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Objectives: This study describes an unsupervised machine learning approach used to estimate the homeostatic model assessment-insulin resistance (HOMA-IR) cut-off for identifying subjects at risk of IR in a given ethnic group based on the clinical data of a representative sample. Methods: The approach was applied to analyse the clinical data of individuals with Arab ancestors, which was obtained from a family study conducted in Nizwa, Oman, between January 2000 and December 2004. First, HOMA-IR-correlated variables were identified to which a clustering algorithm was applied. Two clusters having the smallest overlap in their HOMA-IR values were retrieved. These clusters represented the samples of two populations, which are insulin-sensitive subjects and individuals at risk of IR. The cut-off value was estimated from intersections of the Gaussian functions, thereby modelling the HOMA-IR distributions of these populations. Results: A HOMA-IR cut-off value of 1.62 ± 0.06 was identified. The validity of this cut-off was demonstrated by showing the following: 1) that the clinical characteristics of the identified groups matched the published research findings regarding IR; 2) that a strong relationship exists between the segmentations resulting from the proposed cut-off and those resulting from the two-hour glucose cut-off recommended by the World Health Organization for detecting prediabetes. Finally, the method was also able to identify the cut-off values for similar problems (e.g. fasting sugar cut-off for prediabetes). Conclusion: The proposed method defines a HOMA-IR cut-off value for detecting individuals at risk of IR. Such methods can identify high-risk individuals at an early stage, which may prevent or delay the onset of chronic diseases such as type 2 diabetes. Keywords: Unsupervised Machine Learning; Cluster Analysis; Insulin Resistance; Diabetes Mellitus, Type II.

Background: Serum creatinine and estimated glomerular filtration rate (eGFR) are keys to assess kidney function and suggest a propensity for development of renal failure. Genetic factors are reported in different ethnic groups to play a role in the variability of these phenotypes. In this study, we investigate the heritability and quantitative trait loci (QTL) of serum creatinine and eGFR. Multiple phenotypes were collected from a multi-generation pedigree of 281 subjects form Oman family study. Genotype analysis was used to calculate heritability and linkage was performed using variance components decomposition-based methods implemented in SOLAR. Results: The multivariate-adjusted heritability estimates for serum creatinine and eGFR were 0.70 and 0.63 (p-value 2.5x10-11 and 1.8x10-11), respectively. Genome-wide linkage analysis showed significant loci with LOD score ≥2 at chromosomes 9p21.1, 9p21.3, 15p26.3 and 16.p13.3. Functional annotation identified angiopoietin 1-TEK pathway as a candidate pathway where TEK is associated with chronic kidney disease and expressed in renal glomeruli. Conclusion: This study showed high heritability of serum creatinine and eGFR with significant QTLs in chromosomes 9, 15 and 16. Further research is needed to study the genetic association studies of angiopoietin 1-TEK axis with glomerulopathies like type 2 diabetes and to predict and diagnose progression of renal diseases.

Objective:To more precisely and comprehensively estimate the genetic and environmental correlations between various indices of obesity and BP.Methods:We estimated heritability and genetic correlations of obesity indices with BP in the Oman family study (n=1231). Ambulatory and office beat-to-beat BP was measured and mean values for SBP and DBP during daytime, sleep, 24-h and 10min at rest were calculated. Different indices were used to quantify obesity and fat distribution: BMI, percentage of body fat (%BF), waist circumference and waist-to-height ratio (WHtR). SOLAR software was used to perform univariate and bivariate quantitative genetic analyses adjusting for age, age2, sex, age-sex and age2- sex interactions.Results:Heritabilities of BP ranged from 30.2 to 38.2% for ambulatory daytime, 16.8 - 21.4% for sleeping time, 32.1 - 40.4% for 24-h and 22 - 24.4% for office beat-to-beat measurements. Heritabilities for obesity indices were 67.8% for BMI, 52.2% for %BF, 37.3% for waist circumference and 37.9% for WHtR. All obesity measures had consistently positive phenotypic correlations with ambulatory and office beat-to-beat SBP and DBP (r-range: 0.14 - 0.32). Genetic correlations of obesity indices with SBP and DBP were higher than environmental correlations (rG: 0.16 - 0.50; rE: 0.01 - 0.31).Conclusion:The considerable genetic overlap between a variety of obesity indices and both ambulatory and office beat-to-beat BP highlights the relevance of pleiotropic genes. Future GWAS analyses should discover the specific genes both influencing obesity indices and BP to help unravel their shared genetic background.

Introduction:Individual differences in heart rate variability (HRV) can be partly attributed to genetic factors that may be more pronounced during stress. Using data from the Oman Family Study (OFS), we aimed to estimate and quantify the relative contribution of genes and environment to the variance of HRV at rest and during stress; calculate the overlap in genetic and environmental influences on HRV at rest and under stress using bivariate analyses of HRV parameters and heart rate (HR).Methods:Time and frequency domain HRV variables and average HR were measured from beat-to-beat HR obtained from electrocardiogram recordings at rest and during two stress tests [mental: Word Conflict Test (WCT) and physical: Cold Pressor Test (CPT)] in the OFS - a multigenerational pedigree consisting of five large Arab families with a total of 1326 participants. SOLAR software was used to perform quantitative genetic modelling.Results:Heritability estimates for HRV and HR ranged from 0.11 to 0.31 for rest, 0.09-0.43 for WCT, and 0.07-0.36 for CPT. A large part of the genetic influences during rest and stress conditions were shared with genetic correlations ranging between 0.52 and 0.86 for rest-WCT and 0.60-0.92 for rest-CPT. Nonetheless, genetic rest-stress correlations for most traits were significantly smaller than 1 indicating some stress-specific genetic effects.Conclusion:Genetic factors significantly influence HRV and HR at rest and under stress. Most of the genetic factors that influence HRV at rest also influence HRV during stress tests, although some unique genetic variance emerges during these challenging conditions.

