of syndromic cases are missing the majority of cases. The undiagnosed infections are driving further transmissions, and a larger CT prevalence. Opportunistic targeted screening could be a meaningful starting point for CT screening programs in Qatar, with potentially routine Pap smear testing as an entry point. Our findings indicate the utility of developing STI-specific programs in Qatar as part of the large expansion of health care services in this country. Detecting CT infections and linking them with appropriate treatment channels could alleviate an unnecessary disease burden and its consequences in the population.
Osteopontin regulates hypoxic induction of NHE1 activity in H9C2 cells
Authors: Bouchoucha Soumaya
Published: November 2013

Osteopontin regulates hypoxic induction of NHE1 activity in H9C2 cells. Soumaya Bouchoucha, Fatima Mraiche Hypoxia, an important component of ischemia, is the result of an imbalance between oxygen supply and demand. Severe impairment of oxygen supply may result in a maladaptive cardiac phenotype. During myocardial ischemia, the Na+/H+ exchanger isoform 1 (NHE1), the main regulator of pHi, has been shown to be increased. It has been shown recently that NHE1 elevation increases Osteopontin (OPN) expression, a matricellular protein and proinflammatory cytokine that has been reported to have a protective role in ischemic injury. In this study we tested the hypothesis that hypoxic induction of NHE1 expression and subsequent alterations in H9c2 cells are mediated by OPN. H9c2 cardiomyoblasts were infected with GFP, NHE1 in the presence and absence of OPN adenoviruses following a hypoxic insult using cobalt chloride (CoCl2). Western blotting was performed to investigate the expression of OPN and NHE1. NHE1 activity was measured using BCECF-AM. H9c2 infected cells exposed to hypoxia were characterized by measuring cell viability. Inducing hypoxia for 6 hours caused a significant decrease in cell viability in H9c2 cells (GFP: 87±2.5% Vs 70.76±8.17% GFP + hypoxia; P<0.05). In NHE1 + hypoxia infected cells, viability was significantly lower than the control (NHE1 + hypoxia: 69.36±13.71% Vs 100.0 GFP + hypoxia; P<0.05). Interestingly, when overexpressing both OPN and NHE1+hypoxia, cell viability tended to increase. Compared to the control groups, CoCl2 increased the rate of recovery, which reflects the activity of NHE1, in all groups. These results were accompanied by an increase in OPN expression in the NHE1+ hypoxia infected cells (NHE1 + hypoxia: 167.36±10.01% Vs. 100.0 GFP + hypoxia; P<0.05), which validates that NHE1 activates the expression of OPN under hypoxic conditions. These results reveal a suspected role of osteopontin in protecting cell against ischemic injury owing to the increase of NHE1 expression and activity. Taken together, identified osteopontin may function as a survival factor against hypoxic induction of NHE1 cell death. Keywords: NHE1, Osteopontin, hypoxia.
Output-feedback sliding mode control for a nonlinear multicompartment respiratory system with amplitude and integral input constraints
Authors: Meskin Nader
Published: November 2013

Acute respiratory failure is one of the major causes for concern in intensive care units (ICU). It is a condition that occurs when fluid builds up in the air sacs in the lungs. When this happens the lungs cannot release oxygen into the blood and get rid of carbon dioxide from the body. The lack of oxygen in the blood will cause the organs to malfunction and in severe cases could lead to failure of vital organs such as heart and brain. Patients with acute respiratory failure are usually supported by the mechanical ventilator. The goal of mechanical ventilation is to ensure adequate ventilation, which involves a magnitude of gas exchange that leads to the desired blood level of carbon dioxide, and adequate oxygenation, which involves a blood concentration of oxygen that will ensure proper function of vital organs. A plausible reference lung volume pattern, which corresponds to an optimal patient outcome, is specified by clinical personnel and the task of automated mechanical ventilation is to apply appropriate input pressure so that the output from the system is able to track the given reference voulme pattern. One of the main challenges in mechanical ventilation that needs to be carefully considered is that the applied pressure cannot be arbitrarily large since large applied pressure could potentially damage the lungs, and hence, worsen patients outcome. Another challenge in designing an efficient control algorithm for mechanical ventilation is that the parameters characterizing the dynamics of the lungs, that is, the lung resistances and lung compliances, vary from patient to patient as well as within the same patient under different conditions. Furthermore, the volume of each compartment of the lungs cannot be directly measured and only the total volume of the lungs is available. Therefore, a robust control methodology, which only uses output information and limited applied pressure, is needed in order to design an efficient control algorithm for automated mechanical ventilation. In this research work, we propose an output-feedback sliding mode control methodology for a nonlinear multicompartment respiratory system with amplitude and integral input constraints. The amplitude input constraint is needed to ensure that the applied pressure is not too large, as not to damage the lungs, while the integral input constraint enforces the upper bound on the amount of work done by the ventilator. The proposed controller only uses output information (i.e., the total volume of the lungs) and automatically adjusts the applied input pressure so that the system is able to track a given reference volume pattern in the presence of parameter uncertainty (i.e., modeling uncertainty of the lung resistances and lung compliances) and system disturbances. A Lyapunov-based approach is presented for the stability analysis of the system and the proposed control framework is applied to a two compartment lung model to show the efficacy of the proposed control method.
Hypertension in Middle-Eastern Arab and South-Asian patients hospitalized with atrial fibrillation: From a 20-year registry in Qatar (1991-2010)
Authors: Salam Amar
Published: November 2013

