Health and Biomedicine
http://dx.doi.org/10.5339/qfarf.2012.BMO1
How to treat diabetes in Arabs: A rational approach based
upon the pathogenesis of the disease
Muhammad Abdul-Ghani, Ralph DeFronzo, Mahmoud Zirie, Amin Jayyousi, Abdul-Bari Bener
University of Texas Health Science Center at San Antonio, San Antonio, UNITED STATES; Hamad Medical
Corporation, Doha, QATAR
[email protected]
Background and Aims:
Type 2 diabetes mellitus (T2DM) is a complex disease with multiple metabolic defects including insulin resistance and
beta cell dysfunction. Although both insulin resistance and beta cell dysfunction are present in type 2 diabetic individuals
in all ethnic groups, we previously have shown that the contribution of each abnormality to the deterioration of glucose
homeostasis is ethnic dependent with the greatest role of beta cell dysfunction being in Arab individuals. In the present
study, we compare the efficacy and safety of a novel therapeutic approach of initiating subjects with new onset T2DM
on triple therapy with agents that correct the metabolic defects in T2DM (metformin/pioglitazone/exenatide) versus the
American Diabetes Association guidelines (starting metformin and sequential addition of sulfonylurea and basal insulin)
which are based upon the concept of lowering the plasma glucose concentration.
Research Design and Methods:
133 new onset T2DM patients (age = 45±1 y; BMI=36±0.5; HbA1c = 8.8±0.1%; diabetes duration = 5.6±0.5 mo) were
randomized to receive metformin (2000 mg/d), plus pioglitazone (45 mg/d), plus exenatide (10 micrograms BID) (triple
therapy, n=64) or escalating doses of metformin (2000 mg/d), followed by sequential addition of sulfonylurea (glipizide, 20
mg/d) and basal insulin to maintain HbA1c <6.5 (conventional therapy, n = 69).
Results:
Subjects who received triple therapy, HbA1c decreased from 8.6 to 6.1% at 6 mo and to 6.0% at 24 mo, while in the
conventional therapy, HbA1c declined to 6.2% at 6 mo and subsequently increased to 6.5% at 24 mo. Despite lower
HbA1c, subjects in triple therapy arm experienced a 13.6-fold lower rate of hypoglycemia compared to subjects in
conventional therapy arm. 14 of 66 (21%) of T2DM patients in the conventional therapy arm have required insulin therapy
to maintain the target A1c value. Subjects in the triple therapy arm experienced mean weight loss of 1.2 kg compared to
mean weight gain of 3.6 kg (p=0.02) in subjects in the conventional therapy arm.
Conclusion:
The present results demonstrate that antidiabetic therapy targeting the metabolic abnormalities responsible for
hyperglycemia is more effective and safe than therapy simply aimed at lowering the plasma glucose concentration in
T2DM.
This abstract is available through QScience.com
HbA1c (%)
9
8
Conventional Therapy
7
6
Triple Therapy
0
6
12
18
Time (months)
24
Health and Biomedicine
http://dx.doi.org/10.5339/qfarf.2012.BMO2
Biochemical and cellular characterization of human
atherosclerotic carotid plaque and blood flow: Implications for
stroke prevention
Ahmed Khattab, Leopold Streletz, Dirk Deleu, David Wertheim, Nick Petford, Joseph Kwan,
Lasantha Wijesinghe, Steve Allen
Bournemouth University, Bournemouth, UNITED KINGDOM; Weill Cornell Medical College in Qatar, Doha,
QATAR; Kingston University, Kingston upon Thames, UNITED KINGDOM; University of Northampton,
Northampton, UNITED KINGDOM; Royal Bournemouth Hospital, Bournemouth, UNITED KINGDOM
[email protected]
Background and Objectives:
The Arabian Gulf region is rapidly developing, with major changes in lifestyle that can increase the risk of cardiovascular
diseases, including stroke. Stroke constitutes a major cause of morbidity and mortality in Qatar. This research focuses
mainly on ischaemic stroke, aiming to study carotid plaque morphology at biochemical, cellular and molecular levels. The
objectives are to identify markers that can be measured in surrogate tissues (e.g., blood) in order to identify patients at risk
of developing the criteria for clinical intervention to prevent or reduce the risk of stroke.