This study examined the utility of a family-based model for replicating the results of genome-wide association studies (GWAS) of type 2 diabetes (T2D).In a total of 232 members of a large consanguineous Omani Arab pedigree (age: 16-80years), there were 27 diabetics and 50 prediabetics (17 with impaired fasting glucose and 33 with impaired glucose tolerance). All 232 individuals underwent anthropometric and biochemical investigations and genotyped for 14 known common gene variants of modest effect on T2D risk. Power analysis at a LOD score of 3, gave 80% power to locate a single specific locus that accounts for 52% of the total phenotypic variation. Measured genotype analysis (MGA) was used to determine heritability of various quantitative traits (QTs) which ranged 25-56%. Using MGA, some common gene variants were found to have little (5%) but significant impact on the heritability of T2D related QTs [KCNJ11 (rs5219), p=0.004]; [IGF2BP2 (rs4402960), p=0.02]; [SLC30A8 (rs13266634), p=0.05]; [CAPN10 (rs2975760), p=0.031]; [FTO (rs8050136), p=0.023]; [FTO (rs9939609), p=0.018] and [SLC30A8 (rs13266634), p=0.05]. Sib-TDT analysis showed that some gene variants were significantly associated with T2D risk but didn't reach the level of significance after Bonferroni correction [KCNJ11 (rs5219), p=0.047] and [CAPN10 (rs41266971), p=0.035].We have demonstrated that, in principle, a family-based model with minor limitations could be used to replicate some of the results of large GWAS case-control studies. This model could successfully be applied for the future discovery, by deep sequencing, of rare gene variants.

In November 2013, The College of Medicine and Health Sciences (COMHS) at Sultan Qaboos University (SQU) was “fully accredited” for a ten-year period (on its first attempt) by the Association for Medical Education in the Eastern Mediterranean Region (AMEEMR) in association with and in accordance with the standards of the World Federation for Medical Education (WFME).The accreditation decision was made on the basis that the MD Programme complies with the WFME’s “Basic and Quality Development Standards”.1 It is notable that COMHS’ “Quality Development Standards” are considered by the WFME as “Best Practice” thus conferring distinguished status on the COMHS’ MD Programme. This article describes the actions taken by the COMHS which led to this success. The achievement of accreditation was neither a sudden nor an unsystematic accomplishment. It was the result of a lengthy and extensive process of continuous improvement of the COMHS’ abilities and capacities that started long before the accreditation endeavour per se began in 2008. The process began by the construction of the “new” curriculum—an exercise that was accompanied and followed by other complementary measures. Only after that was the accreditation process initiated. Before explaining the process in more detail, a description of SQU and the COMHS might be helpful.

The aim of this work was to investigate the effect of 10 weeks of lisinopril treatment to spontaneously hypertensive rats (SHRs) on day/night variations of blood pressure, heart rate and autonomic cardio-regulation parameters. Male SHR with surgically implanted radio-telemetry implant that provided direct measurements of arterial pressure and electrocardiogram wave were used. Animals were allocated to two groups (n=5 each). The first group was treated with lisinopril (20 mg/kg by gavage) daily for 10 weeks (treated group); whereas the second was gavaged daily with tap water (untreated group). Arterial blood pressure, ECG and other telemetry parameters were recorded at the start and at the end of 10-week treatment. Collected data were analyzed using specialized software and were statistically tested. In addition to the expected lowering of blood pressure, spectral analysis of R-R intervals revealed that lisinopril treatment for 10 weeks significantly caused 2-3 fold increase in heart rate variability (HRV) during both active and inactive periods. However, R-R interval durations demonstrated variable distribution patterns during those periods. The cause of observed distribution pattern of R-R intervals during active and inactive periods may be of significance to better understand HRV changes and warrants further investigations.

Calcium channel blockers are widely used to treat cardiovascular disease (CVD) including hypertension. As aging is an independent risk factor for CVD, the use of calcium channel blockers increases with increasing age. Hence, this study was designed to evaluate the effect of aging on the sensitivity of small mesenteric arteries to L-type voltage-gated calcium channel (LTCC) blockers and also to investigate whether there was a concomitant change in calcium current density. Third order mesenteric arteries from male F344 rats, aged 2.5 - 3 months (young) and 22 - 26 months (old) were mounted on wire myograph to measure the tension during isometric contraction. Arteries were contracted with 100 mM KCl and were then relaxed in a cumulative concentration-response dependent manner with nifedipine (0.1nM - 10 µM), verapamil (0.1nM-10 µM) or diltiazem (0.1nM - 10µM). Relaxation-concentration response curves produced by cumulative concentrations of three different calcium channel blockers (CCBs) in arteries of old rats were shifted to the right with statistically significant IC50s. pEC50 ± s.e.m: (8.37 ± 0.06 vs 8.04 ± 0.05 , 7.40 ± 0.07 vs 6.81 ± 0.04 and 6.58 ± 0.07 vs 6.34 ± 0.06) in young vs old. It was observed that the maximal contractions induced by 100 mM KCl, phenylephrine and reversed by sodium nitroprusside were not different between young and old groups. However, Bay K 8644 increased resting tension by 23±4.8% in young arteries and 4.7±1.6% in old arteries. LTCC current density were also significantly lower in old arteries (-2.77 ± 0.45 pA/pF) compared to young arteries (-4.5 ± 0.40 pA/pF); with similar steady-state activation and inactivation curves. Parallel to this reduction, the expression of Cav1.2 protein was reduced by 57 ± 5% in arteries from old rats compared to those from young rats. In conclusion, our results suggest that aging reduces the response of small mesenteric arteries to the vasodilatory effect of the CCBs and this may be due to, at least in part, reduced current density of LTCC.

