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1.  Inhibition of p38 MAPK Signaling Augments Skin Tumorigenesis via NOX2 Driven ROS Generation 
PLoS ONE  2014;9(5):e97245.
p38 mitogen-activated protein kinases (MAPKs) respond to a wide range of extracellular stimuli. While the inhibition of p38 signaling is implicated in the impaired capacity to repair ultraviolet (UV)-induced DNA damage—a primary risk factor for human skin cancers—its mechanism of action in skin carcinogenesis remains unclear, as both anti-proliferative and survival functions have been previously described. In this study, we utilized cultured keratinocytes, murine tumorigenesis models, and human cutaneous squamous cell carcinoma (SCC) specimens to assess the effect of p38 in this regard. UV irradiation of normal human keratinocytes increased the expression of all four p38 isoforms (α/β/γ/δ); whereas irradiation of p53-deficient A431 keratinocytes derived from a human SCC selectively decreased p38α, without affecting other isoforms. p38α levels are decreased in the majority of human cutaneous SCCs assessed by tissue microarray, suggesting a tumor-suppressive effect of p38α in SCC pathogenesis. Genetic and pharmacological inhibition of p38α and in A431 cells increased cell proliferation, which was in turn associated with increases in NAPDH oxidase (NOX2) activity as well as intracellular reactive oxygen species (ROS). These changes led to enhanced invasiveness of A431 cells as assessed by the matrigel invasion assay. Chronic treatment of p53-/-/SKH-1 mice with the p38 inhibitor SB203580 accelerated UV-induced SCC carcinogenesis and increased the expression of NOX2. NOX2 knockdown suppressed the augmented growth of A431 xenografts treated with SB203580. These findings indicate that in the absence of p53, p38α deficiency drives SCC growth and progression that is associated with enhanced NOX2 expression and ROS formation.
doi:10.1371/journal.pone.0097245
PMCID: PMC4019556  PMID: 24824222
2.  Evaluation of the T helper 17 cell specific genes and the innate lymphoid cells counts in the peripheral blood of patients with the common variable immunodeficiency 
Background:
Common variable immunodeficiency (CVID) is characterized by a deficiency in the immune system with a heterogeneous collection of disorders resulting in antibody deficiency and recurrent infections. T helper 17 (Th17) cells promote B-cell survival and synergize with the B-cell activating factor to induce their differentiation into the plasma cells. A sub-population of innate lymphoid cells (ILCs) also produces interleukin 17 (IL-17). This study aimed to measure the Th17 specific genes and ILCs counts in the CVID patients in comparison with control subjects.
Materials and Methods:
Total messenger ribonucleic acid (mRNA) was extracted from the whole blood samples of 10 CVID patients and 10 healthy individuals. IL-17, retinoic acid receptor-related orphan receptor C2 (RORC2), IL-23R, and IL-9 gene expression were measured using the quantitative reverse transcriptase-polymerase chain reaction. Count of lineage negative/CD127+/CD90+ ILCs in the blood samples was performed by the flow cytometry method.
Results:
The transcript levels of IL-17 and RORC2 in CVID patients was strongly lower than control subjects (P = 0.049 and P = 0.046, respectively), but slight reduction in the IL-23R expression (P = 0.252) have seen in the CVID patients. Accordingly, the number of ILCs decreased significantly (P = 0.04). Interestingly, IL-9 mRNA level was more significantly in the CVID patients (P = 0.001).
Conclusion:
The results presented in this study show that the Th17 cell specific genes expression (as the determiner Th17 cells) and ILCs (another lymphoid source of IL-17) are decreased in patients with CVID and this could be an explanation for the defect of their humoral immune response. In addition, elevation of the IL-9 gene expression may shed a new light into the way toward the understanding of the mechanism of autoimmunity in the CVID patients.
PMCID: PMC4078375
Common variable immunodeficiency; innate lymphoid cells; interleukin 9; interleukin 17; interleukin 23R; T helper 17 cells
3.  Comparison of effects of soft margarine, blended, ghee, and unhydrogenated oil with hydrogenated oil on serum lipids: A randomized clinical trail 
ARYA Atherosclerosis  2013;9(6):363-371.
BACKGROUND
Trans fatty acids (TFAs) are known as the most harmful type of dietary fats. Therefore, this study was done to compare the effects of some different oils including unhydrogenated, blended, ghee, and soft magazine with hydrogenated oil on serum lipid profile of healthy adults.
