Sequence analysis of the VSX1 and SOD1 genes in families with Keratoconus and a review of the literature

AbstractObjectiveKeratoconus (KC) is a non-inflammatory disorder of the cornea in which the cornea becomes thin and conical, inducing myopia and irregular astigmatism and resulting in mild to marked impairment of vision. The present study was designed to screen two candidate KC genes to identify pathogenic sequence variants responsible for KC in Saudi families.MethodsPeripheral blood samples from members of five Saudi families with KC from the Northern region were collected. Genomic DNA was isolated, and bidirectional sequencing was performed of all coding exons of VSX1 and SOD1 genes using Sanger sequencing.ResultsAll five of the KC families showed a pattern of autosomal recessive inheritance. Phenotyping of these families was performed by a senior ophthalmologist. Sequence analysis of the VSX1 and SOD1 genes failed to reveal any pathogenic sequence variant that could account for KC in the affected individuals.ConclusionOur failure to detect sequence variants in two of the known KC associated genes triggers an interest in other known KC candidate genes, including miR-184, DOCK9, IL1RN and SLC4A11. Future genotyping with dense SNP arrays followed by exome sequencing in these families will be a useful approach to identify the gene(s) underlying KC in this Saudi cohort, which may be different from those reported elsewhere

Dysglycemia risk score in Saudi Arabia: A tool to identify people at high future risk of developing type 2 diabetes

Abstract Aims/Introduction To develop a non-invasive risk score to identify Saudis having prediabetes or undiagnosed type 2 diabetes. Methods Adult Saudis without diabetes were recruited randomly using a stratified two-stage cluster sampling method. Demographic, dietary, lifestyle variables, personal and family medical history were collected using a questionnaire. Blood pressure and anthropometric measurements were taken. Body mass index was calculated. The 1-h oral glucose tolerance test was carried out. Glycated hemoglobin, fasting and 1-h plasma glucose were measured, and obtained values were used to define prediabetes and type 2 diabetes (dysglycemia). Logistic regression models were used for assessing the association between various factors and dysglycemia, and Hosmer?Lemeshow summary statistics were used to assess the goodness-of-fit. Results A total of 791 men and 612 women were included, of whom 69 were found to have diabetes, and 259 had prediabetes. The prevalence of dysglycemia was 23%, increasing with age, reaching 71% in adults aged ≥65 years. In univariate analysis age, body mass index, waist circumference, use of antihypertensive medication, history of hyperglycemia, low physical activity, short sleep and family history of diabetes were statistically significant. The final model for the Saudi Diabetes Risk Score constituted sex, age, waist circumference, history of hyperglycemia and family history of diabetes, with the score ranging from 0 to 15. Its fit based on assessment using the receiver operating characteristic curve was good, with an area under the curve of 0.76 (95% confidence interval 0.73?0.79). The proposed cut-point for dysglycemia is 5 or 6, with sensitivity and specificity being approximately 0.7. Conclusion The Saudi Diabetes Risk Score is a simple tool that can effectively distinguish Saudis at high risk of dysglycemia.Peer reviewe

Identification of a putative anti-rheumatoid arthritis molecule by virtual screening

Purpose: To propose an improved chemical skeleton whose scaffolds could be used for the design of future thymidylate synthase (TS)-inhibitors against rheumatoid arthritis. Methods: The drug discovery platform, ‘MCULE’, was employed for inhibitor-screening. The ‘methotrexate-interaction site’ in the crystal (PDB ID 5X66) was used as a target. One ‘RO5 violation’ was permitted. A maximum of ‘10 rotatable bonds’ and ‘100 diverse molecules’ were also allowed in the protocol. The ‘threshold similarity cut off’ was 0.7. The input values describing the remaining parameters were kept as ‘default’. The ‘Open Babel Linear Fingerprint’ was used for the analyses of molecular descriptors, followed by ADME-check. Results: 4-(4-Methyl-1-piperazinyl)-2-phenyl[1]benzofuro[3,2-d]pyrimidine corresponding to the MCULE ID-7590816301-0-93 exhibited the overall best binding with TS. The free energy of binding was -8.6 kcal/mol. A total of 17 amino acid residues were significant for the binding interactions. Importantly, 9 residues were common to methotrexate binding. It satisfied pertinent ADME conditions. Conclusion: 4-(4-Methyl-1-piperazinyl)-2-phenyl[1]benzofuro[3,2-d]pyrimidinemay emerge as a potent seed molecule for TS-inhibitor design in the context of rheumatoid arthritis. It has satisfied pertinent ADME features. However, there is need for further wet laboratory validation. Keywords: Anti-rheumatoid arthritis, Inhibitor design, Methotrexate, Seed molecule, Thymidylate synthase, Virtual screenin

The association between hypertension and other cardiovascular risk factors among non-diabetic Saudis adults-A cross sectional study