Background:We performed a genome-wide scan in a homogeneous Arab population to identify genomic regions linked to blood pressure (BP) and its intermediate phenotypes during mental and physical stress tests.Methods:The Oman Family Study subjects (N= 1277) were recruited from five extended families of ~10 generations. Hemodynamic phenotypes were computed from beat-to-beat BP, electrocardiography and impedance cardiography. Multi-point linkage was performed for resting, mental (word conflict test, WCT) and cold pressor (CPT) stress and their reactivity scores (s), using variance components decomposition-based methods implemented in SOLAR.Results:Genome-wide scans for BP phenotypes identified quantitative trait loci (QTLs) with significant evidence of linkage on chromosomes 1 and 12 for WCT-linked cardiac output (LOD = 3.1) and systolic BP (LOD = 3.5). Evidence for suggestive linkage for WCT was found on chromosomes 3, 17 and 1 for heart rate (LOD = 2.3), DBP (LOD = 2.4) and left ventricular ejection time (LVET), respectively. For △WCT, suggestive QTLs were detected for CO on chr11 (LOD = 2.5), LVET on chr3 (LOD = 2.0) and EDI on chr9 (LOD = 2.1). For CPT, suggestive QTLs for HR and LVET shared the same region on chr22 (LOD 2.3 and 2.8, respectively) and on chr9 (LOD = 2.3) for SBP, chr7 (LOD = 2.4) for SV and chr19 (LOD = 2.6) for CO. For △CPT, CO and TPR top signals were detected on chr15 and 10 (LOD; 2.40, 2.08) respectively. Conclusion: Mental stress revealed the largest number of significant and suggestive loci for normal BP reported to date. The study of BP and its intermediate phenotypes under mental and physical stress may help reveal the genes involved in the pathogenesis of essential hypertension.

Physical inactivity and ageing are widely recognized as risk factors for development of coronary artery disease. One of the characteristic changes that occurs in aged coronary artery is downregulation of their large-conductance voltage- and calcium-activated K(+) (BK(Ca)) channels. In this study, we investigated the effects of moderate exercise training (ET) on the activity of BK(Ca) channels in coronary arteries of aged rats. Old Fischer 344 rats (23-26 months old) were randomly assigned to sedentary (O-SED, n = 24) or exercise-trained groups (O-ET, n = 28). The O-ET rats underwent a progressive treadmill exercise-training programme for 60 min day(1), 5 days week(1) for 12 weeks. Young animals were used for comparison. Coronary arteries were mounted on a wire myograph, and contractions in response to 1, 10, 30, 50 and 100 nmoll(1) iberiotoxin were compared. Iberiotoxin (100 nmol l(1)) contracted coronary arteries of young, O-SED and O-ET rats by 115 +/- 14, 36 +/- 5.6 and 61 +/- 5% of 5-hydroxytryptamine-induced contractions, respectively. Patch-clamp studies revealed a larger magnitude of BK(Ca) current in young (104 +/- 15.6 pA pF(1)) compared with O-ET (44 +/- 9 pA pF(1)) and least in O-SED coronary smooth muscle cells (8.6 +/- 2 pA pF(1)). Western immunoblotting was performed to study expression levels of BK(Ca) channel proteins. The alpha and beta1 subunits of the BK(Ca) channel were reduced by 40 +/- 3.5 and 30 +/- 2.6%, respectively, in coronary arteries of old compared with young rats, and ET attenuated this reduction in expression level to 28 +/- 2 and 12 +/- 4%, respectively. Our results showed that ageing was associated with a reduction in BK(Ca) channels, and ET partly reversed this reduction. We conclude that low-intensity ET may be beneficial in restoring age-related decline in coronary vasodilatory properties mediated by BK(Ca) channels.

Background:Exaggerated cardiovascular reactivity to stressful stimuli may be a risk factor for the development of hypertension. The genetic influence on blood pressure (BP) reactivity to stress and its control mechanisms has been receiving considerable support. This study aims at examining the heritability of BP and its intermediate hemodynamic phenotypes to acute stress in a homogeneous Arab population.Methods:Parameters were computed from continuous BP, electrocardiography and impedance cardiography measurements, during rest, word conflict (WCT) and cold pressor (CPT) tests. Heritability estimates (h2) were obtained using the variance components-based approach implemented in the SOLAR software package.Results:Reactivity scores for WCT and CPT increased significantly (P< .05) for systolic (SBP), diastolic (DBP), heart rate (HR), cardiac output (CO), and total peripheral resistance (TPR). They decreased significantly (P< .05) for stroke volume (SV), left ventricular ejection time (LVET), end diastolic (EDI) and cardiac contractility (IC) indices. Univariate analysis detected heritability estimates that ranged from 0.19–0.35 for rest, 0.002–0.40 for WCT and 0.08–0.35 for CPT.Conclusion:In this unique cohort, resting as well as challenged cardiovascular phenotypes are significantly influenced by additive genetic effects. Heritability estimates for resting phenotypes are in a relatively narrow range, while h2for their reactivity is somewhat broader with lower estimates. Further analyses of this study may offer important opportunities for gene finding in hypertension.What is Known About the Topic:(1) cardiovascular reactivity to stress predicts cardiovascular disease; (2) genetic susceptibility plays an important role in stress reactivity. Family studies using the cold pressure test reported significant heritability for blood pressure.What this Study Adds:(1) this cohort is from five highly consanguineous isolated Arab pedigrees with genetically verified genealogical records and environmental homogeneity; (2) This is the first study to estimate heritability of detailed intermediate hemodynamic phenotypes that make up normal blood pressure.

The aim of this research was to study the effects of overweight and leisure-time activities on maximal aerobic capacity (VO(2)max) in urban and rural Omani adolescents.A total of 529 (245 males, 284 females) adolescents, aged 15-16 years were randomly selected from segregated urban and rural schools. Maximal aerobic capacity was estimated using the multistage 20-meter shuttle-run test.The body mass index (BMI) of urban boys and girls was significantly higher than that of rural boys and girls. Urban boys and girls spent significantly less weekly hours on sports activities and significantly more weekly hours on TV/computer games than their rural counterpart. Urban boys and girls achieved significantly less VO(2)max than rural boys and girls (44.2 and 33.0 vs. 48.3 and 38.6 mL/kg/min, respectively). Maximal aerobic capacity was negatively correlated with BMI in urban boys.Overweight and inactivity had significant negative effects on cardiorespiratory fitness in urban boys and girls as compared to their rural counterparts. Weight gain in adolescence requires early intervention.

