Factors Affecting Vancomycin Trough Concentration; a Population Pharmacokinetic Model in Non-Critical Care Saudi Patients.

Background And Objective: Vancomycin is commonly prescribed in treatment of methicillin-resistant Staphylococcus aureus infections. While, vancomycins' pharmacokinetic vary among older patients, there is a paucity of data regarding specific characteristics influencing pharmacokinetics in Saudi adult patients. This study aims to establish a population-pharmacokinetic (Pop-PK) model for vancomycin in patients admitted to medical wards, with the focus on identification of patient characteristics influencing vancomycin trough concentrations.

Pattern of Prescribing Proton Pump Inhibitors: Evaluating Appropriateness and Factors Contributing to Their Adverse Effect Reaction Risk.

: Proton pump inhibitors (PPIs) are amongst the most commonly prescribed classes of medication. However, inappropriate PPI use can lead to several adverse drug reactions (ADRs). Limited data exist on factors contributing to the risk of ADRs associated with PPI prescribing patterns in the Eastern Region of Saudi Arabia.

Impact of telemedicine on glycemic control in type 2 diabetes mellitus during the COVID-19 lockdown period.

Background: The lockdown at the start of coronavirus disease 2019 (COVID-19) pandemic in Saudi Arabia (March 2020 to June 2020) shifted routine in-person care for patients with type 2 diabetes mellitus (T2DM) to telemedicine. The aim of this study was to investigate the impact telemedicine had during this period on glycemic control (HbA1c) in patients with T2DM.

Methods: 4,266 patients with T2DM were screened from five Ministry of National Guard Health Affairs hospitals in the Kingdom of Saudi Arabia.

HIV-Tat Exacerbates the Actions of Atazanavir, Efavirenz, and Ritonavir on Cardiac Ryanodine Receptor (RyR2).

The incidence of sudden cardiac death (SCD) in people living with HIV infection (PLWH), especially those with inadequate viral suppression, is high and the reasons for this remain incompletely characterized. The timely opening and closing of type 2 ryanodine receptor (RyR2) is critical for ensuring rhythmic cardiac contraction-relaxation cycles, and the disruption of these processes can elicit Ca waves, ventricular arrhythmias, and SCD. Herein, we show that the HIV protein Tat (HIV-Tat: 0-52 ng/mL) and therapeutic levels of the antiretroviral drugs atazanavir (ATV: 0-25,344 ng/mL), efavirenz (EFV: 0-11,376 ng/mL), and ritonavir (RTV: 0-25,956 ng/mL) bind to and modulate the opening and closing of RyR2.

Elevated plasma level of the glycolysis byproduct methylglyoxal on admission is an independent biomarker of mortality in ICU COVID-19 patients.

Biomarkers to identify ICU COVID-19 patients at high risk for mortality are urgently needed for therapeutic care and management. Here we found plasma levels of the glycolysis byproduct methylglyoxal (MG) were 4.4-fold higher in ICU patients upon admission that later died (n = 33), and 1.

A Link Between Methylglyoxal and Heart Failure During HIV-1 Infection.

Early-onset heart failure (HF) continues to be a major cause of morbidity and mortality in people living with human immunodeficiency virus type one (HIV-1) infection (PLWH), yet the molecular causes for this remain poorly understood. Herein NOD.Cg-PrkdcIl2rg/SzJ humanized mice (Hu-mice), plasma from PLWH, and autopsied cardiac tissues from deceased HIV seropositive individuals were used to assess if there is a link between the glycolysis byproduct methylglyoxal (MG) and HF in the setting of HIV-1 infection.

Efavirenz, atazanavir, and ritonavir disrupt sarcoplasmic reticulum Ca homeostasis in skeletal muscles.

While muscle fatigue, pain and weakness are common co-morbidities in HIV-1 infected people, their underlying cause remain poorly defined. To this end, we evaluated whether the common antiretroviral drugs efavirenz (EFV), atazanavir (ATV) and ritonavir (RTV) could be a contributing factor by pertubating sarcoplasmic reticulum (SR) Ca cycling. In live-cell imaging, EFV (6.

Adeno-Associated Viral Transfer of Glyoxalase-1 Blunts Carbonyl and Oxidative Stresses in Hearts of Type 1 Diabetic Rats.

Accumulation of methylglyoxal (MG) arising from downregulation of its primary degrading enzyme glyoxalase-1 (Glo1) is an underlying cause of diabetic cardiomyopathy (DC). This study investigated if expressing Glo1 in rat hearts shortly after the onset of Type 1 diabetes mellitus (T1DM) would blunt the development of DC employing the streptozotocin-induced T1DM rat model, an adeno-associated virus containing Glo1 driven by the endothelin-1 promoter (AAV2/9-Endo-Glo1), echocardiography, video edge, confocal imaging, and biochemical/histopathological assays. After eight weeks of T1DM, rats developed DC characterized by a decreased E:A ratio, fractional shortening, and ejection fraction, and increased isovolumetric relaxation time, E: e' ratio, and circumferential and longitudinal strains.

