Nucleotide regulation of vascular system

Previously, acyl derivatives of CoA were shown to antagonise human native and recombinant P2Y1 purine receptors. The main aim of this thesis was to study the effect of these endogenous nucleotide derivatives at endogenous P2Y1 receptors in blood vessels. Using isometric tension recordings, CoA, acetyl-CoA and palmitoyl-CoA (PaCoA) appeared to show selectivity for P2Y1 receptors (over P2Y2 and adenosine receptors) in the rat isolated thoracic aorta, with PaCoA being the most potent of the CoA derivatives used. In porcine isolated mesenteric arteries (PMA) and porcine isolated coronary arteries (PCA), isometric tension recordings indicated that ADP mediated endothelium-dependent and endothelium-independent relaxations, respectively. Relaxations in PMA were blocked by the P2Y1 receptor antagonist MRS2500 and PaCoA, whilst these were ineffective against ADP relaxations in the PCA. A FlexStation was used to monitor calcium responses in native HEK293 cells expressing P2Y1 and P2Y2 receptors using ADP and UTP, respectively. Responses to UTP were not significantly altered in the presence of PaCoA. In contrast, ADP-evoked responses were significantly inhibited in the presence of either MRS2500 or PaCoA. These data raise the possibility of an endogenous selective antagonism of P2Y1 receptors via CoA compounds, irrespective of species or cellular environment. Nicotinamide adenine dinucleotide (NAD) is an intracellular nucleotide which has been identified as an agonist at P2Y1, P2Y11, P2X and adenosine receptors. NAD evoked endothelium-independent concentration-dependent contractions of the pre-contracted PMA, which were unaltered in the presence of PaCoA. In contrast, αβ-methylene ATP (a desensitizing P2X receptor agonist) significantly reduced these responses suggesting the involvement of P2X1-like receptors. In both RTA and PCA, NAD evoked endothelium-independent concentration-dependent relaxations of the pre-contracted vessels, which were attenuated by SCH58261, but not PaCoA, which suggests the involvement of smooth muscle A2A receptors. These results together emphasise the possibility of a tissue and receptor-specific role of NAD as an endogenous extracellular nucleotide in purinergic signalling

Effects of NAD at purine receptors in isolated blood vessels

Nicotinamide adenine dinucleotide (NAD) belongs to the family of naturally occurring adenine dinucleotides, best known for their various intracellular roles. However, there is evidence that they can also be released from cells to act as novel extracellular signalling molecules. Relatively little is known about the extracellular actions of NAD, especially in the cardiovascular system. The present study investigated the actions of NAD in the rat thoracic aorta, porcine coronary artery and porcine mesenteric arteries, mounted in organ baths for isometric tension recording. In the rat thoracic aorta and porcine coronary artery, NAD caused endothelium-independent concentration-dependent vasorelaxations which were unaffected by palmitoylCoA, a P2Y1 receptor antagonist, but which were blocked by CGS15943, a non-selective adenosine receptor antagonist. In the porcine coronary artery, NAD-evoked relaxations were abolished by SCH58261, a selective A2A receptor antagonist. In the rat thoracic aorta, NAD-evoked relaxations were attenuated by A2A receptor antagonism with SCH58261 but were unaffected by an A2B receptor antagonist, MRS1754. In contrast, in the porcine mesenteric artery, NAD-evoked endothelium-independent contractions, which were unaffected by a P2 receptor antagonist, suramin, or by NF449, a P2X1 receptor antagonist, but were attenuated following P2X receptor desensitisation with αβ-meATP. In conclusion, the present results show that NAD can alter vascular tone through actions at purine receptors in three different arteries from two species; its molecular targets differ according to the type of blood vessel

Awareness and prevalence of metabolic syndrome among high-risk individuals attending internal medicine clinics across Jordan

Purpose: To examine the prevalence and awareness of metabolic syndrome (MetS) in high-risk individuals attending 30 internal medicine clinics in Amman, Jordan, and also to evaluate the various factors associated with increased risk of MetS among them.Methods: This retrospective cross-sectional study was carried out across Amman, Jordan from October to December 2014. During the study period, 900 high-risk individuals (with hypertension, diabetes, central obesity and/or dyslipidemia) were recruited from thirty internal medicine clinics in Amman, Jordan. Data collection forms were filled based on patient interview and medical case file.Results: The prevalence of MetS among high-risk individuals was around 40 % (361/900), with around 79 % (284/361) of MetS patients unaware of their condition. Older age, lower income and family history of premature cardiovascular diseases were associated with a higher prevalence of MetS.Conclusion: Although MetS was found to be highly prevalent among high-risk individuals in this study, the awareness of the condition in this group is very poor. These findings support the need for educational programs that involve both health care providers and patients. These programs should especially target those at risk of MetS, in order to improve awareness of the concept of MetS.Keywords: Prevalence, Metabolic syndrome, Jordan, Awareness, Risk factor