The cerebral arteries of hypertensive rats are depolarized and highly myogenic, suggesting a loss of K+ channels in the vascular smooth muscle cells (VSMCs). The present study evaluated whether the dilator function of the prominent Shaker-type voltage-gated K+ (KV1) channels is attenuated in middle cerebral arteries from two rat models of hypertension. Block of KV1 channels by correolide (1 μmol/l) or psora-4 (100 nmol/l) reduced the resting diameter of pressurized (80 mmHg) cerebral arteries from normotensive rats by an average of 28 ± 3% or 26 ± 3%, respectively. In contrast, arteries from spontaneously hypertensive rats (SHR) and aortic-banded (Ao-B) rats with chronic hypertension showed enhanced Ca2+-dependent tone and failed to significantly constrict to correolide or psora-4, implying a loss of KV1 channel-mediated vasodilation. Patch-clamp studies in the VSMCs of SHR confirmed that the peak K+ current density attributed to KV1 channels averaged only 5.47 ± 1.03 pA/pF, compared with 9.58 ± 0.82 pA/pF in VSMCs of control Wistar-Kyoto rats. Subsequently, Western blots revealed a 49 ± 7% to 66 ± 7% loss of the pore-forming α1.2- and α1.5-subunits that compose KV1 channels in cerebral arteries of SHR and Ao-B rats compared with control animals. In each case, the deficiency of KV1 channels was associated with reduced mRNA levels encoding either or both α-subunits. Collectively, these findings demonstrate that a deficit of α1.2- and α1.5-subunits results in a reduced contribution of KV1 channels to the resting diameters of cerebral arteries from two rat models of hypertension that originate from different etiologies.

The aim of this study was to investigate causes of the prevalence of the metabolic syndrome in multiparous Omani Arab women using the International Diabetes Federation definition (IDF).Of 392 married women (mean age 40 years), 354 (90%) were multiparous with an average parity of 8. They were divided into four parity groups: Para 0, Para 1-3, Para 4-6, and Para6. Body mass index (BMI), waist circumference, fasting, and 2-hour glucose and insulin, plasma lipids, serum leptin, and homeostasis model assessment for insulin resistance (HOMA-IR) and blood pressure (BP) were measured.In the whole cohort, the IDF definition identified 28% women with the metabolic syndrome, whereas it identified 48% in Para6. In comparison, the National Cholesterol Education Program (NCEP) definition identified 21% and 39%, respectively (kappa = 0.642). Waist circumference was positively associated with the number of live births (beta = 0.78, p = 0.0001). Compared to other individual IDF criteria, only age-adjusted large waist circumference carried the highest risk for having the metabolic syndrome in all groups (odds ratio [OR], 2.3, 95% confidence interval [CI], 1.0-5.4, 3.2, CI, 1.3-8 and 4.8, CI, 2.1-11.2).The high prevalence of the metabolic syndrome in multiparous Omani Arab women appeared to be influenced by the parity-related large waist circumference. The high dependency of the IDF criteria on waist circumference for the definition of the metabolic syndrome in this population has led to the misclassification of such women.

Objective: The objective was to examine the circadian changes in blood pressure and their relation to the metabolic syndrome and its components in Omani Arabs. Research Methods and Procedures: Ambulatory blood pressure (ABPM) was recorded in 1124 subjects from 5 large, extended, consanguineous, and young Arab pedigrees. According to the International Diabetes Federation's definition, 264 subjects had the metabolic syndrome, a prevalence of 23%. Subjects were defined as non-dippers when their nocturnal systolic blood pressure (SBP) fell by

The current density of L-type voltage-gated calcium (L-VGC) channels was reported to be inversely proportional to the diameter of coronary arteries. Since aging is a major risk factor for coronary artery disease, we investigated if the above relationship is altered with aging. Smooth muscle cells were isolated from coronary arteries of young (3-4 months) and old (22-26 months) male F344 rats. Whole-cell L-VGC currents were recorded using 10 mM Ba2+ as charge carrier from small (˂100µm) and large (250 to 400 µm) diameter arteries. Student's t-test was used to compare peak inward current densities (pA/pF; mean± S.E.M) between young and old arteries of similar size and the 2-way ANOVA was used to compare all four groups (P

The arterial baroreflex is important for buffering blood pressure (BP) responses to stress. Whether the sensitivity of the arterial baroreflex (BRS) is associated with hemodynamic responses to ment...

To investigate lisinopril effect on the contribution of nitric oxide (NO) and K(Ca) channels to acetylcholine (ACh)-induced relaxation in isolated mesenteric arteries of spontaneously hypertensive rats (SHRs). Third branch mesenteric arteries isolated from lisinopril treated SHR rats (20 mg/kg/day for ten weeks, SHR-T) or untreated (SHR-UT) or normotensive WKY rats were mounted on tension myograph and ACh concentration-response curves were obtained. Westernblotting of eNOS and K(Ca) channels was performed. ACh-induced relaxations were similar in all groups while L-NMMA and indomethacin caused significant rightward shift only in SHR-T group. Apamin and TRAM-34 (SK(Ca) and IK(Ca) channels blockers, respectively) significantly attenuated ACh-induced maximal relaxation by similar magnitude in vessels from all three groups. In the presence of L-NMMA, indomethacin, apamin and TRAM-34 further attenuated ACh-induced relaxation only in SHR-T. Furthermore, lisinopril treatment increased expression of eNOS, SK(Ca) and BK(Ca) proteins. Lisinopril treatment increased expression of eNOS, SK(Ca), BK(Ca) channel proteins and increased the contribution of NO to ACh-mediated relaxation. This increased role of NO was apparent only when EDHF component was blocked by inhibiting SK(Ca) and IK(Ca) channels. Such may suggest that in mesenteric arteries, non-EDHF component functions act as a reserve system to provide compensatory vasodilatation if (and when) hyperpolarization that is mediated by SK(Ca) and IK(Ca) channels is reduced.