METHODS
This study was a randomized clinical trial conducted on 206 healthy participants of 20 to 60 years of age. Subjects were randomly divided into 5 groups and each of them was treated with a diet containing unhydrogenated oil, ghee, blended oil, soft margarine, or hydrogenated oil for 40 days. Fasting serum lipids were measured before and after the study.
RESULTS
Compared to hydrogenated oil, total cholesterol (TC) and triglyceride (TG) had a significant reduction in all groups, LDL-C declined in unhydrogenated oil and soft margarine groups, and apolipoprotein (Apo) B only in unhydrogenated oil group (all P < 0.05). However, there was a significant enhancement in ApoA of ghee oil (P < 0.001).
CONCLUSION
Consuming unhydrogenated oil, ghee, soft margarine, and blended oil had some beneficial effects on serum lipids.
PMCID: PMC3933054  PMID: 24575140
Clinical Trial; Dietary Fat; Commercial Oil; Lipid
4.  In Vitro Cytotoxicity Assessment of an Orthodontic Composite Containing Titanium-dioxide Nano-particles 
Background and aims. Incorporation of nano-particles to orthodontic bonding systems has been considered to prevent enamel demineralization around appliances. This study investigated cytotoxicity of Transbond XT adhesive containing 1 wt% titanium dioxide (TiO2) nano-particles.
Materials and methods. Ten composite disks were prepared from each of the conventional and TiO2-containg composites and aged for 1, 3, 5, 7 and 14 days in Dulbecco’s Modified Eagle’s Medium (DMEM). The extracts were obtained and exposed to culture media of human gingival fibroblasts (HGF) and mouse L929 fibroblasts. Cell viability was measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay.
Results. Both adhesives were moderately toxic for HGF cells on the first day of the experiment, but the TiO2-containing adhesive produced significantly lower toxicity than the pure adhesive (P<0.05). No significant differences were found in cell viability percentages between the two groups on the other days (P>0.05). There was a significant reduction in cell toxicity with increasing pre-incubation time (P<0.001). L929 cells showed similar toxicity trends, but lower sensitivity to detect cytotoxicity of dental composites.
Conclusion. The orthodontic adhesive containing TiO2 nano-particles indicated comparable or even lower toxicity than its nano-particle-free counterpart, indicating that incorporation of 1 wt% TiO2 nano-particles to the composite structure does not result in additional health hazards compared to that occurring with the pure adhesive.
doi:10.5681/joddd.2013.031
PMCID: PMC3935549  PMID: 24578816
Adhesive; biocompatibility; cytotoxicity; nano-particles; orthodontics; titanium dioxide
5.  Genome-wide meta-analyses of multi-ethnic cohorts identify multiple new susceptibility loci for refractive error and myopia 
Verhoeven, Virginie J.M. | Hysi, Pirro G. | Wojciechowski, Robert | Fan, Qiao | Guggenheim, Jeremy A. | Höhn, René | MacGregor, Stuart | Hewitt, Alex W. | Nag, Abhishek | Cheng, Ching-Yu | Yonova-Doing, Ekaterina | Zhou, Xin | Ikram, M. Kamran | Buitendijk, Gabriëlle H.S. | McMahon, George | Kemp, John P. | St. Pourcain, Beate | Simpson, Claire L. | Mäkelä, Kari-Matti | Lehtimäki, Terho | Kähönen, Mika | Paterson, Andrew D. | Hosseini, S. Mohsen | Wong, Hoi Suen | Xu, Liang | Jonas, Jost B. | Pärssinen, Olavi | Wedenoja, Juho | Yip, Shea Ping | Ho, Daniel W. H. | Pang, Chi Pui | Chen, Li Jia | Burdon, Kathryn P. | Craig, Jamie E. | Klein, Barbara E. K. | Klein, Ronald | Haller, Toomas | Metspalu, Andres | Khor, Chiea-Chuen | Tai, E-Shyong | Aung, Tin | Vithana, Eranga | Tay, Wan-Ting | Barathi, Veluchamy A. | Chen, Peng | Li, Ruoying | Liao, Jiemin | Zheng, Yingfeng | Ong, Rick T. | Döring, Angela | Evans, David M. | Timpson, Nicholas J. | Verkerk, Annemieke J.M.H. | Meitinger, Thomas | Raitakari, Olli | Hawthorne, Felicia | Spector, Tim D. | Karssen, Lennart C. | Pirastu, Mario | Murgia, Federico | Ang, Wei | Mishra, Aniket | Montgomery, Grant W. | Pennell, Craig E. | Cumberland, Phillippa M. | Cotlarciuc, Ioana | Mitchell, Paul | Wang, Jie Jin | Schache, Maria | Janmahasathian, Sarayut | Igo, Robert P. | Lass, Jonathan H. | Chew, Emily | Iyengar, Sudha K. | Gorgels, Theo G.M.F. | Rudan, Igor | Hayward, Caroline | Wright, Alan F. | Polasek, Ozren | Vatavuk, Zoran | Wilson, James F. | Fleck, Brian | Zeller, Tanja | Mirshahi, Alireza | Müller, Christian | Uitterlinden, Andre’ G. | Rivadeneira, Fernando | Vingerling, Johannes R. | Hofman, Albert | Oostra, Ben A. | Amin, Najaf | Bergen, Arthur A.B. | Teo, Yik-Ying | Rahi, Jugnoo S. | Vitart, Veronique | Williams, Cathy | Baird, Paul N. | Wong, Tien-Yin | Oexle, Konrad | Pfeiffer, Norbert | Mackey, David A. | Young, Terri L. | van Duijn, Cornelia M. | Saw, Seang-Mei | Wilson, Joan E. Bailey | Stambolian, Dwight | Klaver, Caroline C. | Hammond, Christopher J.
Nature genetics  2013;45(3):314-318.
Refractive error is the most common eye disorder worldwide, and a prominent cause of blindness. Myopia affects over 30% of Western populations, and up to 80% of Asians. The CREAM consortium conducted genome-wide meta-analyses including 37,382 individuals from 27 studies of European ancestry, and 8,376 from 5 Asian cohorts. We identified 16 new loci for refractive error in subjects of European ancestry, of which 8 were shared with Asians. Combined analysis revealed 8 additional loci. The new loci include genes with functions in neurotransmission (GRIA4), ion channels (KCNQ5), retinoic acid metabolism (RDH5), extracellular matrix remodeling (LAMA2, BMP2), and eye development (SIX6, PRSS56). We also confirmed previously reported associations with GJD2 and RASGRF1. Risk score analysis using associated SNPs showed a tenfold increased risk of myopia for subjects with the highest genetic load. Our results, accumulated across independent multi-ethnic studies, considerably advance understanding of mechanisms involved in refractive error and myopia.
doi:10.1038/ng.2554
PMCID: PMC3740568  PMID: 23396134
6.  The Direct Medical Costs of Breast Cancer in Iran: Analyzing the Patient's Level Data from a Cancer Specific Hospital in Isfahan 
Background:
Breast cancer is one of the main causes of mortality and morbidity world-wide. The estimation of the direct medical costs of breast cancer can help payers of the cost to understand the burden of breast cancer on their limited financial resources as well as the society.
Methods:
We used a cross-sectional study to calculate the direct medical costs of breast cancer among women in Isfahan, Iran. The medical records of all patients which were registered in Seyed Al-Shohada Hospital between March 2005 and March 2010 were reviewed. The relevant data from patients’ profiles extracted. The direct medical costs of received services were calculated with both public and private tariffs.
Results:
The total numbers of 467 patients in various disease stages were included into the study. The average age of patients was 49 years. The average direct cost per patient per month in stages I to IV were 222.17, 224.61, 316.51 and 828.52 US$, respectively. The surgery cost was the main cost driver for stages I and II with private tariffs. However for stages III and IV, the medication cost was the main cost component for managing breast cancer.
Conclusions:
The direct economic cost of breast cancer in Iran is very high; nonetheless, as the age of breast cancer in Iran is nearly 10 years lower than Western countries, the burden of the disease in Iran is expected to be significantly high. Medication therapy is the main cost component of the breast cancer.
PMCID: PMC3775213  PMID: 24049592
Breast cancer; costs analysis; direct medical cost; Iran
7.  First Report on Self-Rated Health in a Nationally-Representative Sample of Iranian Adolescents: The CASPIAN-iii study 
Objective:
To evaluate predictive factors of adolescents’ appraisal of their health.
