Molecular assessment of drug-phospholipid interactions consequent to cancer treatment: a study of anthracycline-induced cardiotoxicity.

Cardiotoxicity limits the use of anthracyclines as potent chemotherapeutics. We employ classical molecular dynamics to explore anthracycline interactions with a realistic myocardial membrane and compare to an ideal membrane widely used in literature. The interaction of these two membranes with four anthracyclines; doxorubicin, epirubicin, daunorubicin, and idarubicin are studied. Careful analysis was conducted on three forms of each drug; pristine, primary metabolite, and cationic salt. By examining the molecular residence time near the membrane's surface, the average number of molecule/membrane hydrogen bonds, the immobilization of the molecules near the membrane, and the location of those molecules relative to the mid-plane of the membrane we found out that salt forms exhibit the highest cardiotoxic probability, followed by the metabolites and pristine forms. Additionally, all forms have more affinity to the upper layer of the realistic myocardial membrane. Meanwhile, an ideal membrane consisting of a single type of phospholipids is not capable of capturing the specific interactions of each drug form. These findings confirm that cardiotoxic mechanisms are membrane-layer and drug-form dependent.

Charged species redistribution at electrochemical interfaces: a model system of the zirconium oxide/water interface.

Quantifying the local distribution of charged defects in the solid state and charged ions in liquid solution near the oxide/liquid interface is key to understanding a range of important electrochemical processes, including oxygen reduction and evolution, corrosion and hydrogen evolution reactions. Based on a grand canonical approach relying on the electrochemical potential of individual charged species, a unified treatment of charged defects on the solid side and ions on the water side can be established. This approach is compatible with first-principles calculations where the formation free energy of individual charged species can be calculated and modulated by imposing certain electrochemical potential. Herein, we apply this framework to a system of monoclinic ZrO2(1̄11)/water interface. The structure, defect chemistry and dynamical behavior of the electric double layer and space charge layer are analyzed with different pH values, water chemistry and doping elements in zirconium oxide. The model predicts ZrO2 solubility in water and the point of zero charge consistent with the experimentally-measured values. We reveal the effect of dopant elements on the concentrations of oxygen and hydrogen species at the surface of the ZrO2 passive layer in contact with water, uncovering an intrinsic trade-off between oxygen diffusion and hydrogen pickup during the corrosion of zirconium alloys. The solid/water interface model established here serves as the basis for modeling reaction and transport kinetics under doping and water chemistry effects.

Association between oral clefts and periodontal clinical measures: A meta-analysis.

AIM: To conduct a systematic review and to evaluate the clinical parameters for periodontal diseases in individuals with cleft lip and/or palate (CL/P). DESIGN: The authors searched six indexed databases without any linguistic limitation through July 2021. The eligibility criteria were observational studies that compared the periodontal clinical measures of individuals with CL/P to those without CL/P. A meta-analysis was conducted using random-effects models with inverse variance weighting. RESULTS: The literature search generated 1277 records, and 40 full-text articles were reviewed. Twenty-three studies comprising 3235 individuals from four continents fulfilled our selection criteria. The meta-analysis revealed a significant difference in mean plaque index scores (MD = 0.31, 95% CI = 0.22, 0.41), gingival index scores (MD = 0.50, 95% CI = 0.24, 0.77), and periodontal pocket depth (MD = 0.64, 95% CI = 0.12, 1.16) between individuals with and without CL/P. A slight increase in clinical attachment loss was detected among individuals with CL/P; however, such an increase may have little clinical significance. CONCLUSIONS: As age is positively related to periodontal disease progression, and individuals with CL/P are more likely to present with more plaque accumulation and gingival inflammation, clinicians should reinforce preventive dental care from an early age.

Complex Oxides under Simulated Electric Field: Determinants of Defect Polarization in ABO3 Perovskites.

Polarization of ionic and electronic defects in response to high electric fields plays an essential role in determining properties of materials in applications such as memristive devices. However, isolating the polarization response of individual defects has been challenging for both models and measurements. Here the authors quantify the nonlinear dielectric response of neutral oxygen vacancies, comprised of strongly localized electrons at an oxygen vacancy site, in perovskite oxides of the form ABO3 . Their approach implements a computationally efficient local Hubbard U correction in density functional theory simulations. These calculations indicate that the electric dipole moment of this defect is correlated positively with the lattice volume, which they varied by elastic strain and by A-site cation species. In addition, the dipole of the neutral oxygen vacancy under electric field increases with increasing reducibility of the B-site cation. The predicted relationship among point defect polarization, mechanical strain, and transition metal chemistry provides insights for the properties of memristive materials and devices under high electric fields.