Lower mortality rates from coronary heart disease and higher levels of serum high-density lipoprotein cholesterol (HDL-C) have been observed in populations residing at high altitude. However, this effect has not been investigated in Arab populations, which exhibit considerable genetic homogeneity. We assessed the relationship between residing altitude and HDL-C in 2 genetically similar Omani Arab populations residing at different altitudes. The association between the levels of HDL-C and other metabolic parameters was also investigated. The levels of HDL-C were significantly higher in the high-altitude group compared with the low-altitude group. Stepwise regression analysis showed that altitude was the most significant factor affecting HDL-C, followed by gender, serum triglycerides, and finally the 2-hour postprandial plasma glucose. This finding is consistent with previously published studies from other populations and should be taken into consideration when comparing cardiovascular risk factors in populations residing at different altitudes.

Abderrahim Nemmar,1 Sulayma Albarwani,2 Sumaya Beegam,1 Priya Yuvaraju,1 Javed Yasin,3 Samir Attoub,4 Badreldin H Ali5 1Department of Physiology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates; 2Department of Physiology, College of Medicine and Health Sciences, Sultan Qaboos University, Al-Khod, Sultanate of Oman; 3Department of Internal Medicine, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates; 4Department of Pharmacology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates; 5Department of Pharmacology, College of Medicine and Health Sciences, Sultan Qaboos University, Al-Khod, Sultanate of Oman Abstract: Amorphous silica nanoparticles (SiNPs) are being used in biomedical, pharmaceutical, and many other industrial applications entailing human exposure. However, their potential vascular and systemic pathophysiologic effects are not fully understood. Here, we investigated the acute (24hours) systemic toxicity of intraperitoneally administered50nm and500nm SiNPs in mice (0.5mg/kg). Both sizes of SiNPs induced a platelet proaggregatory effect in pial venules and increased plasma concentration of plasminogen activator inhibitor-1. Elevated plasma levels of von Willebrand factor and fibrinogen and a decrease in the number of circulating platelets were only seen following the administration of50nm SiNPs. The direct addition of SiNPs to untreated mouse blood significantly induced in vitro platelet aggregation in a dose-dependent fashion, and these effects were more pronounced with50nm SiNPs. Both sizes of SiNPs increased lactate dehydrogenase activity and interleukin1β concentration. However, tumor necrosis factor α concentration was only increased after the administration of50nm SiNPs. Nevertheless, plasma markers of oxidative stress, including8-isoprostane, thiobarbituric acid reactive substances, catalase, and glutathione S-transferase, were not affected by SiNPs. The in vitro exposure of human umbilical vein endothelial cells to SiNPs showed a reduced cellular viability, and more potency was seen with50nm SiNPs. Both sizes of SiNPs caused a decrease in endothelium-dependent relaxation of isolated small mesenteric arteries. We conclude that amorphous SiNPs cause systemic inflammation and coagulation events, and alter vascular reactivity. Overall, the effects observed with50nm SiNPs were more pronounced than those with500nm SiNPs. These findings provide new insight into the deleterious effect of amorphous SiNPs on vascular homeostasis. Keywords: amorphous silica nanoparticles, thrombosis, toxicity, systemic inflammation

Aging is the major cause of decline in cardiovascular function and for structural and functional alterations of coronary microvasculature. There is close association between cardiac function and co...

Hypertension causes impairment of endothelium-dependent relaxation. There is evidence that nanoparticles may affect vascular relaxation. This study investigated effect of silica nanoparticles (50nm; SiNP) on EDR and independent relaxations of small mesenteric arteries of spontaneously hypertensive rats. Rats (4 month) were divided into 6 groups, each injected intravenously with one dose of SiNP (0.5, 1.0, 10, 25.0 and 50mg/Kg; treated) or normal saline (control). After 24 hours, rats were sacrificed with an overdose of a mixture of ketamine (140 mg kg−1 I.M.) and xylazine (40 mg kg−1 I.M.). Third order mesenteric arteries were dissected out and mounted on wire myograph; tension was recorded. Arteries were sub-maximally pre-contracted with phenyephrine (PE; 4µM) and then relaxed in a cumulative concentration-response manner with acetylcholine (Ach 0.1-10µM) or sodium nitroprusside (SNP; 0.1-10 µM). Relaxations induced by Ach were not significantly different in arteries obtained from treated compared to con...

Effect of light-dark cycle shift on autonomic nervous system modulation hasn’t been previously investigated. We studied the effect of alternating light-dark cycle on autonomic biomarkers in spontan...

Objective: The aim of this study was to screen Omani individuals for the familial aggregation of type 2 diabetes mellitus. Methods: A random cohort of 1182 Omani individuals visiting the Family Medicine Clinic at Sultan Qaboos University Hospital (SQUH), Muscat, Oman, for regular medical checkup, aged ≥40 years, were sampled. Patients were categorized into three groups: (1) individuals who claim not to have diabetes and had no family history of diabetes; (2) individuals who claim not to have diabetes but had family history of diabetes; (3) individuals with diabetes. Only 16% of these Omani individuals had no diabetes and no family history of diabetes. Another separate random cohort of 234 Omani type 2 diabetes mellitus patients, from the Diabetes Clinic at SQUH, were interviewed and questioned about their family history of type 2 diabetes mellitus. Results: Ninety five percent of the patients had a family history of diabetes. Eighty percent had first degree relatives with diabetes and 46% had second degree relatives with diabetes. At least one parent with diabetes was reported among 55% of these diabetics, while maternal diabetes (55%) was found to be higher than paternal diabetes (47%). However, only 15% had both parents with diabetes. Furthermore, almost half of the 234 diabetics were having at least one of the following relatives with diabetes: brother, sister, aunt or an uncle. Conclusion: The findings of this study confirm familial aggregation of diabetes among the Omani population. Compared to other populations, familial aggregation of type 2 diabetes mellitus among Omanis is relatively very high, and is perhaps due to the very high degree of consanguinity among Omanis. Since almost everyone seems to have a genetic predisposition to diabetes, the dramatic lifestyle changes over the past 25 years, could tip the population into an epidemic of type 2 diabetes mellitus.

