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.

     

Functional MR of the primary auditory cortex: an analysis of pure tone activation and tone discrimination.

PURPOSETo use functional MR imaging to measure the effect of frequency (pitch), intensity (loudness), and complexity of auditory stimuli on activation in the primary and secondary auditory cortexes.METHODSMultiplanar echo-planar images were acquired in healthy subjects with normal hearing to whom auditory stimuli were presented intermittently. Functional images were processed from the echo-planar images with conventional postprocessing methods. The stimuli included pure tones with a single frequency and intensity, pure tones with the frequency stepped between 1,000, 2,000, 3,000, or 4,000 Hz, and spoken text. The pixels activated by each task in the transverse temporal gyrus (TTG) and the auditory association areas were tabulated.RESULTSThe pure tone task activated the TTG. The 1,000-Hz tone activated significantly more pixels in the TTG than did the 4,000-Hz tone. The 4,000-Hz tone activated pixels primarily in the medial TTG, whereas the 1,000-Hz tone activated more pixels in the lateral TTG. Higher intensity tones activated significantly more pixels than did lower intensity tones at the same frequency. The stepped tones activated more pixels than the pure tones, but the difference was not significant. The text task produced significantly more activation than did the pure tones in the TTG and in the auditory association areas. The more complex tasks (stepped tones and listening to text) tended to activate more pixels in the left hemisphere than in the right, whereas the simpler tasks activated similar numbers of pixels in each hemisphere.CONCLUSIONAuditory stimuli activate the TTG and the association areas. Activation in the primary auditory cortex depends on frequency, intensity, and complexity of the auditory stimulus. Activation of the auditory association areas requires more complex auditory stimuli, such as the stepped tone task or text reading.     

The role of nebulised budesonide in the treatment of exacerbations of COPD.

The present study was designed to evaluate the hypothesis that nebulised budesonide (NB) might be an alternative to systemic corticosteroids (SC) in the treatment of patients with exacerbations of chronic obstructive pulmonary disease (ECOPD). Patients hospitalised with ECOPD (n = 159) were randomised into three groups. Group 1 received only standard bronchodilator treatment (SBDT), group 2 received SC (40 mg prednisolone) plus SBDT, and group 3 received NB (1,500 microg q.i.d.) plus SBDT. Improvement during 10-day hospitalisation was compared with exacerbation and rehospitalisation rates after discharge. While mean+/-sd age was 64.1+/-8.9 yrs (female/male = 0.1), mean forced expiratory volume in one second (FEV(1)) at admission was found to be 37.2+/-12.2% predicted. Arterial blood gases and spirograms recovered faster in groups 2 and 3. While improvements in arterial oxygen tension (P(a,O(2))) and forced vital capacity (FVC) in group 2, and improvements in P(a,O(2)), FVC and FEV(1) in group 3, became significant at 24-h control, the first significant improvement in group 1 appeared in arterial oxygen saturation at 72-h control. The mean improvement of P(a,O(2)) after 10 days was 1.20 and 1.06 kPa (9 and 8 mmHg) higher in group 2 and 3, respectively, than in group 1. Blood glucose exhibited an upward trend only in group 2. The study demonstrates that nebulised budesonide may be an effective and safe alternative to systemic corticosteroids in the treatment of exacerbations of chronic obstructive pulmonary disease.     

Systemic lupus erythematosus and thrombotic thrombocytopenic purpura: a case report.

BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) is a multisystem disorder characterised by platelet aggregation causing microvascular occlusion. Early diagnosis and utilization of plasmapheresis can provide an improvement in prognosis. CASE REPORT: A 17 year old male with classical findings of TTP was later diagnosed as systemic lupus erythematosus (SLE). Plasmapheresis resulted in the significant amelioration of the course. CONCLUSION: The coexistence of TTP and SLE may facilitate a better understanding of in the pathophysiology of TTP. These association may provide the role of autoimmunity in TTP. SLE should be considered in the differential diagnosis of patients with TTP because of therapeutic implications.     

Laparoscopy or laparotomy for the management of endometrial cancer.