Methods:
Fifteen carotid plaques were collected from routine carotid endarterectomy surgery. A range of laboratory techniques were
used, including SDS-PAGE, Western blotting, histology, immuno-histochemistry, DD-PCR, flow-modelling, bright-field and
laser scanning confocal microscopy (LSCM).
Results:
Levels of matrix metalloproteinase-3 (MMP-3) and its precursor (pro-MMP-3) were higher in echolucent than in echogenic
plaques, especially near regions of ulceration, necrosis and where the fibrous cap was thin or torn. Isoforms of nitric oxide
synthase (NOS) were seen in all carotid plaques irrespective of intraplaque features however, levels of inducible NOS
(NOS-II) were higher in echolucent than in echogenic plaques. Higher levels of immunoreactive superoxide dismutase
were observed in plaques with higher degree of stenosis (>75%-80% measured by ultrasonography). 3D imaging using
LSCM showed evidence of carotid plaque vulnerability demonstrated by reduced fibrous cap thickness and a large lipidnecrotic core with evidence of cracking. Five PCR products were identified in echogenic plaques and three PCR products
were identified in echolucent plaques which were absent from echogenic plaques. Some of these PCR bands are the
products of genes which appear to be up- or down-regulated during plaque development. Blood flow simulation models
showed how blood velocity changes could occur associated with reduction in lumen diameter caused by the plaque.
Conclusions:
Our findings could help in understanding factors affecting plaque morphology. The switching 'off or on' of genes and
their encoded proteins may play an important role in stabilisation or destabilisation of carotid plaques. This may lead to
digestion of fibrous tissue, leading to thinning or tearing of the fibrous cap and to plaque disruption, initiating embolization
and stroke.
This abstract is available through QScience.com
Health and Biomedicine
http://dx.doi.org/10.5339/qfarf.2012.BMO3
Involvement of renal cytochrome P450 and arachidonic acid
metabolites in diabetic nephropathy
Stephanie Eid, Miran Jaffa, Ayad Jaffa, Fuad Ziyadeh, Assaad Eid
American University of Beirut, Beirut, LEBANON
[email protected]
Background and Objectives:
Diabetic nephropathy (DN), a serious complication of diabetes, is characterized by hyperfiltration, hypertrophy,
extracellular matrix accumulation, fibrosis and proteinuria leading to loss of renal function. In renal hypertrophy, tubules
increase in size and cause accumulation of the extracellular matrix, and are also associated with alterations in renal
sodium handling as well as hypertension; processes linked by involvement of the arachidonic acid (AA) metabolites 20HETE and EETs. This study aims to determine the specific AA-metabolizing CYP450 isoforms present in proximal tubules
(PT) that are altered by high glucose (HG) in cultured PTs, and in an animal model of diabetes. It intends to investigate
the effects of alterations in CYP isoforms and/or AA-metabolite levels in DN. This work will investigate the mechanism
of PT injury and the effect of inhibition of AA-metabolites in vitro and will also provide insight into the cross-talk between
CYP450 isoforms and other sources of reactive oxygen species (ROS).
Methods:
Immunohistochemistry, hypertrophy, apoptosis, fibrosis, ROS generation, 20-HETE and EET formation, CYP4A and Nox
protein expression, and mRNA levels were measured in vitro and in vivo.
Results:
Exposure of PT cells to HG resulted in apoptosis and hypertrophy. HG treatment increased ROS production and was
associated with CYP4A and CYP2C upregulation, 20-HETE and EETs formation, and Nox oxidases upregulation. The
effects of HG on Nox proteins and mRNA expression, matrix protein accumulation and apoptosis were blocked by
HET0016, an inhibitor of CYP4A, and were mimicked by 20-HETE. Inhibition of EETs in vitro promoted the effects of
HG on cultured proximal tubular cells. In parallel, the levels of CYPs 2B, 2C, and 4A were assessed in a rat model of
streptozotocin-induced diabetes. There was significant induction of expression and activity over control of these CYPs
associated with an increase in ROS production, Noxs expression, PTs injury, and this was prevented by insulin therapy.
Conclusion:
Our results indicate that hyperglycemia in diabetes has a significant effect on the expression of AA-metabolizing CYPs,
manifested by increased AA metabolism, and might thus alter kidney function through alteration of type and amount of AA
metabolites; this pathway is through an oxidative stress-dependant mechanism.