Background: Most of available literature on atrial fibrillation (AF) is based on studies in the developed world and included mainly Caucasian patients. Data about AF in other ethnicities is very limited. The aim of the current study is to evaluate the effect of hypertension (HTN) in Middle-eastern Arab and South-Asian patients hospitalized with AF from a 20 year national registry in a Middle-Eastern country. Methods: Retrospective analysis of all patients hospitalized with AF in Qatar from 1991 through 2010 was made. Patients were divided into two groups according to the presence or absence of HTN on presentation. Clinical characteristics and outcomes were analyzed. Results: During the 20-years period, 3850 patients were hospitalized for AF; 1483 (38.3%) had HTN on presentation while 2367 (61.5%) had no HTN. HTN patients were 11 years older, had significantly more prevalence of diabetes mellitus, chronic kidney disease and dyslipidemia on presentation. Underlying coronary artery disease and heart failure were significantly more common in patients with HTN while valvular and rheumatic heart disease was more common in non-HTN patients. The in-hospital mortality and stroke rates were significantly higher in HTN patients (5.3% versus 3.5%, and 0.7% versus 0.2% respectively, p= 0.001) [table]. Conclusions: Our study demonstrates that in a cohort of Middle-eastern Arab and South-Asian patients hospitalized with AF, HTN is significantly associated with worse in-hospital outcomes. Our study underscores the need to study AF in different ethnicities.
Betaine feature as a powerful tool in prevention of biofouling of biosensor surfaces and membranes
Authors: Kasak Peter
Published: November 2013

Various betaine materials - single molecules or polymers - represent one of the best tools for prevention of biofouling on surfaces due to their biomimetic character and unique properties [1]. Betaines consist of internal salts in a single unit between positive quaternary ammonium and negative sulfo, carboxy or phosphate groups. This contribution highlights our progress in preparation and application of betaine materials to resist non-specific interactions on a surface of biosensors and membranes. Various betaine derivates with sulfo- [2] or carboxylbetaine groups were synthetized from lipoic acid as a natural precursor. Disulfide moiety from lipoic acid structure assists in attachment of a betaine derivative to a gold surface applied for preparation of biosensors. Biosensor devices were characterized by a set of tools including electrochemical impedance spectroscopy, FTIR, AFM, XPS, QCM, etc. Betaine derivatives introduced to the surface of various biosensors allowed their effective work in complex samples such as human plasma with a high reliability of detection and with a detection limit down to a femtomolar level for detection of specific glycoproteins. Carboxybetaine derivate provided a dual function for preparing biosensors i.e. a non biofouling surface and introduction of functional groups for covalent immobilization of sensoric biomolecules after performing a NHS/EDC coupling chemistry, as well. Moreover, formation, characterization and application of nanofibres and hydrogel from sulfo and carboxybetaine polymer as a membrane precursor will be discussed. Optimal formation of nanofibres was performed via an electrospinning process from trifluoroethanol solution. Characterization of membranes prepared was done by water sorption, FTIR, AFM and SEM techniques. Preliminarily proteins and cells attachment tests showed a dramatic decrease in adsorption and adhesion. Keywords: betaines, biomimetic, biosensor Acknowledgement: The financial support from the Slovak research and development agency APVV 0282-11 is acknowledged. The research leading to these results has received funding from the European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013)/ERC Grant Agreement No. 311532 References: [1] P. Sobolciak, I. Lacik, P. Kasak Chem. Papers, 2011, 105, 918-925. [2] T. Bertok, L. Klukova, A. Sediva, P. Kasak, V. Semak, M. Micusik, M. Omastova, L. Chovanová, M. Vlcek, R. Imrich, A. Vikartovska, J. Tkac Anal. Chemistry 2013, 85, 7324-7332.
High resolution optical mapping of cardiac tissue slices: A powerful tool in heart research
Authors: Bollensdorff Christian
Published: November 2013