A complete ab initio thermodynamic and kinetic catalogue of the defect chemistry of hematite α-Fe2O3, its cation diffusion, and sample donor dopants.

This paper studies comprehensively the defect chemistry of and cation diffusion in α-Fe2O3. Defect formation energies and migration barriers are calculated using density functional theory with a theoretically calibrated Hubbard U correction. The established model shows a good agreement with experimental off-stoichiometry and cation diffusivities available in the literature. At any temperature, and are the predominant ionic defects in hematite at the two extremes of oxygen partial pressure (pO2) range, reducing and oxidizing, respectively. Between these two extremes, an intrinsic electronic regime exists where small polaronic electrons and holes are the dominant charge carriers. The calculated migration barriers show that Fe ions favor the diffusion along the 〈111〉 direction in the primitive cell through an interstitial crowdion-like mechanism. Our model suggests that cation diffusion in hematite is mainly controlled by the migration of , while may contribute to cation diffusion at extremely low pO2. Our analysis in the presence of two sample donor dopants Ti and Sn indicates that high temperature annealing at T > 1100 K is needed to prepare n-type hematite at ambient pO2, consistently with prior experimental findings. Alternatively, annealing at lower temperatures requires much lower pO2 to avoid compensating the donors with Fe vacancies. A synergistic comparison of our theoretical model and the experimental results on Ti-doped hematite led us to propose that free electrons and small polarons coexist and both contribute to n-type conductivity. Our validated model of defective hematite is a foundation to study hematite in applications such as corrosion and water splitting.

Tuning metal oxide defect chemistry by thermochemical quenching.

The low-temperature defect chemistry of monoclinic and tetragonal ZrO2 and hematite Fe2O3 is studied in the non-equilibrium state of thermochemical quenching; that is, rapid cooling starting from a certain high temperature and oxygen chemical potential. This non-equilibrium state is of great interest because many metal oxides are used at low temperatures below their growth temperatures. This paper addresses the importance of considering this non-equilibrium state rather than applying equilibrium thermodynamics as commonly used when studying point defects from first principles. Based on point defect formation energies calculated previously using density functional theory, we compare the type of dominant defects at equilibrium to those at a quenched state originating from a certain initial growth temperature and oxygen partial pressure. The comparison is facilitated by casting the dominant defects in a dominance diagram on the temperature - oxygen partial pressure plane. We consider two scenarios to model the quenched state. In the first, only electronic defects equilibrate whereas all ionic defects are frozen. Whereas, in the second, electronic defects and interstitials are allowed to equilibrate under the assumption of mobile interstitials at low temperatures. We find that new ionic charge compensation modes can appear on the dominance diagram after quenching. Additionally, purely ionic charge compensation modes consisting of vacancies and/or interstitials expand in the dominance diagram at the expense of purely electronic compensation modes. For the ZrO2 phases, we argue that scenario 2 is more realistic and leads to difficulty in achieving n-type doping by thermochemical quenching. For Fe2O3, and regardless of the quenching scenario, iron vacancies occupy a wider zone of domination, which limits the performance of this oxide as a water splitting photoanode. Our study shows that by controlling the growth thermochemical conditions, it is possible to tune the Fermi level of oxides over a considerable range within the band gap by quenching. This provides an extra tool to tune the electric conductivity of metal oxides beyond traditional extrinsic doping. This work indicates that non-equilibrium thermodynamic analysis is necessary to understand and control defect chemistry at low temperatures.

Predicting point defect equilibria across oxide hetero-interfaces: model system of ZrO2/Cr2O3.