Population specific associations between cardiovascular disease with various risk factors including pre-hypertension and hypertension were reported. We aimed to investigate the association of higher than optimal blood pressure with measures of dysglycemia, dyslipidemia, and markers of inflammation in non-diabetic Saudi adults hoping to improve current Saudi guidelines to prevent cardiovascular disease. Volunteers were recruited randomly from public healthcare centers in Jeddah. Demographic information, blood pressure (BP), and anthropometric measurements were taken. Fasting blood samples were drawn, then again following 1-hour oral glucose tolerance test. Glycated hemoglobin, fasting plasma glucose (FPG), lipid profile, highly sensitive C- reactive protein, gamma glutamyl transferase, and 1-hour plasma glucose were measured. Complete data was found for 742 men and 592 women. Pre-hypertension was found in 47.2% of men, and 24.7% of women, while 15.1% of men, and 14.6% of women were hypertensive. Means of measured variables differed significantly between normotensive, pre-hypertensive, and hypertensive groups of men and women in gender specific manner. Association between measured variables and elevated BP, and hypertension were assessed using logistic regression models. After adjustment for age, body mass index and waist circumference, elevated blood pressure was associated with elevated triglycerides in men, while hypertension was significantly associated with elevated fasting plasma glucose, total cholesterol, triglycerides, low density lipoprotein- cholesterol, and low high density lipoprotein- cholesterol in men, and elevated triglycerides, and total cholesterol in women. Therefore, it is strongly recommended to measure lipid profile, specifically TG, for all diagnosed pre-hypertensive and hypertensive patients in addition to FPG for men.Peer reviewe

Association Between Anthropometric Indices and Nonanthropometric Components of Metabolic Syndrome in Saudi Adults

Context: Waist circumference (WC) is used in screening for metabolic syndrome (MetS) based on its association with cardiometabolic risk.This might apply differently in ethnically different populations. Associations with other measures are also unclear. Objective: This work aimed to investigate the association between neck circumference (NC), WC, WC:hip circumference, WC:height (VVC:Ht), NC:Ht, fat percentage, body mass index (BMI), conicity index, abdominal volume index, and weight-adjusted waist index with nonanthropometric components of MetS in nondiabetic Saudi adults. Methods: This cross-sectional study took place in public health centers in Jeddah, comprising 1365 Saudi adults (772 men and 593 women) aged 18 years or older not previously diagnosed with diabetes. Main outcome measures included the presence of 2 or more nonanthropometric components of the MetS were used to define clinical metabolic abnormality (CMA). The predictive ability of studied anthropometric indices for CMA was determined using the area under receiver operating characteristics (AUC) curve and binary logistic regression. Results: A total of 157 men and 83 women had CMA. NC and NC:Ht had the highest predictive ability for CMA in men (odds ratio [OR](NC) = 1.79, P < .001 and ORNC:Ht = 1.68, P < .001; AUC(NC) = 0.69 [95% CI, 0.64-0.74] and ALS, = 0.69 [95% CI, 0.64-0.73]). In women, WC had the highest predictive ability ORWC = 1.81, P< .001; AUC(WC) = 0.75 [95% CI, 0.69-0.80]). Conclusion: Upper-body anthropometric indicators that were associated with subcutaneous fat had the highest predictive ability for CMA in men whereas abdominal obesity indictors had the best predictive ability in women, suggesting that fat distribution might contribute to CMA in a sex-specific manner.Peer reviewe

Molecular interaction of 4-amino-N’-(benzoyloxy)-N-(2,4- dimethylphenyl)-1,2,5-oxadiazole-3-carboximidamide with the methotrexate binding site of human DHFR, and its implication in rheumatoid arthritis

Purpose: To identify an improved lead molecule for the human dihydrofolate reductase (DHFR) inhibition that ‘sits’ in the same binding cavity as methotrexate by high throughput computationalscreening.Methods: The 3-D structure of the DHFR binding site was examined using ‘CASTp3.0’. Structure based in silico screening of about 5 million drug candidates housed in the MCULE database was performed. The obtained molecule-hits were ranked in accordance with their VINA scores, made to pass through drug-likeness filters, ΔG cut-off criterion, toxicity-checker and finally ‘zero RO5 criterion’.Results: The ‘top molecule’, namely, 4-amino-N'-(benzoyloxy)-N-(2,4-dimethylphenyl)-1,2,5-oxadiazole- 3-carboximidamide, displayed robust binding with human DHFR through 21 amino acid residues (ΔG = - 9.6 kcal/mol) while 10 of these residues were the same as those displayed by ‘methotrexate binding interactions’. It passed through relevant drug screening filters including the ‘Toxicity Checker’.Conclusion: This research work describes the molecular interaction of human DHFR with an improved lead molecule named, 4-amino- N’-(benzoyloxy)-N-(2,4-dimethylphenyl)-1,2,5-oxadiazole-3- carboximidamide, with a ΔG of -9.6 kcal/mol, thus satisfying adequate ADME features for further in vitro and in vivo validation in the context of rheumatoid arthritis. Keywords: Dihydrofolate reductase, In silico screening, Methotrexate, Rheumatoid arthritis, DHF