Heart failure (HF) is one of the most common causes for death, to prevent HF the understanding of the (patho-)physiology is key and the development of efficient tools is an important contribution for cardiac research. Cardiac tissue slice is an increasingly popular model for cardiac electrophysiology research and pharmacological compound testing. We use optical mapping to investigate cardiac tissue slices. In this study, we perform dual imaging of trans-membrane potential (Vm) and the intracellular free calcium concentration transient (CaT) in tissue slices from the rabbit, using a relatively high spatio-temporal resolution. We detail our method for processing of the data to extract relevant characteristics of the action potential (AP) and CaT. We found that slices needed a recovery time of about 40-70 minutes after cutting, before the AP reaches a steady-state. To characterise the CaT, AP and conduction properties, we used a combination of multi-point and field stimulation, to avoid results biased by source-sink mismatches. The tight control of experimental conditions (e.g. slice 'recovery protocol' and stimulation method), leads to reproducible results, this was shown in our other studies based on using this standardised methodology [1,2]. The monitoring of multiple parameters (Vm, CaT) simultaneously at high spatial resolution (compared to patch clamp, sharp electrode, or multi-electrode arrays) allows one to study not only the properties of each parameter in a spatially detailed manner, but also the spatio-temporal interrelation between them. Especially for drug safety studies this method is superior to lower resolution methods. References: 1. Lee P, Klos M, Bollensdorff C, Hou L, Ewart P, Kamp TJ, Zhang J, Bizy A, Guerrero-Serna G, Kohl P, Jalife J, Herron TJ (2012) Simultaneous Voltage and Calcium Mapping of Genetically Purified Human Induced Pluripotent Stem Cell-Derived Cardiac Myocyte Monolayers. Circ Res 2. Lee P, Wang K, Woods CE, Yan P, Kohl P, Ewart P, Loew LM, Terrar DA, Bollensdorff C (2012) Cardiac electrophysiological imaging systems scalable for high-throughput drug testing. Pflugers Arch 464 (6):645-656. doi:10.1007/s00424-012-1149-0
علاج التوحد بدون أدوية باستخدام برمجة العقل
Authors: Hassan Mohammad
Published: November 2013