Factors associated with lipid control in outpatients with heart failure

BackgroundDyslipidemia is common among patients with heart failure, and it negatively impacts clinical outcomes. Limited data regarding the factors associated with poor lipid control in patients with HF patients. Therefore, this study aimed to evaluate lipid control and to explore the factors associated with poor lipid control in patients with HF.MethodsThe current cross-sectional study was conducted at outpatient cardiology clinics at two major hospitals in Jordan. Variables including socio-demographics, biomedical variables, in addition to disease and medication characteristics were collected using medical records and custom-designed questionnaire. Medication adherence was assessed using the validated 4-item Medication Adherence Scale. Binary logistic regression analysis was conducted to explore significant and independent predictors of poor lipid control among the study participants.ResultsA total of 428 HF patients participated in the study. Results showed that 78% of the participants had poor lipid control. The predictors that were associated with poor lipid control included uncontrolled BP (OR = 0.552; 95% CI: 0.330–0.923; P < 0.05), higher Hb levels (OR = 1.178; 95% CI: 1.013–1.369; P < 0.05), and higher WBC (OR = 1.133; 95% CI: 1.031–1.246; P < 0.05).ConclusionsThis study revealed poor lipid control among patients with HF. Future intervention programs should focus on blood pressure control in order to improve health outcomes among HF patients with dyslipidemia

Parental views of antibiotic use in children with upper respiratory tract infections in Jordan

Purpose: To assess the knowledge, attitudes and practices of parents towards antibiotics use for upper respiratory tract infections (URTIs) in Jordan.Methods: A cross-sectional study was carried out at 10 private outpatients’ pediatric clinics across Amman-Jordan from September to December 2013. During the study period, 1329 parents of young children who fulfilled the inclusion criteria and agreed to participate were interviewed, and completed a validated structured questionnaire.Results: A large proportion of parents (903, 68 %) believed that weather change was the main cause of acute URTIs in their children. Although 1098 (82.8 %) of parents were aware that the recurrent use of antibiotics leads to a decrease in effectiveness due to bacterial resistance, 859 (64.6 %) of the respondents reported that they would give antibiotics without prescription. Fathers (135, 40.2 %), were significantly more aware that URTIs follow its natural course without antibiotic administration compared to mothers (N = 327, 32.9 %), respectively (p = 0.005).Conclusion: There is a lack of adequate parental knowledge concerning the use and misuse of antibiotics in children in Jordan. National publicity campaign should be mounted to improve awareness. Furthermore, existing laws should be enforced to prevent parents from purchasing antibiotics over-thecounter (OTC).Keywords: Antibiotics, Attitude, Knowledge, Parents, Upper respiratory tract infections, Publicity campaig

Structural and Electrical Remodeling of the Sinoatrial Node in Diabetes: New Dimensions and Perspectives

The sinoatrial node (SAN) is composed of highly specialized cells that mandate the spontaneous beating of the heart through self-generation of an action potential (AP). Despite this automaticity, the SAN is under the modulation of the autonomic nervous system (ANS). In diabetes mellitus (DM), heart rate variability (HRV) manifests as a hallmark of diabetic cardiomyopathy. This is paralleled by an impaired regulation of the ANS, and by a pathological remodeling of the pacemaker structure and function. The direct effect of diabetes on the molecular signatures underscoring this pathology remains ill-defined. The recent focus on the electrical currents of the SAN in diabetes revealed a repressed firing rate of the AP and an elongation of its tracing, along with conduction abnormalities and contractile failure. These changes are blamed on the decreased expression of ion transporters and cell-cell communication ports at the SAN (i.e., HCN4, calcium and potassium channels, connexins 40, 45, and 46) which further promotes arrhythmias. Molecular analysis crystallized the RGS4 (regulator of potassium currents), mitochondrial thioredoxin-2 (reactive oxygen species; ROS scavenger), and the calcium-dependent calmodulin kinase II (CaMKII) as metabolic culprits of relaying the pathological remodeling of the SAN cells (SANCs) structure and function. A special attention is given to the oxidation of CaMKII and the generation of ROS that induce cell damage and apoptosis of diabetic SANCs. Consequently, the diabetic SAN contains a reduced number of cells with significant infiltration of fibrotic tissues that further delay the conduction of the AP between the SANCs. Failure of a genuine generation of AP and conduction of their derivative waves to the neighboring atrial myocardium may also occur as a result of the anti-diabetic regiment (both acute and/or chronic treatments). All together, these changes pose a challenge in the field of cardiology and call for further investigations to understand the etiology of the structural/functional remodeling of the SANCs in diabetes. Such an understanding may lead to more adequate therapies that can optimize glycemic control and improve health-related outcomes in patients with diabetes

Corrigendum: Evolution, ecology, and zoonotic transmission of betacoronaviruses: A review