We present a multi-scale approach to predict equilibrium defect concentrations across oxide/oxide hetero-interfaces. There are three factors that need to be taken into account simultaneously for computing defect redistribution around the hetero-interfaces: the variation of local bonding environment at the interface as epitomized in defect segregation energies, the band offset at the interface, and the equilibration of the chemical potentials of species and electrons via ionic and electronic drift-diffusion fluxes. By including these three factors from the level of first principles calculation, we build a continuum model for defect redistribution by concurrent solution of Poisson's equation for the electrostatic potential and the steady-state equilibrium drift-diffusion equation for each defect. This model solves for and preserves the continuity of the electric displacement field throughout the interfacial core zone and the extended space charge zones. We implement this computational framework to a model hetero-interface between the monoclinic zirconium oxide, m-ZrO2, and the chromium oxide Cr2O3. This interface forms upon the oxidation of zirconium alloys containing chromium secondary phase particles. The model explains the beneficial effect of the oxidized Cr particles on the corrosion and hydrogen resistance of Zr alloys. Under oxygen rich conditions, the ZrO2/Cr2O3 heterojunction depletes the oxygen vacancies and the sum of electrons and holes in the extended space charge zone in ZrO2. This reduces the transport of oxygen and electrons thorough ZrO2 and slows down the metal oxidation rate. The enrichment of free electrons in the space charge zone is expected to decrease the hydrogen uptake through ZrO2. Moreover, our analysis provides a clear anatomy of the components of interfacial electric properties; a zero-Kelvin defect-free contribution and a finite temperature defect contribution. The thorough analytical and numerical treatment presented here quantifies the rich coupling between defect chemistry, thermodynamics and electrostatics which can be used to design and control oxide hetero-interfaces.

Polarizing Oxygen Vacancies in Insulating Metal Oxides under a High Electric Field.

We demonstrate a thermodynamic formulation to quantify defect formation energetics in an insulator under a high electric field. As a model system, we analyzed neutral oxygen vacancies (color centers) in alkaline-earth-metal binary oxides using density functional theory, Berry phase calculations, and maximally localized Wannier functions. The work of polarization lowers the field-dependent electric Gibbs energy of formation of this defect. This is attributed mainly to the ease of polarizing the two electrons trapped in the vacant site, and secondarily to the defect induced reduction in bond stiffness and softening of phonon modes. The formulation and analysis have implications for understanding the behavior of insulating oxides in electronic, magnetic, catalytic, and electrocaloric devices under a high electric field.

Prediction of 10-year risk of hard coronary events among Saudi adults based on prevalence of heart disease risk factors.

AIM: Cardiovascular disease is becoming the lead cause of mortality and morbidity worldwide, and developing countries are the main contributors to this trend. Saudi Arabia, which is considered a rapidly developing country, faces progressive urbanization and the adoption of a westernized lifestyle, factors which contribute to the rising burden of cardiovascular disease. Our study evaluates the prevalence of coronary risk factors and predicts hard coronary artery events over 10 years in an urban Saudi cohort. METHODS: A cross-sectional observational study was conducted on a Saudi population. The study involved Saudi subjects aged more than 20 years without a history of coronary heart disease. Demographic variables and hard coronary events (HCE) risk factors were measured. Each subject's 10-year HCE risk was estimated by means of the Framingham Risk Score (FRS). RESULTS: A total of 4932 subjects (2215 men and 2717 women) were examined, the majority (85%) of whom were less than 40 years old. The risk of developing HCE within the next 10 years was low in 92.6% of subjects, intermediate in 3.2% and high in 4.1%. On considering diabetes as coronary heart disease (CHD) risk-equivalent, 26% of subjects were at high risk for hard coronary events in 10 years. The HCE risk progressively increased with age and was higher in men. CONCLUSIONS: Our study, the first to estimate the 10-year risk of HCE among adults in an emerging country, determined that a significant proportion of a younger aged population is at risk for the development of hard coronary events. Public awareness programs to control risk factors are warranted.

Right and Left Atrial Dissimilarities in Normal Subjects Explored by Speckle Tracking Echocardiography.