Plasma levels of adiponectin are decreased in type 2 diabetes, obesity and hypertension. Our aim was to use a family-based analysis to identify the genetic variants of the adiponectin (ADIPOQ) gene that are associated with obesity, insulin resistance, dyslipidemia and hypertension, among Arabs. We screened 328 Arabs in one large extended family for single nucleotide polymorphisms (SNPs) in the promoter region of the ADIPOQ gene. Two common SNPs were detected: rs17300539 and rs266729. Evidences of association between traits related to the metabolic syndrome and the SNPs were studied by implementing quantitative genetic association analysis. Results showed that SNP rs266729 was significantly associated with body weight (p-value=0.001), waist circumference (p-value=0.037), BMI (p-value=0.015) and percentage of total body fat (p-value=0.003). Up to 4.1% of heritability of obesity traits was explained by the rs266729 locus. Further cross-sectional analysis showed that carriers of the G allele had significantly higher values of waist circumference, BMI and percentage of total body fat (p-values 0.014, 0.004 and 0.032, respectively). No association was detected between SNP rs266729 and other clusters of metabolic syndrome or their traits except for HOMA-IR and fasting plasma insulin levels, p-values 0.035 and 0.004, respectively. In contrast, both measured genotype and cross-sectional analysis failed to detect an association between the SNP rs17300539 with traits and clusters of metabolic syndrome. In conclusion, we showed family-based evidence of association of SNP rs266729 at ADIPOQ gene with traits defining obesity in Arab population. This is important for future prediction and prevention of obesity in population where obesity is in an increasing trend.

Using the patch-clamp recording technique, we observed that endothelin-1 (ET-1; 0.8-16 nM) enhanced a voltage-activated outward current (Iout) and induced periodic oscillations of inward current in smooth muscle cells isolated from small pulmonary arteries (200-400 microns in diameter). Anion substitution experiments revealed that the ET-1-induced inward current was carried by Cl- ions. Application of bosentan (10 microM; and ETA and ETB receptor antagonist) and FR 139317 (1-10 microM; a selective ETA receptor antagonist) prevented initiation of inward currents or enhancement of Iout by ET-1. The ETB receptor agonist tetra-Ala-endothelin-1 (1-20 nM) failed to evoke these responses. Caffeine (10 mM) induced a single transient inward current and prevented any further activation of inward current, or enhancement of Iout, by subsequent application of 16 nM ET-1, suggesting that these currents were mediated by Ca2+ release from internal stores. Rapid intracellular release of Ca2+ by photolysis of nitr-5 activated an inward Cl- current and increased the magnitude of Iout. These results demonstrate the existence of Ca(2+)-activated Cl- and K+ channels in pulmonary arterial smooth muscle. The physiological role of these channels is at present uncertain, although their activation may be involved in the contractile responses of pulmonary arterial smooth muscle to ET-1.

Intracellular photorelease of Ca 2+ demonstrated the presence of Ca 2+ -activated K + channels in smooth muscle cells isolated from different locations of the rat pulmonary arterial tree. However, cell-free patch studies revealed marked differences in K + channel distribution. In the main pulmonary artery the most frequently observed K + channel was a ∼245pS conductance Ca 2+ - and ATP-activated (K Ca,ATP ) channel. In small pulmonary arteries two K + channel types predominated: the K Ca,ATP channel and a ∼185pS conductance K + channel insensitive to intracellular Ca 2+ , ATP and voltage. This difference in K + channel distribution may highlight a more complex regulatory mechanism for controlling membrane potential in small pulmonary arteries, reflecting their physiologically more important role in governing pulmonary vascular reactivity.

Objective: To estimate the heritability of ambulatory blood pressure (BP), heart rate (HR), and beat-to-beat office BP and HR in an isolated, environmentally and genetically homogeneous Omani Arab population. Methods: Ambulatory BP measurements were recorded in 1,124 subjects with a mean age of 33.8 ± 16.2 years, using the auscultatory mode of the validated Schiller ambulatory BP Monitor. Beat-to-beat BP and HR were recorded by the Task Force Monitor. Heritability was estimated using quantitative genetic analysis. This was achieved by applying the maximum-likelihood-based variance decomposition method implemented in SOLAR software. Results: We detected statistically significant heritability estimates for office beat-to-beat, 24-hour, daytime, and sleep HR of 0.31, 0.21, 0.20, and 0.07, respectively. Heritability estimates in the abovementioned conditions for systolic BP (SBP)/diastolic BP (DBP)/mean BP (MBP) were all significant and estimated at 0.19/0.19/0.19, 0.30/0.44/0.41, 0.28/0.38/0.39, and 0.21/0.18/0.20, respectively. Heritability estimates for 24-hour and daytime ambulatory SBP, DBP, and MBP ranged from 0.28 to 0.44, and were higher than the heritability estimates for beat-to-beat recordings and sleep periods, which were estimated within a narrow range of 0.18–0.21. Conclusion: In this cohort, because shared environments are common to all, the environmental influence that occurs is primarily due to the variation in non-shared environment that is unique to the individual. We demonstrated significant heritability estimates for both beat-to-beat office and ambulatory BP and HR recordings, but 24-hour and daytime ambulatory heritabilities are higher than those from beat-to-beat resting levels and ambulatory night-time recordings.

