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.     

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.     

Identification and characterization of a novel FBN1 gene variant in an extended family with variable clinical phenotype of Marfan syndrome

Marfan syndrome (MFS) is a multi-systemic autosomal dominant condition caused by mutations in the gene (FBN1) coding for fibrillin-1. Mutations have been associated with a wide range of overlapping phenotypes. Here, we report on an extended family presenting with skeletal, ocular and cardiovascular clinical features. The 37-year-old male propositus, who had chest pain, dyspnea and shortness of breath, was first diagnosed based on the revised Ghent criteria and then subjected to molecular genetic analyses. FBN1 sequencing of the proband as well as available affected family members revealed the presence of a novel variant, c.7828G>C (p.Glu2610Gln), which was not present in any of the unaffected family members. In silico analyses demonstrated that the Glu2610 residue is part of the conserved DINE motif found at the beginning of each cbEGF domain of FBN1. The substitution of Glu2610 with Gln decreased fibrillin-1 production accordingly. Despite the fact that this variation appears to be primarily responsible for the etiology of MFS in the present family, our findings suggest that variable clinical expressions of the disease phenotype should be considered critically by the physicians.     

The Supplemental Nutrition Assistance Program,Food Insecurity,Dietary Quality,and Obesity Among US Adults

Objectives. We examined whether Supplemental Nutrition Assistance Program (SNAP) participation changes associations between food insecurity, dietary quality, and weight among US adults.Methods. We analyzed adult dietary intake data (n = 8333) from the 2003 to 2010 National Health and Nutrition Examination Survey. Bivariate and multivariable methods assessed associations of SNAP participation and 4 levels of food security with diet and weight. Measures of dietary quality were the Healthy Eating Index 2010, total caloric intake, empty calories, and solid fat; weight measures were body mass index (BMI), overweight, and obesity.Results. SNAP participants with marginal food security had lower BMI (1.83 kg/m²; P < .01) and lower probability of obesity (9 percentage points; P < .05). SNAP participants with marginal (3.46 points; P < .01), low (1.98 points; P < .05), and very low (3.84 points; P < .01) food security had better diets, as illustrated by the Healthy Eating Index. Associations between SNAP participation and improved diet and weight were stronger among Whites than Blacks and Hispanics.Conclusions. Our research highlights the role of SNAP in helping individuals who are at risk for food insecurity to obtain a healthier diet and better weight status.Food insecurity, broadly defined as having limited access to adequate food,1 is associated with increased stress levels and reduced overall well-being.2 In addition, food insecurity has been shown to diminish dietary quality and affect nutritional intake and has been associated with chronic morbidity (e.g., type 2 diabetes, hypertension) and weight gain.1,3–5 In 2012, approximately 14.5% of US households (17.6 million households) experienced food insecurity, of whom 5.7% (7.0 million households) experienced very low food security (i.e., reduction in food intake).6 The Supplemental Nutrition Assistance Program (SNAP), formerly known as food stamps, is the largest government assistance program in the United States and seeks to alleviate food insecurity in US households.7 SNAP has the potential to mitigate the adverse effects of food insecurity on health outcomes not only through attenuating food insecurity but also by enhancing the dietary quality of its participants.8,9Although cross-sectional studies have found no significant differences in food insecurity levels between SNAP participants and nonparticipants,10,11 in a longitudinal study, Nord observed a 28% reduction in the odds for very low food security among households that remained on SNAP throughout the year relative to those who left before the last 30 days of the year.12 In addition, studies by Leung and Villamor13 and Webb et al.14 found that independent of food insecurity, SNAP participation is associated with the increased likelihood of obesity, and other studies have observed lower dietary quality specifically among SNAP participants.15,16 Kreider et al. used partial identification bounding methods to take into account the endogenous selection and misreporting of SNAP enrollment and found that SNAP reduced the prevalence of food insecurity, poor general health, and obesity among children.17Thus, the interrelationships among SNAP participation, food insecurity, dietary quality, and weight status warrant further investigation to inform SNAP programming, policy, and outreach to ultimately improve the health and well-being of SNAP participants. We explored these relationships in data from the National Health and Nutrition Examination Survey (NHANES) over multiple years. We aimed to determine mitigating effects SNAP participation might have on the association of food insecurity with dietary quality and obesity among a nationally representative sample of US adults.     

Long-Term Weight Loss and Metabolic Health in Adults Concerned With Maintaining or Losing Weight: Findings From NHANES

More than two-thirds of American adults are overweight or obese, with many attempting to lose weight to avoid adverse health outcomes and improve well-being. Achieving long-term weight loss (LTWL) success, defined as reaching at least a 5% to 10% weight loss goal, is challenging, yet important for overall metabolic health. It is currently unclear whether achieving higher thresholds of LTWL is associated with improved health. Therefore, the purpose of this study was to examine the association between LTWL thresholds (5%-9.9%, 10%-14.9%, 15%-19.9%, ≥20%) and metabolic health (metabolic syndrome and metabolic risk z score) among 7670 US adult respondents to the National Health and Nutrition Examination Survey (2007-2014) who were overweight or obese (past or present), were not underweight in the past year, not pregnant, and attempting to lose or maintain weight. A subsample of 3362 participants was used in the analysis of the metabolic risk z score. Multivariable regression models were constructed adjusting for covariates. Results indicate that the lowest and the 2 highest LTWL thresholds were related to lower odds for metabolic syndrome; for example, greater than or equal to 20% LTWL (odds ratio=0.52; 95% CI, 0.23-0.44; P<.001). All LTWL thresholds were significantly associated with the metabolic risk z score, with the largest effect among the 2 highest LTWL thresholds, that is, 15% to 19.9% LTWL (β=?0.45; 95% CI, ?0.54 to ?0.36; P<.001) and greater than or equal to 20% LTWL (β=?0.35; 95% CI, ?0.53 to ?0.17; P<.001). In conclusion, although achieving the currently recommended LTWL target was related to improved metabolic health, the 15% LTWL threshold was associated with more favorable outcomes.