BACKGROUND: Atrial function is an important contributor of ventricular function and has a prognostic role in various cardiovascular diseases. We tested the hypothesis that right and left atrial (RA & LA) function may not be equal despite their accommodating identical cardiac output. METHODS: Two-dimensional (2D) speckle tracking echocardiography was acquired from the apical four-chamber view in 100 normal subjects. Both RA/LA subendocardial borders were traced to obtain atrial volumes, strain (ε) and strain rate (SR). Reservoir, conduit, and booster pump functions were evaluated. Consequently, εNeg (corresponding to pump function) and εPos (corresponding to conduit function) were gauged. The SR parameters (SRLateNeg, SRPos, and SREarlyNeg), corresponding respectively to atrial systole, inception of ventricular systole, and inception of ventricular diastole, were measured. RESULTS: Mean age was 39 ± 15 years with 50 men (50%). Volumetric indices revealed that reservoir (Filling Volume = 35.1 ± 10.4 mL for LA vs. 27.47 ± 11.93 mL for RA, expansion index = 52.18 ± 16.89% for LA vs. 45.03 ± 16.49% for RA and diastolic emptying index = 52.85 ± 16.85 for LA vs. 45.62 ± 16.5 for RA, P < 0.001) and conduit (passive emptying (%) of total emptying = 34.49 ± 10.4 for LA vs. 26.82 ± 11.98 for RA and passive emptying index = 52.63 ± 16.86 for LA vs. 45.39 ± 16.5 for RA, P < 0.001) functions were significantly higher in the LA compared to the RA. Nevertheless, deformation indices demonstrated an opposite pattern (SRpos = 1.88 ± 0.74 for RA vs. 1.56 ± 0.54 for LA, P = 0.03 and εPos = 59.56 ± 30.63 for RA vs. 45.94 ± 16.67 for LA, P < 0.001). Reservoir, conduit, and booster pump functions showed no statistical significance among both genders. CONCLUSIONS: Evaluation of global and regional RA/LA function by speckle tracking echocardiography is feasible. The current report provides insights regarding dissimilarities between both atria in healthy individuals. The significance of these findings and their potential application will warrant further work.

Coronary bypass using bilateral internal mammary arteries in an achondroplast.

Coronary bypass grafting for ischemic heart disease in achondroplastic dwarfs is very rare. Shortage of veins and inadequate vein quality may cause difficulties during surgery. Only 2 cases of coronary bypass surgery in an achondroplastic dwarf, in which the left internal mammary artery and vein grafts were used, have been reported. We describe the case of a 55-year-old male achondroplastic dwarf who had triple-vessel coronary disease and underwent successful coronary bypass surgery using one saphenous vein graft and bilateral internal mammary artery grafts. The anatomic and surgical challenges in achondroplasia are highlighted.

Metastatic adenocarcinoma presenting as choroidal mass and recurrent cardiac tamponade.

Cardiac tamponade is an unusual earliest presentation of undiagnosed metastatic adenocarcinoma of unknown origin. Malignant pericardial effusion requiring drainage is also a poor prognostic marker with reported median survival of 6.1 months. A choroidal mass may be the presenting sign of systemic malignancy; the diagnosis of metastatic ocular tumour is important as it portends poor prognosis. We are reporting an unusual presentation of an undiagnosed metastatic adenocarcinoma presenting in an elderly male primarily with loss of vision due to choroidal mass causing retinal detachment and repeated episodes of dyspnea due to recurrent pericardial effusion causing cardiac tamponade. Fluid analysis from pleura and breast biopsy revealed evidence of metastatic adenocarcinoma. Immunohistochemistry finding were suggestive of possible lung or gastrointestinal tract as a primary source. Imaging studies showed widely spread malignancy involving abdominal viscera, mediastinum, lung, pericardium, choroid and brain. He showed features of pericardial constriction on echocardiography after fluid drainage due to pericardial infiltration. He expired before he could have received palliative chemotherapy.

Female gender doubles pre-hospital delay times for patients experiencing ST segment elevation myocardial infarction in Saudi Arabia.