الفكرة هي اعتبار عقل الطفل لا يوجد به البرنامج التشغيلي ي للعقل أو أن برنامج التشغيل الأولي لا يعمل كما يجب وهو فرضية أن عقل الطفل عندما يولد يكون عقله محمل ببرنامج مكتسب من الجينات وضعه الخالق سبحانه وتعالى نصه * انتبه إلى ما هو مكرر في بيئتك * انتبه إلى المثيرات البصرية التي تتكرر * انتبه إلى المثيرات السمعية التي تتكرر * سوف تتعرف على نفسك ومن حولك في حالة الطفل تم إهماله في الشهور الأولى مثل ترك الطفل ليشاهد قنوات الأطفال في أول 6 أشهر أو أن الدماغ لم يحفز فيصبح اقل نشاطا في السنوات اللاحقة فيكون اهتمام العقل بالأشياء التي اعتاد عليها فقط مثل اللعب الفردي بدون هدف الاهتمام الأكبر بقنوات الأطفال مع عدم الاهتمام بأي جديد وتكون سرعة التعلم بطيئة جدا بدليل انه لا يستجيب لنداء أمه 80 في المية من أطفال التوحد هم حالات طيف توحد ناتج من ترك الطفل أمام التلفزيون في العام الأول أو عدم تفاعل مع الطفل مثال تركه لخادمة غير عربية وبذلك يحدث خلل في البرنامج التشغيلي لعقل الطفل وهو ما يجعل الطفل كأنه فاصل عن الشبكة الخارجية لا يستجيب للنداء لا يطيل النظر ينعزل - وهذه الطريقة تصلح بنسبة مرتفعة بمثل هذه الحالات الطريقة هي وضع برنامج لعقل طفل التوحد يختلف هذا البرنامج باختلاف ما ينقصه لإعادة تحفيز البرنامج الأصلي الناتج من جينات الطفل هذا البرنامج يساعد على أن يعرف الطفل نفسه من هو ومن حوله ويبدأ من الصفر بداية التعلم ولكن بشخصية أخرى ويصبح على الفطرة طريقة البرمجة سريعة و مشجعة بفضل الله وسريعة قد تكون هذا العام احدي الطرق الرئيسية لكسر سمات التوحد في العالم طفلا عمره الزمني 4 سنوات وعمره العقلي 2 سنه سيبدأ إعادة تشغيل للعقل بعمر سنتين وكأننا قمنا بإعادة تشغيل الجهاز reset ويقوم بإعادة تحفيز البرنامج الأصلي فينتبه إلى ماهو مكرر سينتبه إلى المثيرات البصرية والسمعية وتنشط جميع الحواس ذاتيا فيبدأ العقل بضبط كيماويا ت العقل وهرمونات الجسم ذاتيا فيبدأ بالتعلم ويقود الدماغ الى اكتساب المعرفة وتختفي تدريجيا أعراض سمات التوحد وتزداد سرعة التعلم ويجب تكثيف برامج التعلم له ليستطيع تعويض ما فاته الاستجابة لبعض الأطفال في الأسبوع الأول حتى مشاكل الهضم سواء إمساك أو إسهال أما إذا كان العقل لا يحتوي على البرنامج التشغيلي أصلا نتيجة خلل ما أو نتيجة لمرض وراثي أو كان سبب التوحد خلل في الجينات نتيجة تعرض الأب أو الأم لأدوية قبل الحمل أو أن مخ الطفل لم يكتمل فطريقة البرمجة إلى الآن لم تعطي نتائج طريقة العلاج إرسال الاسئلة لمعرفة سلوك الطفل في العام الأول الأدوية المستعملة التشخيص بعد الإجابة على الأسئلة ومعرفة هل تصلح الطريقة أم لا يتم كتابة البرنامج الأول ويرسل إلى الأسرة يتم تسجيل البرنامج بصوت الأب والأم و إرساله لنا نقوم بعمل فلترة و دمج ذبذبات مكافئة لموجات الدماغ الثيتا سواء كانت طبيعية أم من أجهزة مع دراسة مراحل النوم وإعادة الملف الصوتي ليسمعه الطفل في أوقات محدده منها أثناء النوم المميزات تصلح لجميع اطفال العالم تم التطبيق على طفل مقيم بأمريكا على طفل مقيم بايطاليا باللغة الايطالية وتسجيله بصوت الام تم تطبيق البرنامج على طفل كردستان العراق تم التطبيق على عشرات الاطفال من السعودية ومصر السودان المغرب تونس لا نحتاج الى رؤية الطفل
Haemodynamic Changes Due To Increased Severity In Stenosed Carotid Artery
Authors: Abdul Khader Shah Mohamed
Published: November 2013

The computational advances in recent times have led to analysis of the complex interaction of blood flow through elastic artery. This aids in prognosing the progression and behaviour of cardiovascular diseases like atherosclerosis, aneurysms etc. In the present investigation, an idealistic 66% eccentric stenosed common carotid artery is analyzed under normal blood pressure condition based on clinical data obtained from ultrasound measurements and 3D FSI model is generated in ANSYS, commercially available Finite Element Analysis software. The blood flow is assumed to be incompressible, homogenous and Newtonian, while artery wall is assumed to behave linearly elastic. The two-way sequentially coupled transient FSI analysis is performed using FSI solver in ANSYS-10.0 for three pulse cycles and haemodynamic parameters such as flow pattern, Wall Shear Stress, pressure contours and arterial wall deformation are studied at throat and downstream of the stenosis. Further, the flow changes with varying the severity of stenosis is also attempted to investigate the changes in flow behaviour by varying the percentage of stenosis in terms of 75%, 80%, 85%, 90% and 95%. Comparison of results concludes that, with the increase in severity of stenosis, the flow changes abruptly causing a significant increase in velocity and WSS at throat region, while highly complex flow is observed in the downstream of stenosis leading to formation of eddies. During flow deceleration, flow is further highly turbulent due to the effect of back pressure and considerably altering the flow behaviour in the downstream end. The results obtained agree very well with available clinical observation during various stenosed conditions.
In Vitro Effects Of Cxcl4 Chemokine On Colorectal Cancer Cell Line
Authors: Adwan Hassan
Published: November 2013

