Computational and experimental studies on the interaction between butyrylcholinesterase and fluoxetine: implications in health and disease

1. Butyrylcholinesterase (BChE) is a serine esterase that plays a role in the detoxification of natural as well as synthetic ester-bond-containing compounds. Alterations in BChE activity are associated with a number of diseases. Cholinergic system abnormalities in particular are correlated with the formation of senile plaques in Alzheimer’s disease (AD), and administration of cholinesterase inhibitors is a common therapeutic approach used to treat AD.

2. Here, our aim was to study the interaction between BChE and fluoxetine.

3. Molecular docking simulations revealed that fluoxetine penetrated deep into the active-site gorge of BChE and that it was engaged in stabilizing noncovalent interactions with multiple subsites. In substrate kinetic studies, the V_m, K_m, k_cat and k_cat/K_m values were found to be 20.59?±?0.36?U mg^?1 protein, 194?±?14?µM, 1.3?×?10⁸?s^?1 and 6.7?×?10⁵?µM^?1s^?1, respectively. Based on inhibitory studies, fluoxetine appeared to inhibit BChE competitively, with an IC₅₀ value of 104?µM and a K_i value of 36.3?±?4.7?µM.

4. Overall, both the low K_i value and the high number of BChE–fluoxetine interactions suggest that fluoxetine is a potent inhibitor of BChE, although in vivo mechanisms for the direct effects of BChE inhibition on various pathologies remain to be further investigated.

     

Survey of the effectiveness of masking noises during dental treatment--a pilot study.

OBJECTIVE: The aim of this study was to test the effectiveness of a newly developed system, using masking noises with specific frequencies and amplitudes, adjusted to typical noises experienced during dental treatment such as the high-speed hand-held drill. METHOD AND MATERIALS: In accordance with an analysis of typical noises experienced during dental treatment, masking noises with specific frequencies (frequency range 0.02 to 20 kHz) and amplitudes were created, with the aim of reducing the patients' awareness of typical treatment noises by overlaying frequencies. Two hundred fifty-four outpatients (113 males, 141 females) with a mean age of 32 years (+/- 10.5 years) were enrolled in this study. Patients were treated 15 minutes with and 15 minutes without the masking noise. Patients and practitioners filled out questionnaires aimed to evaluate the effectiveness of the system, sensitivity to noise (scale 0 to 10; 0 = effective, 10 = noneffective), psychologic aspects, and statements of fear. RESULTS: There was a significant reduction in patients' awareness of noise using this system during dental treatment. Most of the patients regarded the masking noise as a pleasureable supplementation to common treatment and would select this manner of dental treatment employing the device again (81.5%); 48.2% said they were more relaxed. The system does not, in principle, interfere with dental treatment, and in most instances, the device does not impede the communication between practitioners and patients. CONCLUSION: The present study demonstrates that using masking noises during dental treatment reduces the sensitivity to drill noise, reduces fear and stress, and may be useful in dental practice as an adjunct to common dental treatment.     

Physics-Driven CFD Modeling of Complex Anatomical Cardiovascular Flows—A TCPC Case Study

Recent developments in medical image acquisition combined with the latest advancements in numerical methods for solving the Navier-Stokes equations have created unprecedented opportunities for developing simple and reliable computational fluid dynamics (CFD) tools for meeting patient-specific surgical planning objectives. However, for CFD to reach its full potential and gain the trust and confidence of medical practitioners, physics-driven numerical modeling is required. This study reports on the experience gained from an ongoing integrated CFD modeling effort aimed at developing an advanced numerical simulation tool capable of accurately predicting flow characteristics in an anatomically correct total cavopulmonary connection (TCPC). An anatomical intra-atrial TCPC model is reconstructed from a stack of magnetic resonance (MR) images acquired in vivo. An exact replica of the computational geometry was built using transparent rapid prototyping. Following the same approach as in earlier studies on idealized models, flow structures, pressure drops, and energy losses were assessed both numerically and experimentally, then compared. Numerical studies were performed with both a first-order accurate commercial software and a recently developed, second-order accurate, in-house flow solver. The commercial CFD model could, with reasonable accuracy, capture global flow quantities of interest such as control volume power losses and pressure drops and time-averaged flow patterns. However, for steady inflow conditions, both flow visualization experiments and particle image velocimetry (PIV) measurements revealed unsteady, complex, and highly 3D flow structures, which could not be captured by this numerical model with the available computational resources and additional modeling efforts that are described. Preliminary time-accurate computations with the in-house flow solver were shown to capture for the first time these complex flow features and yielded solutions in good agreement with the experimental observations. Flow fields obtained were similar for the studied total cardiac output range (1–3 l/min); however hydrodynamic power loss increased dramatically with increasing cardiac output, suggesting significant energy demand at exercise conditions. The simulation of cardiovascular flows poses a formidable challenge to even the most advanced CFD tools currently available. A successful prediction requires a two-pronged, physics-based approach, which integrates high-resolution CFD tools and high-resolution laboratory measurements.     