Methods:
The nationwide study, entitled “Childhood and Adolescence Surveillance and Prevention of Adult Non-communicable Diseases (CASPIAN) study”, was conducted in 2010 among Iranian school students, aged 10-18. In addition to demographic factors and physical examination, variables as family structure, nutrition habits, physical activity, smoking, hygienic habits, violence, school attachment, family smoking, and family history of chronic diseases were assessed. The dependent variable is the self-rated health (SRH) and it was measured by 12 items, which had already been combined through latent class analysis. We had taken a dichotomous variable, i.e. the higher values indicate better SRH. The dependent variable was regressed on all predictors by generalized additive models.
Results:
75% of adolescents had a good SRH. The linear and smooth effects of independent variables on SRH were observed. Among all the variables, physical activity had a positive linear effect on SRH (β = 0.08, P value = 0.003). Smoking, violence, and family history of disease associated to SRH non-linearly (P value < 0.05). Family smoking (β = −0.01) and hygienic habits (β = 0.27) related to SRH both linearly and non-linearly.
Conclusions:
Physical health and high risk behavior, either of linear or non-linear effect, are factors, which seem to shape the adolescents’ perception of health.
PMCID: PMC3604845  PMID: 23543891
Adolescents; health status; health status indicator; logistic models; non-parametric statistics; school; self-report
8.  RORC2 Gene Silencing in Human Th17 Cells by siRNA: Design and Evaluation of Highly Efficient siRNA 
Background
RNA interference-based gene silencing has recently been applied as an efficient tool for functional gene analysis. RORC2 is the key transcription factor orchestrating Th17 cells differentiation, the cells that are known as the pathogenic elements in various autoimmune diseases. The aim of this study was to design efficient siRNAs specific for RORC2 and to evaluate different criteria affecting their functionality.
Methods
Three siRNA duplexes specific for RORC2 mRNA were designed. Th17 cells were produced from IL-6 and IL-1 treated cord blood CD4+ T cells. The T cells were transfected with three different designed siRNAs against RORC2 and the expression of RORC2 gene was measured using quantitative real time PCR.
Results
Different levels of RORC2 down regulation were observed in the presence of each of the designed siRNAs. Efficient siRNA with 91.1% silencing activity met the majority of the established bioinformatics criteria while the one with 46.6% silencing activity had more deviations from these criteria.
Conclusion
The more bioinformatics criteria are considered, the more functionality were observed for silencing RORC2. However, the importance of the type of criteria per se should not be neglected. Although all recommended criteria are important for designing siRNA but their value is not the same.
PMCID: PMC3572701  PMID: 23626872
RNAi; siRNA; Th17 cells
9.  Effects of dietary supplementation with ghee, hydrogenated oil, or olive oil on lipid profile and fatty streak formation in rabbits 
ARYA Atherosclerosis  2012;8(3):119-124.
BACKGROUND
Coronary heart disease is the leading cause of mortality worldwide. A high-fat diet, rich in saturated fatty acids and low in polyunsaturated fatty acids, is said to be an important cause of atherosclerosis and cardiovascular diseases.
METHODS
In this experimental study, 40 male rabbits were randomly assigned to eight groups of five to receive normal diet, hypercholesterolemic diet, normal diet plus ghee, normal diet plus olive oil, normal diet plus hydrogenated oil, hypercholesterolemic diet plus ghee, hypercholesterolemic diet plus olive oil, and hypercholesterolemic diet plus hydrogenated oil. They received rabbit chow for a period of 12 weeks. At the start and end of the study, fasting blood samples were taken from all animals to measure biochemical factors including total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglyceride (TG), fasting blood sugar (FBS), and C-reactive protein (CRP). Moreover, aorta, left and right coronary arteries were dissected at the end of the study to investigate fatty streak formation (FSF). Data was analyzed in SPSS at a significance level of 0.05.