HIV-1-Associated Left Ventricular Cardiac Dysfunction in Humanized Mice.

The molecular cause(s) for early onset heart failure in people living with HIV-1 infection (PLWH) remains poorly defined. Herein, longitudinal echocardiography was used to assess whether NOD.Cg-Prkdc Il2rgt/SzJ mice reconstituted with human hematopoietic stem cells (Hu-NSG mice) and infected with HIV-1 can recapitulate the salient features of this progressive human disease.

Type 1 diabetes mellitus induces structural changes and molecular remodelling in the rat kidney.

There is much evidence that diabetes mellitus (DM)-induced hyperglycemia (HG) is responsible for kidney failure or nephropathy leading to cardiovascular complications. Cellular and molecular mechanism(s) whereby DM can damage the kidney is still not fully understood. This study investigated the effect of streptozotocin (STZ)-induced diabetes (T1DM) on the structure and associated molecular alterations of the isolated rat left kidney following 2 and 4 months of the disorder compared to the respective age-matched controls.

Hyperglycemia-induced cardiac contractile dysfunction in the diabetic heart.

The development of a diabetic cardiomyopathy is a multifactorial process, and evidence is accumulating that defects in intracellular free calcium concentration [Ca] or its homeostasis are related to impaired mechanical performance of the diabetic heart leading to a reduction in contractile dysfunction. Defects in ryanodine receptor, reduced activity of the sarcoplasmic reticulum calcium pump (SERCA) and, along with reduced activity of the sodium-calcium exchanger (NCX) and alterations in myofilament, collectively cause a calcium imbalance within the diabetic cardiomyocytes. This in turn is characterized by cytosolic calcium overloading or elevated diastolic calcium leading to heart failure.

Smooth muscle-generated methylglyoxal impairs endothelial cell-mediated vasodilatation of cerebral microvessels in type 1 diabetic rats.

Background And Purpose: Endothelial cell-mediated vasodilatation of cerebral arterioles is impaired in individuals with Type 1 diabetes (T1D). This defect compromises haemodynamics and can lead to hypoxia, microbleeds, inflammation and exaggerated ischaemia-reperfusion injuries. The molecular causes for dysregulation of cerebral microvascular endothelial cells (cECs) in T1D remains poorly defined.

Evidence of contribution of iPLA2β-mediated events during islet β-cell apoptosis due to proinflammatory cytokines suggests a role for iPLA2β in T1D development.

Type 1 diabetes (T1D) results from autoimmune destruction of islet β-cells, but the underlying mechanisms that contribute to this process are incompletely understood, especially the role of lipid signals generated by β-cells. Proinflammatory cytokines induce ER stress in β-cells and we previously found that the Ca(2+)-independent phospholipase A2β (iPLA2β) participates in ER stress-induced β-cell apoptosis. In view of reports of elevated iPLA2β in T1D, we examined if iPLA2β participates in cytokine-mediated islet β-cell apoptosis.

Selenite cataracts: activation of endoplasmic reticulum stress and loss of Nrf2/Keap1-dependent stress protection.

Cataract-induced by sodium selenite in suckling rats is one of the suitable animal models to study the basic mechanism of human cataract formation. The aim of this present investigation is to study the endoplasmic reticulum (ER) stress-mediated activation of unfolded protein response (UPR), overproduction of reactive oxygen species (ROS), and suppression of Nrf2/Keap1-dependent antioxidant protection through endoplasmic reticulum-associated degradation (ERAD) pathway and Keap1 promoter DNA demethylation in human lens epithelial cells (HLECs) treated with sodium selenite. Lenses enucleated from sodium selenite injected rats generated overproduction of ROS in lens epithelial cells and newly formed lens fiber cells resulting in massive lens epithelial cells death after 1-5days.

CCDI: a new ligand that modulates mammalian type 1 ryanodine receptor (RyR1).

Background And Purpose: Ryanodine receptors (RyRs) are Ca(2+)-release channels on the sarco(endo)plasmic reticulum that modulate a wide array of physiological functions. Three RyR isoforms are present in cells: RyR1, RyR2 and RyR3. To date, there are no reports on ligands that modulate RyR in an isoform-selective manner.

Methylglyoxal induces endoplasmic reticulum stress and DNA demethylation in the Keap1 promoter of human lens epithelial cells and age-related cataracts.

Age-related cataracts are a leading cause of blindness. Previously, we have demonstrated the association of the unfolded protein response with various cataractogenic stressors. However, DNA methylation alterations leading to suppression of lenticular antioxidant protection remains unclear.

Valproic acid suppresses Nrf2/Keap1 dependent antioxidant protection through induction of endoplasmic reticulum stress and Keap1 promoter DNA demethylation in human lens epithelial cells.

Recent epidemiological studies confirm the prevalence of cataract in epileptic patients. Similarly, the drugs used to treat epilepsy also show the connection with increased cataract formation. In this present study, we investigated the suppression of Nrf2/Keap1 dependent antioxidant protection through induction of endoplasmic (ER) stress and Keap1 promoter DNA demethylation in human lens epithelial cells (HLECs) treated with valproic acid (VPA), an antiepileptic drug.