A novel class of Ca2+-activated K+ channel, also activated by Mg-ATP, exists in the main pulmonary artery of the rat. In view of the sensitivity of these “KCa,ATP” channels to such charged intermediates it is possible that they may be involved in regulating cellular responses to hypoxia. However, their electrophysiological profile is at present unknown. We have therefore characterised the sensitivity of KCa,ATP channels to voltage, intracellular Ca2+ ([Ca2+]i) and Mg-ATP. They have a conductance of 245 pS in symmetrical K+ and are approximately 20 times more selective for K+ ions than Na+ ions, with a K+ permeability (PK) of 4.6×10−13cm s−1. Ca2+ ions applied to the intracellular membrane surface of KCa,ATP channels causes a marked enhancement of their activity. This activation is probably the result of simultaneous binding of at least two Ca2+ ions, determined using Hill analysis, to the channel or some closely associated protein. This results in a shift of the voltage activation threshold to more hyperpolarized membrane potentials. The activation of KCa,ATP channels by Mg-ATP has an EC50 of approximately 50 μM. Although the EC50 is unaffected by [Ca2+]i, channel activation by Mg-ATP is enhanced by increasing [Ca2+]i. One possible interpretation of these data is that Mg-ATP increases the sensitivity of KCa,ATP channels to Ca2+. It is therefore possible that under hypoxic conditions, where lower levels of Mg-ATP may be encountered, the sensitivity of KCa,ATP channels to Ca2+ and therefore voltage is reduced. This would tend to induce a depolarising influence, which would favour the influx of Ca2+ through voltage-activated Ca2+ channels, ultimately leading to increased vascular tone.

Physical inactivity and ageing are widely recognized as risk factors for development of coronary artery disease. One of the characteristic changes that occurs in aged coronary artery is downregulation of their large-conductance voltage- and calcium-activated K(+) (BK(Ca)) channels. In this study, we investigated the effects of moderate exercise training (ET) on the activity of BK(Ca) channels in coronary arteries of aged rats. Old Fischer 344 rats (23-26 months old) were randomly assigned to sedentary (O-SED, n = 24) or exercise-trained groups (O-ET, n = 28). The O-ET rats underwent a progressive treadmill exercise-training programme for 60 min day(1), 5 days week(1) for 12 weeks. Young animals were used for comparison. Coronary arteries were mounted on a wire myograph, and contractions in response to 1, 10, 30, 50 and 100 nmoll(1) iberiotoxin were compared. Iberiotoxin (100 nmol l(1)) contracted coronary arteries of young, O-SED and O-ET rats by 115 +/- 14, 36 +/- 5.6 and 61 +/- 5% of 5-hydroxytryptamine-induced contractions, respectively. Patch-clamp studies revealed a larger magnitude of BK(Ca) current in young (104 +/- 15.6 pA pF(1)) compared with O-ET (44 +/- 9 pA pF(1)) and least in O-SED coronary smooth muscle cells (8.6 +/- 2 pA pF(1)). Western immunoblotting was performed to study expression levels of BK(Ca) channel proteins. The alpha and beta1 subunits of the BK(Ca) channel were reduced by 40 +/- 3.5 and 30 +/- 2.6%, respectively, in coronary arteries of old compared with young rats, and ET attenuated this reduction in expression level to 28 +/- 2 and 12 +/- 4%, respectively. Our results showed that ageing was associated with a reduction in BK(Ca) channels, and ET partly reversed this reduction. We conclude that low-intensity ET may be beneficial in restoring age-related decline in coronary vasodilatory properties mediated by BK(Ca) channels.

Prevalence and heritability of metabolic syndrome (MetS) vary between populations according to the currently used criteria. We examined combinations for joint probabilities and heritabilities of MetS criteria from the National Cholesterol Education Program Adult Treatment Panel III (NCEP), World Health Organization (WHO), and International Diabetes Federation (IDF) in a sample of Omani families.We included 1277 subjects from 5 pedigrees. The likelihood ratio of diagnostic cluster dependence over clustering by chance was LDep = P(dependent)/P(independent). Heritabilities were adjusted by sex and age.The highest LDep were central obesity (CO) + high glucose level (HGl) + triglycerides (IDF, 3.08; NCEP, 4.38; WHO, 3.17; P0.001). Triglycerides combined with any other component were the most common cluster. The lowest LDep for IDF were high blood pressure (HBP) + CO + low HDL-C (1.21, P0.025); for NCEP were HBP + HGl + low HDL-C (1.21, P0.07). These components were gathered almost by chance alone. In contrast, the lowest LDep for WHO were HGl + CO + low HDL-C (2.01, P0.001). The WHO criteria yielded the highest heritability for a MetS diagnosis (h(2) = 0.9), followed by NCEP (0.48) and IDF (0.38). The rationale of the MetS diagnostics is based on insulin resistance. This base would be lost if we continue lowering cut-off points for diagnosis for increasing the sensitivity. The WHO showed the highest values for LDep for all components because they used the highest cut-off points.

The metabolic syndrome, as defined by the International Diabetes Federation, was investigated in five large, extended, highly consanguineous, healthy Omani Arab families of a total of 1277 individuals. Heritability (h2) of the phenotypic abnormalities that make up the syndrome and other related traits was estimated by variance decomposition method using SOLAR software. The overall prevalence of the syndrome was 23%. The prevalence of abnormalities making the syndrome in a descending order were: obligatory waist circumference, hypertension, raised fasting blood glucose, low serum high-density lipoprotein (HDL), and raised serum triglycerides (TGs). Highly significant, but widely spread, h2 values were obtained for: height (0.68), weight (0.68), BMI (0.68), serum HDL (0.63), serum leptin (0.55), percentage body fat (0.53), total serum cholesterol (0.53), fasting serum insulin (0.51), homeostasis model assessment-insulin resistance index (0.48), serum TG (0.43), waist circumference (0.40), diastolic blood pressure (0.38), and 2-hour glucose level (0.17), whereas for the metabolic syndrome itself, h2 was 0.38. The wide spread of h2 results (0.07 to 0.68) indicates that some determinants, such as weight, BMI, and HDL level, are under significant genetic influence among the Omani Arabs. Other determinants such as insulin resistance, abdominal obesity, diastolic blood pressure, and TG levels seem to be more environmentally driven.