INTRODUCTION: Pre-hospital delay has a significant impact on patients' mortality and morbidity in ST segment elevation myocardial infarction (STEMI). Internationally many factors including female gender have been implicated, but no research has been conducted in Arab cultures. We aimed to explore the factors contributing to pre-hospital delay among female STEMI patients in Saudi Arabia. METHOD: This sequential, explanatory mixed methods study comprised a consecutive sample of 311 patients, presenting with STEMI to three hospitals in Riyadh, from March 2011-August 2011. Of these, 189 patients (36 females) were eligible and interviewed using the Response to Symptoms Questionnaire. A purposive sample of 18 patients (9 females) then participated in qualitative interviews that were taped and transcribed prior to thematic analysis. FINDINGS: The median pre-hospital delay for males was 5 h and 12.9 h for females (p<0.002). Standard multiple regression determined female gender as the strongest predictor of transfer delay-from decision to seek help to hospital arrival. Qualitative analysis produced five gender-related themes: (a) women require a male relative's permission to seek medical help; (b) women cannot travel to hospital unless accompanied by a male relative; (c) women prioritise family responsibilities over seeking help; (d) women lack knowledge of myocardial infarction (MI) symptoms and treatment; and (e) perception that women should not attract attention. CONCLUSION: This study provides new insight into how cultural factors increase pre-hospital delay for women within Saudi Arabia. While the quantitative data demonstrates that women experience much longer delays, the qualitative interviews confirm that cultural factors are implicated. Further research is urgently required.

Hydrogen defects in tetragonal ZrO2 studied using density functional theory.

In the energy-structure paradigm, we analyzed the defects that can arise in tetragonal zirconium oxide (T-ZrO2) involving the hydrogen atom or the hydrogen molecule using density functional theory. Our results indicate that the dominant hydrogen defect under reducing conditions is H(·)(0), a complex formed between the hydride ion and a doubly charged oxygen vacancy. This result is consistent with the experimental observation that under reducing conditions, the solubility of hydrogen is proportional to the degree of hypostoichiometry of T-ZrO2. Under oxidizing conditions we found three different hydrogen defects, each predominating in a specific range of the chemical potential of electrons. Starting from the valence band top toward the conduction band bottom, these defects are the interstitial proton, H(·)(i), a complex formed between two hydrogen species and a zirconium vacancy with a net effective charge of (2-), (2H)"(Zr), and finally a complex similar to the latter but with a net effective charge of (4-), (H(2))'''(Zr). In (2H)"(Zr)the two hydrogens exist in the form of hydroxyl groups, while in (H(2))" " (Zr) they exist in the form of a hydrogen molecule. In addition, we found that up to three hydrogen species can favorably accumulate in a zirconium vacancy under oxidizing conditions. The clustering of hydrogen in cation vacancies can be a precursor for the deleterious effects of hydrogen on the mechanical properties and stability of metal oxides, in analogy with hydrogen embrittlement in metals. Finally we observed a red-shift and a blue-shift for the vibrational frequencies of all the hydroxyl groups and all the hydrogen molecules, respectively, in T-ZrO2 when compared to the gas phase frequencies. This is an important characteristic for guiding future experimental efforts to detect and identify hydrogen defects in T-ZrO2. The insights presented in this work advance our predictive understanding of the degradation behavior of T-ZrO2 as a corrosion resistant passive layer, as a gate dielectric and in biomedical applications.

Stenting for huge coronary artery aneurysm and stenosis in a patient with Behçet's disease presenting with non-ST segment elevation myocardial infarction.

Coronary artery aneurysms in patients with Behçet's disease are rare and associated with fatal complications. Covered stents have been used in the management of coronary aneurysms but not in patients with Behçet's disease. We are reporting a rare case of Behçet's disease, admitted with non-ST segment elevation myocardial infarction, whose coronary angiogram revealed huge aneurysm involving proximal left anterior descending artery followed by severe stenosis. The stenosis was treated by drug-eluting stent and the aneurysm was successfully sealed with a covered stent. He remained asymptomatic at 3-month follow-up and repeat angiogram showed patent stents. .

Glassy nature of water in an ultraconfining disordered material: the case of calcium-silicate-hydrate.

We present the structural and dynamic nature of water ultraconfined in the quasi-two-dimensional nanopores of the highly disordered calcium-silicate-hydrate (C-S-H), the major binding phase in cement. Our approach is based on classical molecular simulations. We demonstrate that the C-S-H nanopore space is hydrophilic, particularly because of the nonbridging oxygen atoms on the disordered silicate chains which serve as hydrogen-bond acceptor sites, directionally orienting the hydrogen atoms of the interfacial water molecules toward the calcium-silicate layers. The water in this interlayer space adopts a unique multirange structure: a distorted tetrahedral coordination at short range up to 2.7 Å, a disordered structure similar to that of dense fluids and supercooled phases at intermediate range up to 4.2 Å, and persisting spatial correlations through dipole-dipole interactions up to 10 Å. A three-stage dynamics governs the mean square displacement (MSD) of water molecules, with a clear cage stage characteristic of the dynamics in supercooled liquids and glasses, consistent with its intermediate-range structure identified here. At the intermediate time scales corresponding to the ß-relaxation of glassy materials, coincident with the cage stage in MSD, the non-Gaussian parameter indicates a significant heterogeneity in the translational dynamics. This dynamic heterogeneity is induced primarily because of the heterogeneity in the distribution of hydrogen bond strengths. The strongly attractive interactions of water molecules with the calcium silicate walls serve to constrain their motion. Our findings have important implications on describing the cohesion and mechanical behavior of cement from its setting to its aging.