A glutathione-independent glyoxalase of the DJ-1 superfamily plays an important role in managing metabolically generated methylglyoxal in Candida albicans.

Methylglyoxal is a cytotoxic reactive carbonyl compound produced by central metabolism. Dedicated glyoxalases convert methylglyoxal to d-lactate using multiple catalytic strategies. In this study, the DJ-1 superfamily member ORF 19.

FMLP-, thapsigargin-, and H₂O₂-evoked changes in intracellular free calcium concentration in lymphocytes and neutrophils of type 2 diabetic patients.

Type 2 diabetic (T2DM) patients are immune-compromised having a higher susceptibility to infections and long-term complications in different parts of the body contributing to increased morbidity and mortality. A derangement in the homeostasis of intracellular free calcium concentration [Ca²⁺](i) is known to be associated with several diseases in the body including T2DM. Both neutrophils and lymphocytes play active protective roles in host immune response to infection showing impairment in microbicidal functions including phagocytosis and chemotaxis which are calcium-dependent processes.

Combination of real time three-dimensional echocardiography with diagnostic catheterization to derive left ventricular pressure-volume relations.

Aims: The aim of this study was to investigate the left ventricular (LV) myocardial contractility index-Emax using transesophageal real time three-dimensional echocardiography (RT3DE) combined with catheterization.

Methods: Transesophageal RT3DE (single beat, X7-2 × matrix, iE33, Philips) was used to obtain real time LV volumes in pigs. Volumes were integrated with LV pressures from conductance catheterization (CC) to create RT3DE pressure-volume relations.

Pyruvate restores β-adrenergic sensitivity of L-type Ca(2+) channels in failing rat heart: role of protein phosphatase.

Oxidative stress plays a major role in the pathogenesis of heart failure, where the contractile response to β-adrenergic stimulation is profoundly depressed. This condition involves L-type Ca(2+) channels, but the mechanisms underlying their impaired adrenergic regulation are unclear. Thus the present study explored the basis for impaired adrenergic control of Ca(2+) channels in a rat infarction model of heart failure.

Validation of admittance computed left ventricular volumes against real-time three-dimensional echocardiography in the porcine heart.

The admittance and Wei's equation is a new technique for ventricular volumetry to determine pressure-volume relations that addresses traditional conductance-related issues of parallel conductance and field correction factor. These issues with conductance have prevented researchers from obtaining real-time absolute ventricular volumes. Moreover, the time-consuming steps involved in processing conductance catheter data warrant the need for a better catheter-based technique for ventricular volumetry.

Reactive carbonyl species and their roles in sarcoplasmic reticulum Ca2+ cycling defect in the diabetic heart.

Efficient and rhythmic cardiac contractions depend critically on the adequate and synchronized release of Ca(2+) from the sarcoplasmic reticulum (SR) via ryanodine receptor Ca(2+) release channels (RyR2) and its reuptake via sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2a). It is well established that this orchestrated process becomes compromised in diabetes. What remain incompletely defined are the molecular mechanisms responsible for the dysregulation of RyR2 and SERCA2a in diabetes.

Chronic effects of mild hyperglycaemia on left ventricle transcriptional profile and structural remodelling in the spontaneously type 2 diabetic Goto-Kakizaki rat.

Heart failure in chronic type 2 diabetes mellitus is partly attributable to adverse structural remodelling of the left ventricle (LV), but the contribution of hyperglycaemia (HG) per se in remodelling processes is debated. In this study, we examined the molecular signature of LV remodelling in 18-month-old spontaneously diabetic male Goto-Kakizaki (GK) rats that represent a long-term mildly diabetic phenotype, using histological, immunoblotting and quantitative gene expression approaches. Relative to age-matched Wistar controls, mildly diabetic GK rats presented with LV hypertrophy, increased expression of natriuretic peptides and phosphorylation of pro-hypertrophic Akt.

Malondialdehyde and 4-hydroxynonenal adducts are not formed on cardiac ryanodine receptor (RyR2) and sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2) in diabetes.

Recently, we reported an elevated level of glucose-generated carbonyl adducts on cardiac ryanodine receptor (RyR2) and sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2) in hearts of streptozotocin(STZ)-induced diabetic rats. We also showed these adduct impaired RyR2 and SERCA2 activities, and altered evoked Ca(2+) transients. What is less clear is if lipid-derived malondialdehyde (MDA) and 4-hydroxy-2-nonenal (4-HNE) also chemically react with and impair RyR2 and SERCA2 activities in diabetes? This study used western blot assays with adduct-specific antibodies and confocal microscopy to assess levels of MDA, 4-HNE, N (ε)-carboxy(methyl)lysine (CML), pentosidine, and pyrraline adducts on RyR2 and SERCA2 and evoked intracellular transient Ca(2+) kinetics in myocytes from control, diabetic, and treated-diabetic rats.