Introduction The CXC-chemokine CXCL4 is released from alpha granules of activated platelets and is involved in platelet aggregation. This protein is a chemo-attractant for numerous other cell types and also functions as an inhibitor of hematopoiesis, T-cell function, tumor-induced angiogenesis and modulation of host inflammatory response. Due to its multiple functions, CXCL4 is a potential clinical anti-tumor target. We examined the effects of the CXCL4 gene on biological properties of a colorectal cancer cell line by in vitro functional tests. RNA interference (RNAi) methodology by means of gene specific stealth siRNA technology was used to control the expressional level of the CXCL4 gene. Aim of study * To determine the effect of CXCL4 knockdown by RNAi methodology on biological properties of CC531 cells in vitro. * To evaluate the role of CXCL4 gene in colorectal cancer and later on its metastasis in animal rat liver model. Materials and Methods * Rat colorectal CC531 cancer cells were inplanted into the rat liver. After selected time intervals, CC531 cancer cells were re-isolated and their expression profile was studied by mRNA micro-array analysis. In vitro cultured CC531 cells were used as control in this study. * Transient knockdown of the CXCL4 gene was achieved in CC531 cells by using Lipofectamine 2000 transfection reagent along with 100nM gene specific stealth siRNA. * After 24, 48 and 72 h of treatment with siRNA, the extent of knockdown of CXCL4 was determined at mRNA level by RT-PCR and qPCR. * Functional effects of CXCL4 knockdown on CC531 cells were investigated by proliferation, colony formation, migration and scratch assays. Results In vivo Expression of CXCL4 Implanted colorectal CC531 cancer cells exhibited 3-4 times lower expression in the rat liver for an initial period of 3 weeks and came back to normal level after week 4. Knock-down of CXCL4 Exposure to siRNA species reduced the expression of CXCL4 at mRNA level after 24-72h with maximum reduction of 70% after 24h. MTT Assay Following the post-transfection period, we found a moderate decline in cell proliferation by 20, 26 and 8% for 24, 48 and 72h, respectively, in knockdown CC531 cells. Colony Formation Assay We observed reduced ability of knockdown CC531 cells to produce small and large colonies. Migration Assay Significant reduction in directional migration was observed in the knockdown CC531 cells especially after 48 and 72hr. Scratch Assay Photomicrographs, obtained after 12 and 24 hours of scrape wounding showed a significant reduction of knockdown CC531 cells to cover the scratched area as compare to control CC531 cells. Conclusion Higher expression of CXCL4 contributes to enhanced cell proliferation, migration, colonization and wound healing abilities of colorectal CC531 cancer cells in vitro. Based on these preliminary results, we will also study the effect of CXCL4 in a liver cancer metastasis model to evaluate an anticipated correlation with colorectal cancer progression.
Riproximin Is A New Plat Lectin With Antineoplastic Activity Aganist In Rat Pancreatic Cancer.
Authors: Adwan Hassan
Published: November 2013

Purpose: Pancreatic ductal adenocarcinoma (PDAC) has one of the worst prognoses of all malignancies. At time of diagnosis, 80% of patients with PDAC have unresectable tumors, and conventional therapies are nearly ineffective. The relative poor efficacy of chemo/radiotherapy against PDAC indicates that the development of new therapeutic strategies is a crucial step to improve the survival of patients with this disease. This includes the modification of established therapies, the testing of new targets and the improved delivery of drugs to their target. Riproximin (Rpx) is a new plant agent, which was isolated from the plant Ximenia Americana. Riproximin was classified as a ribosome inactivating protein (RIP) of type II and its anticancer activity has been recently demonstrated in vitro and in vivo Methods: In vivo experiments The rat pancreatic cancer cell line (ASML) was used for its property to mimic liver metastasis in nude rats, as shown before (Eyol et al). Tumor-bearing rats were treated intravenously with different concentrations of Rpx as single agent or in combination with gemcitabine (GEM) or dinaline (DIN). Ripx was administered twice weekly at doses ranging from 500µg/kg to 1500µg/kg. GEM and DIN were administered to animals for a period of 2 weeks either intravenously at a dose of 50mg/kg or perorally at a 5 times weekly dose of 10mg/kg. 98 representative apoptosis genes were analyzed by quantitative-RT/PCR in with Rpx treated cells in comparison to untreated cells. Results: The intravenous administration of Rpx (1500µg/kg and 500µg/kg) reduced the tumor growth significantly by 61% and 67%, respectively (p=0.00174 -p= 0.00024). The survival rate was also significantly increased (21.8 days for riproximin treated versus 17.6 days in untreated control rats; P=0.01349) after the intravenous administration of Rpx. Rats, which were treated with the high dose of Rpx showed no further reduction in tumor size, when compared with rats treated with the low dose. In comparison, no significant effect on tumor size or on survival was observed after treatment with gemcitabine or dinaline. The combination therapy with Rpx and GEM as well as Rpx and DIN produced a significant reduction in mean tumor size when compared with the corresponding untreated control group but it was not superior over the single therapy with Rpx. 17 apoptosis gens have been found to be modulated after exposure to Rpx. Conclusion: Taken together the results of our in vivo experiment suggest that riproximin has a clear potential for pancreatic cancer treatment. Further experiments are required for optimizing the combination therapy with other antineoplastic agents.
Proteomics analysis of human obesity reveals the epigenetic factor HDAC4 as a potential target for obesity
Authors: Dehbi Mohammed
Published: November 2013