This abstract is available through QScience.com
Health and Biomedicine
http://dx.doi.org/10.5339/qfarf.2012.BMO4
Ubiquitous monitoring system for critical cardiac
abnormalities
Uvais Qidwai, Junaid Chaudhry, Mohammed Shakir
Qatar University, Doha, QATAR
[email protected];[email protected]
It is desirable to have a monitoring system that can keep a constant surveillance on the conditions of the heart and
its related patterns. This is particularly important in many patients with critical cardiac abnormalities. This can be very
convenient in clinical settings but may not be possible for individuals who are not in hospital and are in their day-to-day
activities. Wearable ECG-based systems have been proposed for such situations and can perform such monitoring in real
life. However, detecting the abnormality in near real-time is still a challenge in these systems. Similarly, what information
should be relayed to doctors or other caregivers and how soon this can be achieved is a very hot area of research at
present.
This work presents a monitoring system that embeds an intelligent wearable data acquisition system with unique
identification algorithms requiring very little computational time and simple threshold based classification. Once this
is done, the related information is passed to a gateway system that can communicate the criticality flags as well
as the actual ECG waveform data to the pre-defined data node that connects it to the doctor and/or other clinical
representatives. We have used an Android-based cellphone as the gateway. The presented system focuses on intelligent
health monitoring with possible wearable application for long-term monitoring and updating in real-time of patient's ECG
conditions to the physician.
This abstract is available through QScience.com
Health and Biomedicine
http://dx.doi.org/10.5339/qfarf.2012.BMO5
TNRC9 (TOX3) downregulates BRCA1 expression and promotes
breast cancer aggressiveness
Jingxuan Shan, Shoba P Dsouza, Sasha Bakhru, Eman K Al-Azwani, Maria L. Ascierto L Ascierto,
Konduru S Sastry, Shahinaz Bedri, Dhanya Kizhakayil, Idil I Aigha, Joel Malek, Issam Al-Bozom, Salah Gehani,
Stacia Furtado, Edith Mathiew, Ena Wang, Francesco M Marincola, Lotfi Chouchane
Weill Cornell Medical College in Qatar, Doha, QATAR; Brown University, Providence, UNITED STATES; National
Institutes of Health, Bethesda, UNITED STATES; Hamad Medical Corporation, Doha, QATAR
[email protected]
Background:
Although the linkage between germline mutations of BRCA1 and hereditary breast/ovarian cancers is well established,
recent evidence suggests that altered expression of wild type BRCA1 might contribute to the sporadic forms of breast
cancer. The mechanism underlying the downregulation BRCA1 expression is not well understood. It might be dependent
upon repressor activity that governs histone acetylation and DNA accessibility at the BRCA1 promoter. TNRC9 (TOX3)
gene, highly associated with breast cancer susceptibility, encodes a nuclear protein of uncertain function but can modify
chromatin structure. We hypothesized that constitutive expression of TNRC9 could be relevant to breast cancer biology
through the modulation of BRCA1 activity.
Methods:
We assessed the associations of TNRC9 gene amplification with breast cancer onset and survival. The search for targets
and effects of TNRC9 was performed using multifaceted molecular approaches.
Results:
The TNRC9 gene is often amplified and overexpressed in breast cancer, particularly in advanced breast cancer. TNRC9
gene amplification is associated with reduced disease-free and metastasis-free survival rates. TNRC9 significantly
increased breast cancer cell proliferation, migration and survival of exposure to apoptotic stimuli, and tumor progression
both in vitro and in mice models. Gene expression profiling, protein analysis and in silico assays of large datasets of breast
and ovarian cancer samples suggested that TNRC9 and BRCA1 expression are inversely correlated. TNRC9 binds not
only to BRCA1 promoter but also to the CREB complex, a BRCA1-transcriptional regulator. TNRC9 downregulates the
expression of BRCA1 by altering the methylation status of its promoter.
Conclusions:
Our study unveils a molecular basis for a TNRC9 role in breast cancer and highlights a new paradigm in BRCA1
regulation.