RESULTS
In rabbits under normal diet, ghee significantly increased TC, LDL, and HDL compared to the beginning (P < 0.01) and also to the other two types of fat (P < 0.05). Moreover, normal diet plus olive oil significantly enhanced FSF in left coronary arteries and aorta compared to normal diet plus ghee. In groups receiving hypercholesterolemic diets, ghee significantly increased HDL and CRP (P < 0.05) and significantly decreased FBS (P < 0.01). The hypecholesterolemic diet plus olive oil significantly increased HDL (P < 0.01). Supplementation of hypecholesterolemic diet with ghee significantly increased HDL and FBS in comparison with hydrogenated oil. Significant increase of FBS was also detected with the use of ghee compared to olive oil. Ghee also significantly reduced FSF in left and right coronary arteries compared to olive oil. FSF in left coronary arteries was significantly lower in the hypecholesterolemic diet plus ghee group compared to the hypecholesterolemic diet plus hydrogenated oil group.
CONCLUSION
According to the achieved results, future clinical trial studies and investigation of other risk factors such as inflammatory factors are required.
PMCID: PMC3557004  PMID: 23358722
Fatty Streak; Ghee; Hypercholesterolemic; Olive Oil
10.  Common Genetic Determinants of Intraocular Pressure and Primary Open-Angle Glaucoma 
PLoS Genetics  2012;8(5):e1002611.
Intraocular pressure (IOP) is a highly heritable risk factor for primary open-angle glaucoma and is the only target for current glaucoma therapy. The genetic factors which determine IOP are largely unknown. We performed a genome-wide association study for IOP in 11,972 participants from 4 independent population-based studies in The Netherlands. We replicated our findings in 7,482 participants from 4 additional cohorts from the UK, Australia, Canada, and the Wellcome Trust Case-Control Consortium 2/Blue Mountains Eye Study. IOP was significantly associated with rs11656696, located in GAS7 at 17p13.1 (p = 1.4×10−8), and with rs7555523, located in TMCO1 at 1q24.1 (p = 1.6×10−8). In a meta-analysis of 4 case-control studies (total N = 1,432 glaucoma cases), both variants also showed evidence for association with glaucoma (p = 2.4×10−2 for rs11656696 and p = 9.1×10−4 for rs7555523). GAS7 and TMCO1 are highly expressed in the ciliary body and trabecular meshwork as well as in the lamina cribrosa, optic nerve, and retina. Both genes functionally interact with known glaucoma disease genes. These data suggest that we have identified two clinically relevant genes involved in IOP regulation.
Author Summary
Glaucoma is a major eye disease in the elderly and is the second leading cause of blindness worldwide. The numerous familial glaucoma cases, as well as evidence from epidemiological and twin studies, strongly support a genetic component in developing glaucoma. However, it has proven difficult to identify the specific genes involved. Intraocular pressure (IOP) is the major risk factor for glaucoma and the only target for the current glaucoma therapy. IOP has been shown to be highly heritable. We investigated the role of common genetic variants in IOP by performing a genome-wide association study. Discovery analyses in 11,972 participants and subsequent replication analyses in a further 7,482 participants yielded two common genetic variants that were associated with IOP. The first (rs11656696) is located in GAS7 at chromosome 17, the second (rs7555523) in TMCO1 at chromosome 1. Both variants were associated with glaucoma in a meta-analysis of 4 case-control studies. GAS7 and TMCO1 are expressed in the ocular tissues that are involved in glaucoma. Both genes functionally interact with the known glaucoma disease genes. These data suggest that we have identified two genes involved in IOP regulation and glaucomatous neuropathy.
doi:10.1371/journal.pgen.1002611
PMCID: PMC3342933  PMID: 22570627
11.  The relationship between occupational radiation exposure and thyroid nodules 
Background:
Considering that thyroid nodules and thyroid cancer occur more frequently in people chronically exposed to radiation, the aim of this study was to evaluate the prevalence of thyroid nodules in a population occupationally exposed to radiation in hospitals of Isfahan, Iran.
Materials and Methods:
In this case-control study, the prevalence of thyroid nodules in staff members occupationally exposed to radiation was determined by ultrasonography. The results were compared with the results of another study among the adult population of Isfahan which selected by cluster random sampling method. The 2 studied groups were matched according to sex and age.
Results:
The case and control groups included 124 and 471 persons, respectively. The prevalence of thyroid nodules in the case and control groups was 22.6% and 24.6%, respectively (p > 0.05). Although thyroid nodules were significantly more prevalent in females in the control group, no such difference was observed between females and males of the case group (p > 0.05). The number of thyroid nodules (single or multiple) and calcification were not different between the two groups (p > 0.05). In addition, hypoechogenicity of thyroid nodules was not different between the two groups for (p > 0.05).