Abstract Sedentary lifestyle and excessive energy intake are prominent contributors to obesity; a major risk factors for the development of insulin resistance, type 2 diabetes and cardiovascular diseases. The elucidation of the molecular mechanisms underlying these chronic conditions is of relevant importance as it might lead to the identification of novel anti-obesity targets. The purpose of the current study is to investigate differentially expressed proteins between lean and obese subjects through a shot-gun quantitative proteomics approach using peripheral blood mononuclear cells (PBMCs) extracts as well as potential modulation of those proteins by physical exercise. Using this approach, a total of 47 proteins showed at least 1.5 fold change between lean and obese subjects. In obese, the proteomic profiling before and after 3 months of physical exercise showed differential expression of 38 proteins. Thrombospondin 1 (TSP1) was among the proteins that were upregulated in obese subjects and then decreased by physical exercise. Conversely, the histone deacetylase 4 (HDAC4) was downregulated in obese subjects and then induced by physical exercise. The proteomic data was further validated by qRT-PCR, Western blot and immunohistochemistry in both PBMCs and adipose tissue. We also showed that HDAC4 levels correlated positively with maximum oxygen consumption (VO2 Max) but negatively with body mass index, percent body fat, and the inflammatory chemokine RANTES. In functional assays, our data indicated that ectopic expression of HDAC4 significantly impaired TNF-α-dependent activation of NF-κB, establishing thus a link between HDAC4 and regulation of the immune system. Together, the expression pattern of HDAC4 in obese subjects before and after physical exercise, its correlation with various physical, clinical and metabolic parameters along with its inhibitory effect on NF-κB are suggestive of a protective role of HDAC4 against obesity. HDAC4 could therefore represent a potential therapeutic target for the control and management of obesity and presumably insulin resistance.
Next generation genome sequencing identifies inherited mutations contributing to Asperger syndrome in a South African family
Authors: Shaath Hibah
Published: November 2013

Asperger syndrome is one of the Autism Spectrum Disorders (ASD's), characterized by significant difficulties in social interaction and nonverbal communication, alongside restricted and repetitive patterns of behavior and interests. ASD's have a strong and complex genetic basis that cannot be distinguished by the clinical presentation. A South African family with an affected father and three affected sons all with characteristics of Asperger syndrome including repetitive routine physical gestures and Sensory Processing Disorder was studied for the possible identification of the responsible genetic factor(s). Due to the significant proof of heritability and the extreme heterogeneity of Asperger syndrome, next generation sequencing was performed on all members of this family to extrapolate monoallelic variations in the affected father that have been inherited by all three of the affected sons probably through an autosomal dominant pattern of inheritance. These variations, validated by Sanger sequencing, were analyzed, prioritizing significant changes in the encoded protein. Variants that segregate with the affected individuals include one deletion in C17orf80, an unidentified protein expressed in the brain, (c.1745_1748delGTAA), three missense mutations that change highly conserved amino acids in PARK2, which codes for a component of a multiprotein E3 ubiquitin ligase complex that targets proteins for degradation also known to cause juvenile Parkinson disease (c.110 C>T, p.Pro37Leu), FAT1, member of a large cadherin family required for cell-cell association and actin organization, (c.2563 C>A p.Gly855Arg), and OR4C6, an olfactory receptor protein coding gene, (c.293 A>C p.Gln98Pro) and one nonsense mutation introducing a premature stop codon in HYAL4, a hyaluronidase that intracellularly degrades hyaluronan, one of the major glycosaminoglycans in the extracellular matrix (c.628 C>T p.Arg210STOP). The direct link of these previously reported variants to Asperger syndrome is yet unknown, however some of these genes such as PARK2, HYAL4 and FAT1 have previously been reported to be in involved in brain function and development, indicating a possible role in the onset of Asperger syndrome.
Paravertebral block is alternative anesthesia for outpatient lithotripsy
Authors: Hanoura Samy
Published: November 2013