The Saudi Project for Assessment of Coronary Events (SPACE) registry: design and results of a phase I pilot study.

OBJECTIVE: The delay between the availability of clinical evidence and its application to the care of patients with acute coronary syndrome (ACS) in the Kingdom of Saudi Arabia remains undefined. The Saudi Project for Assessment of Coronary Events (SPACE) registry provides a comprehensive view of the current diagnostic and treatment strategies for patients with ACS; thus, the registry may be used to identify opportunities to improve the care of these patients. METHODS: Eight hospitals in different regions of Saudi Arabia were involved in the pilot phase of the registry, from December 2005 to July 2006. The study patients included individuals with ST segment elevation myocardial infarction (STEMI), non-STEMI and unstable angina. RESULTS: A total of 435 patients (77% men and 80% Saudis) with a mean age of 57.1 years were enrolled. Medical history included previously diagnosed ischemic heart disease (32%), percutaneous coronary intervention (12%), diabetes mellitus (53%), hypertension (48%), current smoking (39%), hyperlipidemia (31%) and family history of premature coronary artery disease (11%). The median door-to-needle time for fibrinolytic therapy received by patients with STEMIs was 90 min. Inhospital medications included acetylsalicylic acid (98%), clopidogrel (73%), angiotensin- converting enzyme inhibitors (74%), beta-blockers (73%), statins (88%), unfractionated heparin (80%), low-molecular weight heparin (22%) and glycoprotein IIb/IIIa inhibitors (9%). The inhospital mortality rate was 5%. CONCLUSION: The first nationwide registry of patients with ACS in the Kingdom of Saudi Arabia is presented. In contrast to registries from developed countries, our cohort is characterized by a younger age at presentation and a much higher prevalence of diabetes mellitus. Most patients with STEMIs did not receive fibrinolytic therapy within the time recommended in the American College of Cardiology/American Heart Association guidelines. The results of the present pilot study show potential targets for improvement in care.

Abciximab attenuates coronary microvascular endothelial dysfunction after coronary stenting.

BACKGROUND: Platelet glycoprotein IIb/IIIa receptor blockade with abciximab decreases ischemic events after percutaneous coronary intervention (PCI); however, the mechanism of this benefit has not been fully elucidated. The present study was designed to assess endothelium-dependent vasomotion after coronary stenting and to determine if abciximab alters this response. METHODS AND RESULTS: The study group consisted of 48 patients (59+/-10 years of age) with discrete coronary stenoses who underwent stenting alone (n=28) or stenting plus abciximab (n=20). A control group consisted of 31 additional patients who had vasomotor testing on a non-PCI vessel. Coronary blood flow (CBF) was measured (0.014-inch Doppler wire) 30 minutes after uncomplicated PCI and in response to the intracoronary infusion of acetylcholine (Ach) (10(-7), 10(-6) mol/L Ach) and adenosine (24 microg). Ach-mediated increase in CBF was impaired after stent insertion when compared with the control group (41+/-52% versus 70+/-48%; P<0.05). The stenting plus abciximab group demonstrated a superior CBF response to Ach compared with the stenting alone group (83+/-93% versus 41+/-52%; P<0.05), with no difference between groups in the peak flow or percent change in flow to adenosine. By multivariate analysis, concomitant administration of abciximab was strongly predictive of the change in CBF to Ach (P<0.005). CONCLUSIONS: Abciximab preserves the CBF response to Ach after coronary stenting. The preservation of microvascular endothelial function may help explain the beneficial clinical effect of this agent in patients undergoing PCI.