Conclusion:
In our study, there was not any correlation between chronic occupational exposure to low dose of radiation and the risk of developing thyroid nodules. Further studies with larger sample sizes, at different doses of radiation, and considering iodine status and thyroid function are thus required.
PMCID: PMC3634267  PMID: 23626606
Thyroid Nodule; Radiation; Occupational Exposure; Ultrasonography
12.  Assessing Awareness Level about Warning Signs of Cancer and its Determinants in an Iranian General Population 
The present study was aimed at investigating the awareness level about warning signs of cancer and its determinants in an Iranian general population. This cross-sectional interview-based survey investigated 2,500 people aged 18 years and over, as a representative sample of Tehran population. Latent class regression was applied for analyzing data. A small (18.8%) proportion of the respondents had high level of knowledge, and 54.5% had moderate awareness, and 26.7% had low level of awareness. Most effective predictors for awareness were educational attainment, sex, and marital status. The findings suggest that the overall level of knowledge about warning signs of cancer among the public is low, particularly about some specific signs. Accordingly, educational and intervention programmes, with special attention placed on particular at-risk populations, to increase awareness about the disease leading to its early diagnosis are needed.
PMCID: PMC3259730  PMID: 22283041
Awareness; Cancer; Cross-sectional studies; Health education; Neoplasms; Public education; Signs and symptoms; Iran
13.  Genome-Wide Association Identifies the ABO Blood Group as a Major Locus Associated With Serum Levels of Soluble E-Selectin 
Background
Elevated serum soluble E-selectin levels have been associated with a number of diseases. Although E-selectin levels are heritable, little is known about the specific genetic factors involved. E-selectin levels have been associated with the ABO blood group phenotype.
Methods and Results
We performed a high-resolution genome-wide association study of serum soluble E-selectin levels in 685 white individuals with type 1 diabetes from the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Intervention and Complications (EDIC) study to identify major loci influencing levels. Highly significant evidence for association (P=10−29) was observed for rs579459 near the ABO blood group gene, accounting for 19% of the variance in E-selectin levels. Levels of E-selectin were higher in O/O than O/A heterozygotes, which were likewise higher than A/A genotypes. Analysis of subgroups of A alleles reveals heterogeneity in the association, and even after this was accounted for, an intron 1 SNP remained significantly associated. We replicate the ABO association in nondiabetic individuals.
Conclusion
ABO is a major locus for serum soluble E-selectin levels. We excluded population stratification, fine-mapped the association to sub-A alleles, and also document association with additional variation in the ABO region.
doi:10.1161/ATVBAHA.109.192971
PMCID: PMC3147250  PMID: 19729612
E-selectin; ABO blood group; genome-wide association; SNP
14.  A Genome-Wide Association Study Identifies a Novel Major Locus for Glycemic Control in Type 1 Diabetes, as Measured by Both A1C and Glucose 
Diabetes  2009;59(2):539-549.
OBJECTIVE
Glycemia is a major risk factor for the development of long-term complications in type 1 diabetes; however, no specific genetic loci have been identified for glycemic control in individuals with type 1 diabetes. To identify such loci in type 1 diabetes, we analyzed longitudinal repeated measures of A1C from the Diabetes Control and Complications Trial.
RESEARCH DESIGN AND METHODS
We performed a genome-wide association study using the mean of quarterly A1C values measured over 6.5 years, separately in the conventional (n = 667) and intensive (n = 637) treatment groups of the DCCT. At loci of interest, linear mixed models were used to take advantage of all the repeated measures. We then assessed the association of these loci with capillary glucose and repeated measures of multiple complications of diabetes.
RESULTS
We identified a major locus for A1C levels in the conventional treatment group near SORCS1 (10q25.1, P = 7 × 10−10), which was also associated with mean glucose (P = 2 × 10−5). This was confirmed using A1C in the intensive treatment group (P = 0.01). Other loci achieved evidence close to genome-wide significance: 14q32.13 (GSC) and 9p22 (BNC2) in the combined treatment groups and 15q21.3 (WDR72) in the intensive group. Further, these loci gave evidence for association with diabetic complications, specifically SORCS1 with hypoglycemia and BNC2 with renal and retinal complications. We replicated the SORCS1 association in Genetics of Diabetes in Kidneys (GoKinD) study control subjects (P = 0.01) and the BNC2 association with A1C in nondiabetic individuals.