This study evaluated the effectiveness of paravertebral block as alternative anesthetic technique for extracorporeal shock wave lithotripsy (ESWL) procedure. Fifty patients with renal stones, aged 20 to 60 years, were randomly allocated into two groups; twenty five patients in group P; received unilateral paravertebral block from T8 through L1 with injection of 5ml 0.5%bupivacaine and 25 patients in group L; received local infiltration by bupivacaine 0.25%(2mg/kg) into the 30 cm2 area after localizing the stones site, 10 minutes before the session. 10 mm visual analogue scale (VAS) was used to evaluate pain every 10 minutes during the session. At the end of the procedure, total doses of rescue analgesia, the number of shockwaves, their power and the total duration of shockwave treatment were recorded. After completion of the procedure the patient was assessed for pain and nausea in the post anesthesia Care Unit (PACU) using the Visual Analog Scale. Patient's satisfaction and time needed to discharge patients to home also were recorded. Time to do the anesthetic technique was significantly higher (p<0.001) in group-P than group-L, it was 12.7±2.3 minutes versus 6.9±1.9 minutes respectively, intraoperative rescue analgesia by fentanyl was lesser (P<0.001) in group-P than group-L, 26.7 ± 6.32mcg versus 78.6±5.41mcg, respectively, also time interval between ends of the procedure till discharge to home was significantly higher (P<0.001) in group-P than group-L, it was 99±17 minuets versus 133±31minuits respectively. VAS was not significant difference between both groups either intraoperative or postoperative in first hour. Patient's satisfaction was significantly higher (P<0.05) in group-P than group-L, it was 8.8±1.1 versus 6.1±0.6, respectively. Adverse events were lesser, but not significant in group-P than in group-L. Two patients (8%) in group-L and one patient (4%) in the group-P experienced episodes of postoperative nausea and vomiting (PONV). Paravertebral block is effective alternative anesthesia for outpatient lithotripsy; multiple level paravertebral blocks provide an optimal anesthetic condition, with acceptable adverse events for ESWL. And providing proper analgesia during the procedure and in first hour after finishing of the procedure, early discharge to home and providing better patient's satisfactions.
Traumatic injuries among children and adolescents in Qatar: A hospital-based observational study
Authors: Alyafei Khalid
Published: November 2013

Background: Traumatic injury remains one of the major leading causes for mortality and morbidity in children worldwide. The aim of this study is to describe an epidemiologic profile of pediatric and adolescent traumatic injuries in Qatar. Methods: A retrospective analysis for all pediatric and adolescent patients admitted with severe traumatic injury to the Section of Trauma at Hamad General Hospital between January 2011 - December 2011. Results: A total of 163 children were enrolled in the study with a mean age of 9.6±5.9 years. The mean Glasgow Coma Scale (GCS) on presentation to Emergency Department (ED) was 13.4±3.8 days. Injuries were more prevalent at ages (1-5 years) and (14-18 years). Fall and MVCs are the major MOI among children (35% for each). The mean initial ISS was 13.9± 6.6. The median length of stay (LOS) in hospital was 6 days ranged from 1 -60 days. The LOS was correlated respectively with ISS (r= 0.27, P < 0.001) , age (r=0.27, P < 0.001) , GCS/scene (r= −0.30, P <0.001), GCS/ED (r= −0.53, P <0.001) and Injury Severity Score (ISS) (r= −0.53, P <0.001) . No significant association was observed between ISS and gender, mechanism of injury or type trauma. Head and long bone injuries were the commonest sustained injuries in children (34% and 18%, respectively). Three children died, one has quadriplegia and none of our patients was reported to use safety measures. Conclusion: traumatic injuries are not uncommon and show 2 peaks among children in Qatar. However, none of the cases were reported to use safety measures. The importance of increasing public awareness toward safety measures and injury prevention Programme is warranted.
P90 Ribosomal S6 Kinase Contributes To Na+/H+ Exchanger Isoform1 (Nhe1) Induced Cardiac Hypertrophy In H9C2 Cardiomyoblasts
Authors: Jaballah Maiy
Published: November 2013