This abstract is available through QScience.com
Health and Biomedicine
http://dx.doi.org/10.5339/qfarf.2012.BMO6
Screening for novel natural and synthetic inhibitors for
human alpha-amylases and their structure determination: An
effective approach to control diabetes mellitus and obesity
Sayed Kamel Goda, Fatma Rashidi, Mervat El Sayed, Fatima Ali Abdulla, Fawzy Attaby, Muhammad Al Sayrafi
Anti-Doping Laboratory Qatar, Doha, QATAR; Cairo University, Cairo, EGYPT; Qatar University, Doha, QATAR
[email protected]
Background:
Non-insulin-dependent diabetes mellitus (NIDDM) is one of the most common adult diseases caused by a secretory
decrease in insulin from pancreatic Langerhans cells and/or peripheral cells which become resistant to the action of insulin
as in the case of obesity. Serious side effects such as retinopathy, neuropathy, and cataracts are also brought about
by its long-term manifestation. At present, the direct clinical therapy in NIDDM is to optimize or control the postprandial
blood glucose (PBG) level. Polysaccharide degrading enzyme, such as beta-amylase catalyzes the cleavage of starch to
produce glucose and other smaller polysaccharides which leads to an increase of the glucose level in the blood. Thus,
the retardation of the action of this enzyme by suitable inhibitors may be one of the most effective approaches to control
NIDDM.
Objectives:
The aim of this work was to screen, isolate and determine the structure of novel inhibitors for human polysaccharide
degrading enzymes, salivary and pancreatic alpha-amylases, using natural resources and synthetic compounds.
Methods:
We prepared the total extracts of several herbs and plants collected from different locations in Egypt and in Qatar
randomly and based on traditional use. Each extract was assayed for potential amylase inhibitors. The potential inhibitors
were isolated using silica gel chromatography. The structure of each inhibitor was determined using elemental analysis, IR,
1H-NMR, MS and 13C-NMR. Hundreds of synthetic compounds have also been tested for inhibition capabilities.
Results:
Our study demonstrated that the total extract of four plants showed a significant inhibition of human saliva and pancreatic
alpha-amylases. The active compounds from two plants were isolated and their structures determined. Three synthetic
compounds with a significant but variable degree of inhibition of human saliva alpha-amylase and pancreatic amylase
were identified.
Conclusion:
The novel inhibitors isolated in this study could form the basis for clinical trials to demonstrate the effectiveness of these
compounds in lowering the glucose level in NIDDM patients and obese people.
This abstract is available through QScience.com
Health and Biomedicine
http://dx.doi.org/10.5339/qfarf.2012.BMO7
Akt-activated endothelium constitute the niche for residual
disease and resistance to bevacizumab in ovarian cancer
Bella Samia Guerrouahen, Jennifer Pasquier, Nadine Abu-Kaoud, Mahtab Maleki, Pegah Ghiabi, Ahmad Saleh,
Arash Rafii
Weill Cornell Medical College in Qatar, Doha, QATAR; Hamad Medical Corporation, Doha, QATAR
[email protected]
Background:
Ovarian cancer is the second leading cause of cancer-related death in women worldwide. Despite optimal cytoreduction
and adequate adjuvant therapy, many patients will experience disease recurrence. Targeted therapies have been
evaluated in ovarian cancer as a method to overcome resistant disease. Antiangiogenic therapy such as bevacizumab
(Avastin; Genentech) has limited efficacy. Indeed, it increases hypoxia, drug resistance and, tumor rebound phenomenon
observed after withdrawal.
Hypothesis:
We hypothesized that abnormalities in the tumor endothelium contribute to tumor growth which may be a direct
source for chemotactic factors and might be responsible for residual microscopic disease and rebound effect following
antiangiogenic treatment.
Methods:
Using a feeder-free Matrigel and spheroid models of ovarian cancer, we examined the effect of bevacizumab on residual
disease. We used Akt-activated endothelial cells (EC) that replicates tumor endothelial biology and controls tumor
growth, and human umbilical vein endothelial cells (HUVEC) to investigate the antiangiogenic activity of bevacizumab by
angiogenesis and migration assays. We conducted an XTT assay to examine the effect of bevacizumab on proliferation
of vascular endothelial growth factor (VEGF) producing human ovarian cancer cell lines. Finally, expression of FGF-2,
phospho-Akt was assessed by Western blotting and flow cytometry.
Results:
We demonstrated the role of Akt-activated ECs in supporting expansion and self-renewal of ovarian cancer cells (OCC)
in a residual disease context. We demonstrated that OCCs activate the endothelium, which displays resistance to
bevacizumab. Bevacizumab had no effect on the proliferation of Akt-activated ECs, but significantly inhibited angiogenesis
and delayed wound healing in HUVEC. We demonstrated that in this setting the cross-talk between cancer cells and
ECs activates Pi3k/Akt inducing an autocrine loop through the pro-angiogenic factor fibroblast growth factor-2 (FGF2) bypassing the VEGF-R pathway. We demonstrated that FGF-2 blocking would efficiently reverse the resistance to
bevacizumab.