In the published article, there was an error in the legend for Figure 1 as published. The figure legend did not indicate that it has been adapted from Plowright et al. (2017). Copyright permission was obtained from Springer Nature to adapt Figure 1 from Plowright et al. (2017). The corrected legend appears below. Figure 1. Zoonotic risk distribution, pathway to spillover, and the multimodal role of the determinants of spillover. The zoonotic risk is demonstrated by the accumulated distribution of reservoir hosts and vectors that play a role in the pathway to spillover. The risk of spillover is determined by a series of processes from the ecological dynamics of reservoir host distribution and density, to the susceptibility, replication and dissemination of the biological factors in the recipient host. This is also reflected in the multimodal role of the determinants of spillover, demonstrating the disciplines that are being used to study zoonotic transmission and the determinants of spillover. This figure was adapted from Figure 1 in Plowright et al. (2). Copyright permission was obtained with license number 55218980848529. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated

Allelic variants within the ABO blood group phenotype confer protection against critical COVID-19 hospital presentation

Introduction: Coronavirus disease 2019 (COVID-19) disease severity differs widely due to numerous factors including ABO gene-derived susceptibility or resistance. The objective of this study was to investigate the association of the ABO blood group and genetic variations of the ABO gene with COVID-19 severity in a heterogeneous hospital population sample from the United Arab Emirates, with the use of an epidemiological and candidate gene approach from a genome-wide association study (GWAS). Methods: In this cross-sectional study, a total of 646 participants who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were recruited from multiple hospitals and population-based (quarantine camps) recruitment sites from March 2020 to February 2021. The participants were divided into two groups based on the severity of COVID-19: noncritical (n = 453) and critical [intensive care unit (ICU) patients] (n = 193), as per the COVID-19 Reporting and Data System (CO-RADS) classification. The multivariate logistic regression analysis demonstrated the association of ABO blood type as well as circulating anti-A antibodies and anti-B antibodies as well as A and B antigens, in association with critical COVID-19 hospital presentation. A candidate gene analysis approach was conducted from a GWAS where we examined 240 single nucleotide polymorphisms (SNPs) (position in chr9: 136125788-136150617) in the ABO gene, in association with critical COVID-19 hospital presentation. Results: Patients with blood group O [odds ratio (OR): 0.51 (0.33, 0.79); p = 0.003] were less likely to develop critical COVID-19 symptoms. Eight alleles have been identified to be associated with a protective effect of blood group O in ABO 3\u27untranslated region (UTR): rs199969472 (p = 0.0052), rs34266669 (p = 0.0052), rs76700116 (p = 0.0052), rs7849280 (p = 0.0052), rs34039247 (p = 0.0104), rs10901251 (p = 0.0165), rs9411475 (p = 0.0377), and rs13291798 (p = 0.0377). Conclusion: Our findings suggest that there are novel allelic variants that link genetic variants of the ABO gene and ABO blood groups contributing to the reduced risk of critical COVID-19 disease. This study is the first study to combine genetic and serological evidence of the involvement of the ABO blood groups and the ABO gene allelic associations with COVID-19 severity within the Middle Eastern population

Travel ban effects on SARS-CoV-2 transmission lineages in the UAE as inferred by genomic epidemiology

Global and local whole genome sequencing of SARS-CoV-2 enables the tracing of domestic and international transmissions. We sequenced Viral RNA from 37 sampled Covid-19 patients with RT-PCR-confirmed infections across the UAE and developed time-resolved phylogenies with 69 local and 3,894 global genome sequences. Furthermore, we investigated specific clades associated with the UAE cohort and, their global diversity, introduction events and inferred domestic and international virus transmissions between January and June 2020. The study comprehensively characterized the genomic aspects of the virus and its spread within the UAE and identified that the prevalence shift of the D614G mutation was due to the later introductions of the G-variant associated with international travel, rather than higher local transmissibility. For clades spanning different emirates, the most recent common ancestors pre-date domestic travel bans. In conclusion, we observe a steep and sustained decline of international transmissions immediately following the introduction of international travel restrictions

Travel ban effects on SARS-CoV-2 transmission lineages in the UAE as inferred by genomic epidemiology

Global and local whole genome sequencing of SARS-CoV-2 enables the tracing of domestic and international transmissions. We sequenced Viral RNA from 37 sampled Covid-19 patients with RT-PCR-confirmed infections across the UAE and developed time-resolved phylogenies with 69 local and 3,894 global genome sequences. Furthermore, we investigated specific clades associated with the UAE cohort and, their global diversity, introduction events and inferred domestic and international virus transmissions between January and June 2020. The study comprehensively characterized the genomic aspects of the virus and its spread within the UAE and identified that the prevalence shift of the D614G mutation was due to the later introductions of the G-variant associated with international travel, rather than higher local transmissibility. For clades spanning different emirates, the most recent common ancestors pre-date domestic travel bans. In conclusion, we observe a steep and sustained decline of international transmissions immediately following the introduction of international travel restrictions