Objective: To establish a suitable human model for the study of the genetics of complex diseases. Methods: We have selected an Omani Arab population to provide the statistical power required to study the genetics of complex diseases with confidence. This model consists of five multigenerational highly inbred pedigrees, descending from a small number of founders just a few generations ago with environmental homogeneity, restricted geographical distribution, detailed records and well-ascertained and -validated pedigrees. Stringent criteria were adopted for defining the phenotypes of hypertension, diabetes mellitus, dyslipidemias and obesity. The SOLAR genetic software package was used to draw the pedigree structure. Results: Outstanding statistical power to detect susceptibility loci was obtained. Conclusions: This model represents a large homogeneous human family-based population for the study of genetic and environmental factors contributing to complex diseases.

Voltage-gated potassium (KV) channels represent an important dilator influence in the cerebral circulation, but the composition of these tetrameric ion channels remains unclear. The goals of the present study were to evaluate the contribution of KV1 family channels to the resting membrane potential and diameter of small rat cerebral arteries, and to identify the alpha-subunit composition of these channels using patch-clamp, molecular and immunological techniques. Initial studies indicated that 1 micromol l(-1) correolide (COR), a specific antagonist of KV1 channels, depolarized vascular smooth muscle cells (VSMCs) in pressurized (60 mmHg) cerebral arteries from -55 +/- 1 mV to -34 +/- 1 mV, and reduced the resting diameter from 152 +/- 15 microm to 103 +/- 20 microm. In patch clamped VSMCs from these arteries, COR-sensitive KV1 current accounted for 65 % of total outward KV current and was observed at physiological membrane potentials. RT-PCR identified mRNA encoding each of the six classical KV1 alpha-subunits, KV1.1-1.6, in rat cerebral arteries. However, only the KV1.2 and 1.5 proteins were detected by Western blot. The expression of these proteins in VSMCs was confirmed by immunocytochemistry and co-immunoprecipitation of KV1.2 and 1.5 from VSMC membranes suggested KV1.2/1.5 channel assembly. Subsequently, the pharmacological and voltage-sensitive properties of KV1 current in VSMCs were found to be consistent with a predominant expression of KV1.2/1.5 heterotetrameric channels. The findings of this study suggest that KV1.2/1.5 heterotetramers are preferentially expressed in rat cerebral VSMCs, and that these channels contribute to the resting membrane potential and diameter of rat small cerebral arteries.

Functional, molecular and electrophysiological assays indicate that high-conductance, Ca2+-activated K+ (BKCa) channels of the Slo gene family contribute to the regulation of coronary vascular tone. For example, pharmacological block of BKCa channels with iberiotoxin constricts isolated rat and human coronary arteries, and reduces endothelium-dependent dilation in canine epicardial arteries (Wellman et al. 1996; Node et al. 1997; Nishikawa et al. 1999; Marijic et al. 2001; Koch et al. 2001). BKCa channels of arterial smooth muscle cells (SMCs) are thought to primarily mediate the changes in vascular tone. These channels have been intensively studied in coronary SMCs, and the pore-forming α-subunit and ancillary β-subunit have been cloned and characterized (Tanaka et al. 1997). In contrast, it is unclear if coronary endothelial cells (ECs) also express BKCa channels, although there is evidence for their existence. A voltage- and Ca2+-sensitive K+ channel showing a unitary conductance of 285 pS has been described in primary cultures of porcine coronary ECs (Baron et al. 1996). Its activation partially mediates the hyperpolarizing response to bradykinin, indicating a possible role in regulating the membrane potential of these cells. In contrast, whole-cell current attributable to the BKCa channel was not detected in second or third passages of ECs derived from human coronary macro- or microvessels (Zunkler et al. 1995), and also was not observed in freshly isolated ECs of guinea-pig coronary capillaries (Dittrich & Daut, 1999). In these cells, the regulation of membrane potential apparently relies on a strong component of inwardly rectifying K+ current (von Beckerath et al. 1996). Notably, the detection of BKCa current in cultured ECs may reflect an upregulation of the channel by culture conditions. A recent report has demonstrated that mRNA encoding the BKCa channel α-subunit is absent in freshly isolated human capillary ECs, whereas conditioning the same ECs with culture media or plating them at high density induced its expression (Jow et al. 1999). This report implies that cultured ECs may not express a normal complement of K+ channels, and emphasizes the importance of examining the profile of K+ channel expression in intact or fresh ECs. Notably, the question of whether BKCa channels in ECs contribute to the regulation of coronary tone cannot be resolved by vascular reactivity studies. In vascular preparations with intact endothelium, pharmacological inhibitors simultaneously block both EC and SMC K+ channels, whereas only the functional contribution of SMC K+ channels to vascular tone can be evaluated in endothelium-denuded preparations. To clarify the location of BKCa channels in coronary arteries, the present study compared the expression levels of BKCa channel mRNA, protein and iberiotoxin-sensitive current between freshly isolated bovine coronary ECs and SMCs. Small bovine coronary arteries were used as the source of ECs and SMCs, because BKCa channels within the arterial wall are known to mediate vascular tone (Campbell et al. 1996, 2002; Li et al. 1997). Also, the arteries were large enough to provide adequate ECs for a multifaceted analysis of BKCa channel expression. Finally, because SMCs of bovine coronary arteries densely express BKCa channels (Li et al. 1997; Campbell et al. 2002), the SMCs provided a positive control for antibody and molecular probes used to determine the level of BKCa channel expression in the adjacent ECs.

On 20th April 2009, Steve Jones wrote in the Telegraph that modern genetics research gave hope to patients suffering from diseases such as diabetes, cancer, multiple sclerosis and a variety of brain disorders, conditions could be blamed on a small set of common genetic variants which could be tracked down, scanned using a magic "chip" to enable further understanding of what had gone wrong, diagnose patients before symptoms appeared, and perhaps come up with a few cures.1