Conclusion:
Our data highlights the role of an activated endothelium in the constitution of the residual disease and resistance to
bevacizumab. These results hint on the concept of using combination therapy to override drug resistance in ovarian
cancer and to suppress or eradicate residual disease.
This abstract is available through QScience.com
Health and Biomedicine
http://dx.doi.org/10.5339/qfarf.2012.BMO8
Trends in the mortality and short-term morbidity outcomes of
≤32 week gestation babies in the State of Qatar between 2002
and 2011: A PEARL study analysis
Sajjad ur Rahman, Najeeb Hameed, Hussain Parappil, Nuha Nimeri, Sarrah El Tinay, Walid El Ansari,
Mohammad Tahir
Hamad Medical Corporation, Doha, QATAR; University of Gloucestershire, Gloucester, UNITED KINGDOM
[email protected];[email protected];[email protected]
Background and Objectives:
Preterm births are a major cause of neonatal mortality and morbidity. The number of preterm births is increasing due
to assisted reproductive technology. The intensive care of preterm babies and follow-up care of their post-discharge
morbidities takes up a major share of healthcare expenditure. PEARL study analyzed trends in mortality and pre-discharge
morbidity outcomes of ≤32 week gestation preterm babies in the State of Qatar between 2002 and 2011.
Methods:
The 2011 data of ≤32 week babies, collected prospectively using predesigned, structured questionnaires by a trained
fulltime research team, was ascertained from Qatar's National Perinatal Registry (Q-Peri-Reg). Comparative data for
2002 was ascertained retrospectively from the medical records of the Women's Hospital, Hamad Medical Corporation.
The data was analyzed for outcome measures. The 2011 data was also compared with 2010 report of Vermont Oxford
Network (VON) database, which is an international benchmark of quality of care in NICU's worldwide.
Results:
Between 2002 and 2011 the birth rate of ≤32 week babies increased significantly from 1.19% to 1.75% (p=0001) while
their mortality decreased significantly (p <0.05) from 239/1000 to 163.4/1000 respectively. There was a significant
decrease in the RR of Grade 3 IVH (p <0.012) and a non-significant decrease (p=0.500) in Grade 4 IVH and CLD at 36
weeks. There was a significant increase in the RR of symptomatic PDA (p=0.018), NEC (p=0.003) and ROP stage 3 and
above (p=0.001) and non-significant increase in the RR of cystic PVL (p=0.470) (Table 1). Qatar's ≤32 weeks mortality and
some morbidity outcomes were comparable with VON 2010 database report.
Conclusions:
The mortality and select short-term morbidity outcomes of ≤32 week gestation babies have improved significantly over
the last decade though their birth rate has increased. There is a need to focus on further reduction in morbidity.
This abstract is available through QScience.com
Table-1: Incidence and Relative Risk of Mortality and Short Term Morbidity among extremely premature
(23-32wks) babies in the State of Qatar between 2002 and 2011
Variables
2002
2011
RR(95%CI)
P - Value
(total births 23-32wks=142)
Yes
No
IR/1000
Neonatal
mortality
CLD at 36
weeks
Symptomatic
PDA
NEC
IVH grade 3
IVH grade 4
Cystic PVL
ROP stage 3 &
above
(total births 23-32wks=361)
Yes
No
IR/1000
34
108
239
59
302
163.4
0.68(0.47-0.99)
11
131
77.5
22
339
60.9
0.79(0.39-1.58)
20
122
140.8
87
274
241
1.71(1.09-2.67)
18
11
6
7
124
131
136
135
126.8
77.5
42.3
49.3
88
10
11
24
273
351
350
337
243.8
27.7
11.1
66.5
1.92(1.20-3.07)
0.36(0.16-0.82)
0.72(0.27-1.91)
1.35(0.59-3.06)
0.018
0.003
0.012
0.510
0.470
14
128
98.6
81
280
224.4
2.28(1.34-3.89)
0.001
IR = Incidence Rate per 1000 extremely premature live births (23-32 wks of gestation)
Reference category = incidence in 2002
0.048
0.500
Health and Biomedicine
http://dx.doi.org/10.5339/qfarf.2012.BMO9
Mutations in a zinc finger protein causing a novel autosomal
recessive mental retardation syndrome identified through
homozygosity mapping and whole exome sequencing of a
single affected individual
Marios Kambouris, Tawfeg Ben-Omran, Yasser Al-Sarraj, Rehab Ali, Khaoula Erraffi, Wesal Habbab,
Hatem El-Shanti
Shafallah Medical Genetics Center, Doha, QATAR; Hamad Medical Corporation, Doha, QATAR
[email protected]
A consanguineous Arab family affected by a novel autosomal recessive disorder characterized by severe mental
retardation and failure to thrive, was studied by Illumina 700K SNP genotyping, candidate gene mutation screening and
whole exome sequencing for one affected member. Clinical findings include ptosis, bilateral epicanthic folds, striking
midface hypoplasia, downturned mouth corners, thin upper vermillion, prominent ears, bilaterally short fourth metatarsal
bone, bilateral fifth finger camptodactyly, mildly limited mobility in both knees and hypotonia.