OBJECTIVE: The aim of this study was to evaluate the feasibility of laparoscopy in the management of early stage endometrial cancer. METHODS: Fifty-two patients with endometrial cancer who underwent surgical staging consisting of total hysterectomy, bilateral salpingo-oophorectomy with pelvic lymph node dissection, and cytology between 1998 to 2002 were included in the study. Laparotomy and laparoscopy were randomly offered to patients upon admittance. RESULTS: Of 52 patients, 26 underwent laparotomy and the remaining 26 underwent laparoscopic staging surgery. No significant difference existed between the demographic characteristics of the 2 groups. The mean number of harvested lymph nodes was 18.2 in the laparoscopic group and 21.1 in the laparotomic group (P>0.05). Pelvic lymph node metastases were detected in 7.7% of the patients in the laparoscopy group and 15.4% in the laparotomy group, and the difference was not significant. Adjuvant radiotherapy was applied later to 42.3% of the laparoscopy group and 38.5% of the laparotomy group. Operative morbidity was higher in the laparotomy group mainly because of postoperative wound infection, and the patients in the laparotomy group had a longer hospital stay. CONCLUSION: Laparoscopic surgery is a method that can be applied as well as laparotomy in the management of endometrial cancer. Lymph node number and detection of lymph node metastasis did not differ significantly in laparotomic and laparoscopic approaches. Wound infections were more frequent in laparotomies.     

Functional MR activation correlated with intraoperative cortical mapping.

PURPOSETo evaluate the spatial specificity of functional MR imaging by comparing it with intraoperative electrocortical mapping.METHODSFunctional MR imaging was performed in 28 patients before awake craniotomy and intraoperative electrocortical mapping. Activation was mapped for finger movement, lip movement, tongue movement, word generation, and counting paradigms. During surgery, finger movement, lip movement, tongue movement, counting, and/or speaking were mapped. The functional images and the photographic recordings of the brain functions mapped during surgery were converted to bit maps and coregistered by a computer program. The distance between the intraoperatively mapped function site and the MR activation site for a comparable function was measured.RESULTSForty-six functions were recorded on MR images and intraoperative maps. In 100% of correlations, the intraoperative site and the MR activation site were within 20 mm; in 87% of correlations they were within 10 mm. For each paradigm, 67% or more of the intraoperative stimulation maps correlated within 10 mm of the MR activation site.CONCLUSIONSFor the tasks used in this study, the activation site on functional MR images correlated well with the site at which intraoperative stimulation identified function.     

Early impact of hormone replacement therapy on vascular hemodynamics detected via ocular colour Doppler analysis

Objective: To determine the effects of hormone replacement therapy (HRT) on ocular blood flow.

Study design: In a prospective controlled study, 40 healthy women who presented to the menopause clinic between December 2000 and December 2001 were randomly assigned into the study. The HRT-receiving group was administered estradiol 17-valerate 2 mg the first 11 days, and estradiol 17-valerate 2 mg plus ciproterone acetate 1 mg the next 10 days of the monthly cycle for 6 months. The control group did not receive any HRT for 6 months. The ocular colour Doppler analysis were performed at baseline and after 3 and 6 months. The ocular Doppler analysis was performed in the first half of the cycle in the HRT-receiving group.

Results: Central retinal artery and ophthalmic artery basal Doppler index (peak systolic velocity, end-diastolic velocity, resistive index and pulsatility index) values of the two groups at the beginning of the study did not show any statistically significant difference. Both the right and the left central retinal artery pulsatility index (PI) values of the study group, who received HRT at the end of the third and sixth months, showed a statistically significant decline (paired-samples test, P < 0.05), while the decrease in the resistive indexes was not significant.

Conclusion: These results suggest that 6 months of combined hormone replacement therapy with estradiol 17-valerate 2 mg plus ciproterone acetate 1 mg improves ocular vascular Doppler indices which may be a reflection of cerebral vascular status.     

Tacrolimus-associated mutism after orthotopic liver transplantation

BACKGROUND: Mutism/speech apraxia has been well documented as a toxic effect of cyclosporine after liver transplantation but has been reported only rarely with tacrolimus. Brain imaging with magnetic resonance or computed tomography has failed to demonstrate abnormalities in affected patients. METHODS: We present the first example of an acute onset of loss of speech associated with a sudden elevation of serum tacrolimus level after successful orthotopic liver transplantation. We also describe the positron emission tomography (PET) scan of this patient's brain. RESULTS: PET scan imaging of the brain was abnormal, demonstrating decreased metabolism in the posterior temporo-parieto-occipital regions. Statistical probability mapping revealed additional areas of hypometabolism in the cingulate gyrus. CONCLUSIONS: PET scan revealed abnormalities of the brain in a patient with tacrolimus-induced mutism. The cingulate gyrus may play a role in the mutism/speech apraxia syndrome seen with cyclosporine/tacrolimus neurotoxicity.