p90 Ribosomal S6 Kinase Contributes to Na+/H+ Exchanger Isoform1 (NHE1) Induced Cardiac Hypertrophy in H9c2 Cardiomyoblasts Maiy Jaballah, Bayan Almerayat, Fatima Al-Sulaiti, Fatima Mraiche College of Pharmacy, Qatar University, Doha, Qatar Background Pharmacological and genetical studies have shown that increasing the activity of Na+/H+ exchanger isoform1 (NHE1) plays a critical role in the development of cardiac hypertrophy. Despite the importance of NHE1, direct inhibition of NHE1 has demonstrated several adverse side effects. It is has been demonstrated that p90 ribosomal S6 kinase (RSK) enhances the activity of NHE1. RSK, a downstream regulator of the mitogen activated pathway, has also been implicated in cardiac hypertrophy both in in vitro and in vivo models. The aim of this study is to investigate the cardio protective effects mediated by inhibition of RSK in NHE1 activated cells. Methods In vitro, H9c2 cardiomyoblasts are infected with active NHE1 adenovirus in the absence and presence of dominant negative (Dn) RSK2 (N-terminal kinase dead protein) adenovirus. H9c2 cardiomyoblasts expressing active NHE1 with abolished RSK activity are characterized for cardiac hypertrophy by measuring cell area and protein content. Results Our results showed that infection of H9c2 cells with active NHE1 adenovirus resulted in significant increase in cell area, (NHE1: 154.5±28.47% of GFP), which was reduced by concomitant infection with Dn RSK2 (NHE1+Dn RSK2: 137.4±11.8% of GFP). Similarly, protein content induced by active NHE1 was attenuated in the presence Dn RSK2. Conclusion Taken together, our study demonstrates that active NHE1 induces cardiac hypertrophy. Inhibition of active NHE1 by targeting RSK may regress the hypertrophic effect, thus making RSK a potential therapeutic target for cardiac hypertrophy.
Targeting pro-apoptotic protein BAD inhibits survival and self-renewal of cancer stem cells
Authors: Sastry Konduru Seetharama
Published: November 2013

Background: Accumulating evidence suggests that the resistance of cancer stem cells (CSC) to many conventional therapies accounts for the inability of these therapies to cure cancers. Current cancer therapies can only shrink tumors as they target and kill differentiated tumor cells that constitute the bulk of the tumor, but are unable to target rare CSC population. Thus, despite a wealth of the information in differentiated cancer cells, the active survival and self-renewal pathways in CSC have not been characterized in detail. An understanding of the molecular mechanisms involved in the survival, self-renewal, maintenance, and resistance of cancer stem cells to current therapeutic regimens is of immense clinical interest. Objectives: BAD is a proapoptotic protein that has been shown to modulate apoptosis in cancer cells. However, the potential role of BAD in CSC biology has not been investigated. The objectives of this study are to address the role of pro-apoptotic protein BAD in survival and self-renewal of cancer stem cells, and test whether BAD expression can be used as a biomarker. Methods: Sphere formation method was used to enrich cancer stem cells from breast, prostate and melanoma cell lines. BAD expression was reduced by lentiviral-mediated delivery of shRNA specific to BAD. Apoptosis was induced in CSC by inhibiting the survival kinases PI3K and MAPK using pharmacological inhibitors LY294002 and PD98059, respectively. The cytoprotective and self-renewal effects of growth factors and neuropeptides were assessed. RT-PCR was used to quantify the expression of BAD in tumors of prostate cancer patients. Results and conclusion: Using sphere-derived CSC, we show that the BAD phosphorylation is essential for the survival of CSC as they are addicted to the expression of phosphorylated BAD. While none of CSCs could survive in the absence of BAD phosphorylation, both drugs and growth factors delivered their respective cytotoxic and protective effects by modulating the BAD phosphorylation in CSC. We also show that the self-renewal ability of cancer stem cells is significantly reduced at least in part by specifically knocking down the expression of BAD. In addition, about 65% tumors display increased BAD expression compared to tumor adjacent normal tissue, suggesting a role of BAD in tumor advancement. Taken together, our findings suggest that BAD plays a critical role in both differentiated cancer cells and CSC and thus targeting BAD might be an attractive strategy for development of novel therapeutics, and BAD expression might be used as a biomarker for tumor progression.