The Association between Dyslipidemia, Dietary Habits and Other Lifestyle Indicators among Non-Diabetic Attendees of Primary Health Care Centers in Jeddah, Saudi Arabia

Diet and other lifestyle habits have been reported to contribute to the development of dyslipidemia in various populations. Therefore, this study investigated the association between dyslipidemia and dietary and other lifestyle practices among Saudi adults. Data were collected from adults (>= 20 years) not previously diagnosed with diabetes in a cross-sectional design. Demographic, anthropometric, and clinical characteristics, as well as lifestyle and dietary habits were recorded using a predesigned questionnaire. Fasting blood samples were drawn to estimate the serum lipid profile. Out of 1385 people, 858 (62%) (491 men, 367 women) had dyslipidemia. After regression analysis to adjust for age, body mass index, and waist circumference, an intake of >= 5 cups/week of Turkish coffee, or carbonated drinks was associated with increased risk of dyslipidemia in men (OR (95% CI), 2.74 (1.53, 4.89)p= 0.001, and 1.53 (1.04, 2.26)p= 0.03 respectively), while the same intake of American coffee had a protective effect (0.53 (0.30, 0.92)p= 0.025). Sleep durationPeer reviewe

Critically ill patients with diabetes and Middle East respiratory syndrome:a multi-center observational study

Background: Diabetes is a risk factor for infection with coronaviruses. This study describes the demographic, clinical data, and outcomes of critically ill patients with diabetes and Middle East Respiratory Syndrome (MERS).Methods: This retrospective cohort study was conducted at 14 hospitals in Saudi Arabia (September 2012–January 2018). We compared the demographic characteristics, underlying medical conditions, presenting symptoms andsigns, management and clinical course, and outcomes of critically ill patients with MERS who had diabetes compared to those with no diabetes. Multivariable logistic regression analysis was performed to determine ifdiabetes was an independent predictor of 90-day mortality.Results: Of the 350 critically ill patients with MERS, 171 (48.9%) had diabetes. Patients with diabetes were more likely to be older, and have comorbid conditions, compared to patients with no diabetes. They were more likely topresent with respiratory failure requiring intubation, vasopressors, and corticosteroids. The median time to clearance of MERS-CoV RNA was similar (23 days (Q1, Q3: 17, 36) in patients with diabetes and 21.0 days (Q1, Q3: 10, 33) in patients with no diabetes). Mortality at 90 days was higher in patients with diabetes (78.9% versus 54.7%, p &lt;0.0001). Multivariable regression analysis showed that diabetes was an independent risk factor for 90-day mortality(odds ratio, 2.09; 95% confidence interval, 1.18–3.72).Conclusions: Half of the critically ill patients with MERS have diabetes; which is associated with more severe disease. Diabetes is an independent predictor of mortality among critically patients with MERS

Critically ill patients with diabetes and Middle East respiratory syndrome:a multi-center observational study

Background: Diabetes is a risk factor for infection with coronaviruses. This study describes the demographic, clinical data, and outcomes of critically ill patients with diabetes and Middle East Respiratory Syndrome (MERS).Methods: This retrospective cohort study was conducted at 14 hospitals in Saudi Arabia (September 2012–January 2018). We compared the demographic characteristics, underlying medical conditions, presenting symptoms andsigns, management and clinical course, and outcomes of critically ill patients with MERS who had diabetes compared to those with no diabetes. Multivariable logistic regression analysis was performed to determine ifdiabetes was an independent predictor of 90-day mortality.Results: Of the 350 critically ill patients with MERS, 171 (48.9%) had diabetes. Patients with diabetes were more likely to be older, and have comorbid conditions, compared to patients with no diabetes. They were more likely topresent with respiratory failure requiring intubation, vasopressors, and corticosteroids. The median time to clearance of MERS-CoV RNA was similar (23 days (Q1, Q3: 17, 36) in patients with diabetes and 21.0 days (Q1, Q3: 10, 33) in patients with no diabetes). Mortality at 90 days was higher in patients with diabetes (78.9% versus 54.7%, p &lt;0.0001). Multivariable regression analysis showed that diabetes was an independent risk factor for 90-day mortality(odds ratio, 2.09; 95% confidence interval, 1.18–3.72).Conclusions: Half of the critically ill patients with MERS have diabetes; which is associated with more severe disease. Diabetes is an independent predictor of mortality among critically patients with MERS