Poly(D,L-lactide/epsilon-caprolactone)/hydroxyapatite composites as bone filler: an in vivo study in rats

In this study, a novel composite bone substitute was implanted in animal models (rats) and their in vivo characteristics were examined. A D,L-lactide and E-caprolactone copolymer (Mw: 80,000; Mn:40,000, and PI:2.00) was synthesized by ring-opening polymerization of the respective dimers using stannous octoate as the catalyst. The final ratio of D,L-lactide to epsilon-caprolactone obtained by 1NMR was 60/40. Hydroxyapatite (HA) powder was loaded in the copolymer. The HA/copolymer ratio was 60/40 (w/w). These composites were easily shaped by hand. Animal tests were performed on mature wistar rats (n=30). Defects were created on the proximal, the thickest part of the femur. The bone defects of the first group were filled with polymer/HA composite, the second group filled with only HA and the third group was left empty. Histologic examination of bone tissues showed new bone formation around the yellow-green polymer/HA composite material in the first group of animals whereas no evidence of new bone growth was observed in other groups.     

Systemic inflammatory mediators and cystic fibrosis genotype

Abstract. Morbidity and mortality in cystic fibrosis patients is mainly attributed to pulmonary infection and inflammation. Chemokines play a pivotal role in the inflammatory process. Although genotype-phenotype correlation in cystic fibrosis patients has been defined, a clear relationship between the defect in the cystic fibrosis transmembrane regulator (CFTR) gene and pulmonary inflammation has not been established. The aim of this study was to assess whether serum chemokines levels in cystic fibrosis patients correlate with genotype and pulmonary function tests, as well as with other clinical characteristics. Serum levels of interleukin-8, RANTES, and monocyte chemoattractant protein-1 were measured in 36 cystic fibrosis patients grouped according to their genotype. Group A included 25 patients who carried two mutations associated with a pathological sweat test and pancreatic insufficiency (F508, W1282X, G542X, N1303K, S549R). Group B included 11 compound heterozygote patients who carried one mutation known to cause mild disease with borderline or normal sweat test and pancreatic sufficiency (3849+10kb C to T, 5T). Associations between chemokine levels, genotype, pulmonary function, Pseudomonas aeruginosa colonization, age, sweat chloride level, and pancreatic and nutritional status were examined. Mean interleukin-8 and monocyte chemoattractant protein-1 levels were significantly higher in group A than group B (11.4±2.1 pg/ml vs. 5±0.9 pg/ml and 157±16 pg/ml vs. 88.8±16.4 pg/ml, respectively) (P<0.01). No difference in RANTES levels were found between groups. interleukin-8 levels were inversely related to forced expiratory volume in 1 s (r=-0.37, P<0.02), while there was no association between the latter and RANTES and monocyte chemoattractant protein-1 levels. The Pseudomonas colonization rate was higher among group A patients than group B (88% vs. 40%, P<0.01). No relationship was found between measured chemokines and age, sweat chloride levels, and pancreatic and nutritional status. Our study demonstrates an association between interleukin- 8, forced expiratory volume, and cystic fibrosis genotype. Hence, elevated interleukin-8 serum levels could serve as an indicator of an early inflammatory process and encourage the initiation of anti-inflammatory treatment.     

Clinical and ethical perspective of neurosurgical care in patients from beyond the southern border of Turkey: challenges of patients in war

Journal of Public Health - Because an increasing number of patients travel internationally to seek medical care, Turkey offers comprehensive and outstanding services under extraordinary conditions...     

Helical CT amniography of congenital diaphragmatic hernia

OBJECTIVE: Accurate prenatal diagnosis of congenital diaphragmatic hernia is important for perinatal planning and potential fetal surgery. We describe the application and usefulness of helical CT amniography in the evaluation of suspected congenital diaphragmatic hernia in three fetuses. CONCLUSION: Helical CT amniography is an efficient means for evaluation of congenital diaphragmatic hernia. Accurate diagnosis was made in all three patients.