The gene was mapped by homozygosity mapping to 4 possible genome intervals, as the number of family members
was insufficient for a significant LOD score. The positional candidate MAP2K1 was sequenced. No pathogenic mutations
were identified. Whole exome target enrichment sequencing was performed on ABI SOLiD 4 System and Illumina HiSeq
platforms for a single affected individual. Six non-synonymous variants were positioned within the homozygosity intervals.
Two affecting evolutionary highly conserved amino acids with damaging effects according to PolyPhen and SIFT proteinmodeling software, which were validated by Sanger sequencing to determine whether variants co-segregated with the
disease phenotype. The variants were absent in 188 ethnically matched control chromosomes. One gene shows very
limited expression in the brain while the other, a zinc finger protein, appears to be the disease causing mutation.
Zinc finger proteins, a family of DNA and RNA binding proteins are transcriptional regulators controlling developmental
cascades of gene expression especially during fetal brain development. Mutations in zinc finger domains interfere
with normal brain development, are associated with non-syndromic X-linked mental retardation with impairments in
adaptive behavior, and manifest during the developmental period causing severe mental retardation. The c.C5054G
[p.S1685W] mutation affects 2 of the 3 ZNF407 isoforms, is located in the last third of the zinc finger domains and affects
a serine residue in the alpha-helical part adjoining two zinc finger domains. This is thought to eliminate the functionality
of downstream domains and interferes with expression of various genes under ZNF407 control during fetal brain
development.
Homozygosity mapping and whole exome sequencing of a single affected individual was the most effective, least labor
intensive and most economical approach in identifying the mutation for this novel autosomal recessive zinc finger protein
that causes a mental retardation syndrome.
This abstract is available through QScience.com
Health and Biomedicine
http://dx.doi.org/10.5339/qfarf.2012.BMO10
Biochemical response and effects of bariatric surgeries on
type 2 diabetes
Abdelilah Arredouani, Tyler D Hughes, Jia Lerd Ng, Roberto D Ortiz2, Michel Abou Ghantous, Othman Bouhali,
Roland E Allen
Qatar Biomedical Research Institute, Doha, QATAR; Texas A&M University, Texas, UNITED STATES; Texas
A&M University at Qatar, Doha, QATAR
[email protected]
Background and Objectives:
Bariatric surgery has proved to be a powerful technique that not only induces drastic and long-lasting weight loss
but, also resolves type 2 diabetes and potentially reverses diabetes-related diseases in morbidly obese patients.
Extraordinarily, the remission of type 2 diabetes occurs long before any significant weight loss. The physiological and
biochemical mechanisms underlying the astonishing impact of bariatric surgery on glucose homeostasis are, however,
poorly understood. Our objective is to use mathematical modeling to try to better understand the mechanisms behind
type 2 diabetes remission after bariatric surgery.
Methods:
A general mathematical method is proposed for estimating the biochemical response to pharmaceuticals, surgeries, or
other medical interventions. This method is then applied in an extremely simple model of the response to Roux-en-Y
gastric bypass surgery and related procedures.
Results and Conclusions:
There are clearly multiple and quite complex effects of bariatric surgeries. The results of our model confirm that the
remission of type 2 diabetes after bariatric surgery can be largely explained by the enhanced post-meal excretion of
glucagon-like peptide-1 (GLP-1), an incretin that increases insulin secretion and has been shown to increase proliferation
and decrease apoptosis of pancreatic beta cells, but it also suggests that other mechanisms are likely to be involved,
possibly including an additional insulin-independent pathway for glucose transport into cells.