CONCLUSIONS
A major locus for A1C and glucose in individuals with diabetes is near SORCS1. This may influence the design and analysis of genetic studies attempting to identify risk factors for long-term diabetic complications.
doi:10.2337/db09-0653
PMCID: PMC2809960  PMID: 19875614
15.  Barriers to Physical Activity in a Population-based Sample of Children and Adolescents in Isfahan, Iran 
Objectives:
This study was conducted to explore the barriers to physical activity in a representative sample of Iranian children and adolescents.
Methods:
The study was conducted in 2007 in urban and rural areas of Isfahan district in Iran. In the qualitative part, we used the grounded theory approach, including semi-structured focus group discussions and indepth interviews. The quantitative part comprised 600 randomly selected students.
Results:
The qualitative study included 34 school students (16 girls), 20 parents (11 mothers) and 11 school staff. All students disclosed that studying was a priority. They pointed to lack of safe and easy-access place for physical activity and unsupportive family as the main barriers. Lack of self-confidence and low selfworth were the two other concepts developed in this context. Parents pointed to lack of safe and easy-access place for activity followed by the priority of studying. The concepts derived from interviews with school staff included unhealthy modeling of parents, priority of studying, and inadequate public knowledge about how to integrate physical activity in routine daily life. The quantitative survey comprised 600 students including 286 (47.8%) girls. Parents’ education level had inverse association with children’s physical activity level. Significant inverse associations of self-efficacy and physical activity levels were documented.
Conclusions:
Increasing the public knowledge about adopting physical activity habits in routine daily life, informing the families and students about the benefits of physical activity to improve learning, as well as providing safe places such as using the school facilities in non-school hours should be considered in planning effective preventive strategies and interventions.
PMCID: PMC3075475  PMID: 21566774
Physical activity; Pediatric; Barriers; Prevention; Iran
16.  Genetic analysis of chromosome 20-related posterior polymorphous corneal dystrophy: genetic heterogeneity and exclusion of three candidate genes 
Molecular Vision  2008;14:71-80.
Purpose
Posterior polymorphous corneal dystrophy (PPCD) is a genetically heterogeneous autosomal dominant condition which maps to the pericentromeric region of chromosome 20. Mutations in the VSX1 transcription factor have been reported in patients affected with PPCD, keratoconus, or a combination of both phenotypes. However, no mutation was identified in the coding region of VSX1 in the family used for the original mapping. To clarify the genetic basis of PPCD1, a thorough analysis was performed on the original PPCD1 family and two other PPCD1-linked families. As part of the analysis, the expression profile, transcript variants, and evolutionary conserved regions of VSX1, a key candidate gene within the linkage interval, were characterized.
Methods
Haplotype analysis was performed using highly informative markers on the pericentromeric region of chromosome 20. VSX1 transcript variants were identified using RT–PCR and characterized by 3′RACE assay. Temporal expression profile of VSX1 was evaluated using semi-quantitative real-time RT–PCR on human tissues. Evolutionary conserved regions (ECRs) were identified in the vicinity of VSX1 using publicly available sequence alignments (UCSC and rVista) and sequenced for mutation analysis.
Results
Recombination events were identified that narrow the PPCD1-disease interval from 20 to 16.44 cM. This smaller interval includes the CHED1 locus and a recently described PPCD locus in Czech families. The three strongest candidate genes of the PPCD1-CHED1 overlap region (RBBP9, ZNF133, SLC24A3) did not show any mutations in our PPCD1-linked families. Semi-quantitative real-time RT–PCR detected VSX1 expression in neonatal human cornea. Six transcript variants of VSX1 were characterized. Four of the transcript variants spliced to two novel exons downstream of the gene. Mutation analysis of the PPCD1-linked families did not reveal any mutations in the full genomic sequence of VSX1 (considering all splice variants) or in the six cis- regulatory modules predicted in the vicinity of VSX1 (100 kb).
Conclusions
This is the first documentation of VSX1 expression in human neonatal cornea. We provide evidence for genetic heterogeneity of chromosome 20-related PPCD and refinement of the original PPCD1 interval. The full genomic sequence of VSX1 and coding exons of three other candidate genes were excluded from being pathogenic in the original PPCD1 family.
PMCID: PMC2267740  PMID: 18253095

Results 1-16 (16)