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.

     

The Arg753GLn polymorphism of the human toll-like receptor 2 gene in tuberculosis disease.

Toll-like receptor 2 (TLR2), a member of the Toll-like receptor family, plays an important role in recognition of, and subsequent immune response activation against, mycobacteria. The genetic polymorphism of TLR2 (arginine to glutamine substitution at residue 753 (Arg753Gln)) has been associated with a negative influence on TLR2 function, which may, in turn, determine the innate host response to mycobacteria. The aim of the present study was to investigate the Arg753Gln single nucleotide polymorphism of the TLR2 gene in tuberculosis (TB) patients compared to healthy controls. A retrospective case/control study was carried out. The Arg753Gln polymorphism of the TLR2 gene was studied in 151 TB patients compared to 116 ethnically and age-matched healthy control subjects. The TLR2 polymorphism (adenine (A) allele) was observed in 17.9 and 7.7% of TB patients and controls, respectively. When the ratios of the three genotypes were compared between the two groups, the AA genotype was found to be more significantly associated with TB. Allele frequencies for guanine (G) and A were found to be 0.95 and 0.05 in the control group and 0.86 and 0.14 in the TB patient group, respectively. The risk of developing TB disease was increased 6.04- and 1.60-fold for carriers of the AA and GA genotypes, respectively. In conclusion, the present data suggest that the arginine to glutamine substitution at residue 753 polymorphism of the Toll-like receptor 2 gene influences the risk of developing tuberculosis.     

Effects of Hypothermia on Blood Endogenous Endotoxin Levels During Cardiopulmonary Bypass

A bstract Endotoxin activates white blood cells and complement and produces a spectrum of clinical syndromes ranging from fever to septic shock. Although production of endogenous endotoxemia during cardiopulmonary bypass (CPB) has recently been reported, the role of hypothermia on endotoxemia is not clear. In this study, we evaluated the effects of moderate (24–28°C) and mild (32–34°C) hypothermia on blood endotoxin levels. The study population consisted of 20 patients who underwent coronary artery bypass grafting (CABG) with CPB. Moderate systemic hypothermia was applied during aortic cross-clamping in ten patients (group 1) and mild hypothermia in the remaining ten patients (group 2). The mean rectal temperatures were 26.8 ± 1.2°C in group 1 and 33.8 ± 0.8°C in group 2. The blood samples for endotoxin level measurements were obtained before CPB, during aortic cross-clamping, immediately after the release of the cross-clamp, 20 minutes after the release of the cross-clamp, after CPB, and 2 hours postoperatively. There were no endotoxins in any of the samples before CPB, but it was detected after CPB in both groups. The endotoxin levels were significantly higher in group 1 than in group 2. The present study suggests that when hypothermia is the technique of choice, the deleterious effects of endotoxemia on patients with comorbidity must be considered.     

Tracheobronchopathia osteochondroplastica

Tracheobronchopathia osteochondroplastica (TO) is a rare disorder with unknown aetiology. We report one case of TO in a patient with non-Hodgkin pulmonary lymphoma and benign epidermal and trichylemmal cysts on the periorbital region and scalp. To the authors' knowledge, the coincidence of these processes has never been described before. The case was evaluated with conventional X-ray, computed tomography, magnetic resonance imaging, fibre-optic bronchoscopy with 2 months interval, histopathological evaluation, Tc-99 m MDP bone scintigraphy and microbiological studies including PCR testing of bronchial biopsy and lavage specimens for Mycobacterium tuberculosis. Additionally, case reports of TO in the Turkish literature are summarized.     

Ultrastructural Damage in Vascular Endothelium in Rats Treated with Paclitaxel and Doxorubicin

Endothelium is the first physiological barrier between blood and tissues and can be injured by physical or chemical stress, particularly by the drugs used in the cancer therapy. Paclitaxel and doxorubicin are frequently used anticancer drugs and their cardiac side effects are well observed in clinical setting. Their side effects on the endothelium are still not clear enough. There are few investigations assessing the damages elicited by the combination use of chemotherapy agents in animal experimental models. The purpose of this study was to examine and compare the side effects of doxorubicin and paclitaxel on endothelium in vivo. The drugs were administered weekly to rats via intraperitoneal injections singly or in combinations. Lastly, aorta endothelium was examined. The most familiar parts of the aorta endothelium are the nucleus, free ribosomes, Weibel-Palada granules, plasmalemmal vesicles, and clear basement membrane. Examination of the endothelium and the related structures revealed some clear degenerative findings. Notably, administration of a paclitaxel and doxorubicin combinations caused the most dramatic change in ultrastructure, which may disrupt many functions of the endothelium.     

Single-Center Study of 72 Patients with Severe Combined Immunodeficiency: Clinical and Laboratory Features and Outcomes

Journal of Clinical Immunology - Severe combined immunodeficiency is an inborn error of immunity characterized by impairments in the numbers and functions of T and B lymphocytes due to various...     

The evaluation of flap growth and long‐term results of pediatric mandible reconstructions using free fibular flaps

Currently, the free fibular flap is well accepted as the first choice for mandibular reconstruction. Achieving functional results in pediatric patients requires a different approach than that employed for mature patients. Because the pediatric craniofacial skeleton continues to grow, reconstruction is more challenging, and the long‐term results can be different from those of adult patients. In this study, we sought to measure flap growth objectively in our series. Ten pediatric patients who underwent reconstruction with free fibular flaps were retrospectively reviewed. Flap growth was evaluated by comparing the intraoperative photographs with photographs of the control panoramic mandibular radiographs taken using photo‐anthropometric techniques. The measurements were converted to proportionality indices (PI), and these indices were compared. Subsequent complications and functional results were also evaluated. The mean patient age was 11.8 years, and the mean follow up was 57.7 months. The mean preoperative PI value was 10.74 ± 2.47. The mean postoperative PI value was 12.52 ± 2.34. The mean difference between the preoperative and postoperative PI values was ?1.78±0.53. These photo‐anthropometric data clearly illustrated the growth of the fibular flaps (P = 0.001). None of these patients exhibited nonunion of the fractures; however, one patient experienced a delayed union, one had chronic temporomandibular joint pain, and one had chronic temporomandibular joint luxation. In two patients, the inter‐incisive measurements were below the third percentile, and two additional patients had grade 2 eating abilities, which can be regarded as poor. All of the patients had symmetric mandibular contours. Free fibular flaps continue to grow in pediatric patients. This flap is a “workhorse” flap in children because it adapts to the craniofacial skeleton via its ability to grow, and this ability results in subsequent good cosmetic and functional results. © 2014 Wiley Periodicals, Inc. Microsurgery 35:253–261, 2015.     

Leptomeningeal dissemination and vertebral bone involvement in a child with pilocytic astrocytoma

In low‐grade glioma, metastasis is rarely seen. Few cases of leptomeningeal dissemination have been reported in children. Vertebral bone metastasis has not been reported so far. Herein is described the case of a pediatric patient with the diagnosis of pilocytic astrocytoma, and leptomeningeal dissemination detected at the time of diagnosis, who then received radiotherapy and chemotherapy upon development of vertebral bone metastasis during treatment.