This abstract is available through QScience.com
Health and Biomedicine
http://dx.doi.org/10.5339/qfarf.2012.BMO11
Early detection and treatment of chronic hepatitis C in
a community-based setting in Doha, Qatar: A dynamic
preventive model
Manik Sharma, Saad Al Kaabi, Nazeeh Al Dweik, Anil John, Moataz F Derbala, Muneera Al Mohannadi,
Hameed Wani, Rafae Yakoob, Fuad Pasic, Mamoon Elbedawi, Tariq Butt, Rajvir Singh
Hamad Medical Corporation, Doha, QATAR; Weill Cornell Medical College in Qatar, Doha, QATAR
[email protected]
Background:
Detecting early infection of chronic hepatitis C (CHC) can prevent late-stage complications including the need for
transplant and death. However, screening hepatitis C virus for early detection of the disease has not been found to be
beneficial in average risk individuals according to US Food and Drug Administration guidelines.
Objectives:
The primary aim of this study was to detect infection with hepatitis C antibodies using a rapid immunochromatographic
assay in a community setting. The secondary aims included assessment of prevalence rate, disease characteristics and
response to the standard treatment.
Methods:
A screening survey of 13,704 people (0.9% of the population) was conducted from December 2008 through July 2010. It
was carried out in three phases involving 4000, 3212 and 6492 average and high risk people. Hepatitis C antibodies were
detected using a colloidal gold enhanced rapid immunochromatographic assay. The diagnosis of CHC was confirmed by
measuring the viral load using highly sensitive molecular assays. All patients that were detected as having at least stage 1
disease on the liver biopsy were offered standard treatment with pegylated interferon and ribavirin. The complete cost of
investigation and treatment was either state funded or supported through governmental charities.
Results:
272 (2%) people were detected to have antibodies against hepatitis C virus. 148 subjects (62%) consented for further
confirmation of the disease by molecular assays. 69 subjects (70%) agreed to be treated of which 18 were finally excluded
due to detection of minimal disease (stage zero) on the liver biopsy. Overall, 78% of patients were detected as having
mild disease (stage 1-2) on histology. Of the 51 actually treated with dual antiviral therapy, 37 (72.4%) responded to the
treatment and achieved a sustained viral response (SVR). The response rate was found to be superior to the standard of
care at present. The screening strategy resulted in six times better the response rate (odds ratio 6.4, p-value 0.002, 95%
CI 2.0-20.5).
Conclusion:
Hepatitis C was detected in 2% of the population using this novel method. A dynamic model (screening) resulted in
detection of mild disease with a consequently higher response rate compared to the standard of care.
This abstract is available through QScience.com
Health and Biomedicine
http://dx.doi.org/10.5339/qfarf.2012.BMO12
Computational analysis of a mutation in cardiac myosin
binding protein-C
Magdi Yacoub, Poornima Gajendrarao, Navaneeth Krishnamoorthy
Qatar Cardiovascular Research Center, Doha, QATAR
[email protected]
The cardiac muscle contraction is regulated by a set of proteins known as sarcomeric proteins, which are components of
thick and thin filaments. Mutation in these proteins especially cardiac myosin binding protein-C, a multi-domain (C0-C10)
protein, is one of the major causes of hypertrophic cardiomyopathy (HCM). However, structure-function relationship of this
protein is unclear. Mutation E258K, which is located in the C-terminal of domain C1, has been shown to be associated
with HCM in Egypt. Hence, the purpose of the study was to understand the molecular basis of this missense mutation.
Molecular modelling study was performed using the available crystal structure of the domain C1. Here, we have carried
out molecular dynamic simulations for both WT and E258K for 10 ns, and the structures that showed major changes were
considered for further analyses. Our results suggest that the mutation can change the local structural stability through
altering a series of intramolecular interactions. Moreover, as the mutation results in replacement of a negative amino acid
by a positive one, thus, it affects the surface electrostatic properties of the domain (Figure). Hence, it might interfere with
the binding to neighbouring domains and with the other sarcomeric proteins such as actin and myosin. E258K appears
to affect the structural integrity of the domain C1 both directly and indirectly. It is hoped that these findings can help to
understand the molecular mechanism of the disease.
This abstract is available through QScience.com