Effect of deltamethrin and fluoride co-exposure on the brain antioxidant status and cholinesterase activity in Wistar rats

The study evaluated the effect of commercial preparation of deltamethrin, Butox^®, and fluoride (F^?) co-exposure on the brain antioxidant status and cholinesterase activity in rats. Group A was untreated. Group B was gavaged Butox^®, providing deltamethrin at the dose rate of 1.28?mg per kg body weight per day. Group C was administered F^?, as NaF, in drinking water providing 20?ppm F^?. Group D received both deltamethrin and F^? at the same dosages as groups B and C, respectively. Although, glutathione S-transferase activity was induced only in Butox^® alone treated group, the activities of superoxide dismutase and catalase were inhibited in all treatment groups when compared to the control group. Elevated lipid peroxidation was observed in the groups exposed to F^?. The activity of erythrocyte acetylcholinesterase (AChE) was inhibited in Butox^® treated groups, whereas brain AChE activity was inhibited in all treatment groups. In conclusion, both deltamethrin (given as Butox^®) and F^? inhibit AChE activity and produce oxidative stress in brain with F^? producing more oxidative damage. However, compared to the individual exposures, the co-exposure of these chemicals does not produce any exacerbated alteration in these biochemical parameters.     

Modified combined disc test (mCDT): a novel,labor-saving and 4 times cheaper method to differentiate Class A,B and D carbapenemase-producing Klebsiella species

Carbapenemase-producing organisms have been an immense public health problem in recent years. Combined disc test (CDT) is a simple and widely used phenotypic method for carbapenemase detection, especially in developing countries. This study evaluates the performance of modified combined disc test (mCDT), a novel and 4 times cheaper method than CDT. In total, 572 (15.5%) Klebsiella spp. including 81 (14.2%) carbapenemase producers were isolated from 3993 clinical samples. Both mCDT and CDT showed similar sensitivity, specificity, positive predictive value, and negative predictive value for the differentiation of Class A, B, and D carbapenemase-producing Klebsiella spp.     

Three Dimensional Transient Multifield Analysis of a Piezoelectric Micropump for Drug Delivery System for Treatment of Hemodynamic Dysfunctions

In this paper, we present design of a transdermal drug delivery system for treatment of cardiovascular or hemodynamic disorders such as hypertension. The system comprises of integrated control electronics and microelectromechanical system devices such as micropump, micro blood pressure sensor and microneedle array. The objective is to overcome the limitations of oral therapy such as variable absorption profile and the need for frequent dosing, by fabricating a safe, reliable and cost effective transdermal drug delivery system to dispense various pharmacological agents through the skin for treatment of hemodynamic dysfunction such as hypertension. Moreover, design optimization of a piezoelectrically actuated valveless micropump is presented for the drug delivery system. Because of the complexity in analysis of piezoelectric micropump, which involves structural and fluid field couplings in a complicated geometrical arrangement, finite element (FE) numerical simulation rather than an analytical system has been used. The behavior of the piezoelectric actuator with biocompatible polydimethylsiloxane membrane is first studied by conducting piezoelectric analysis. Then the performance of the valveless micropump is analyzed by building a three dimensional electric-solid-fluid model of the micropump. The effect of geometrical dimensions on micropump characteristics and efficiency of nozzle/diffuser elements of a valveless micropump is investigated in the transient analysis using multiple code coupling method. The deformation results of the membrane using multifield code coupling analysis are in good agreement with analytical as well as results of single code coupling analysis of a piezoelectric micropump. The analysis predicts that to enhance the performance of the micropump, diffuser geometrical dimensions such as diffuser length, diffuser neck width and diffuser angle need to be optimized. Micropump flow rate is not strongly affected at low excitation frequencies from 10 to 200 Hz. The excitation voltage is the more dominant factor that affects the flow rate of the micropump as compared with the excitation frequency. However, at extremely high excitation frequencies beyond 8,000 Hz, the flow rate drops as the membrane exhibits multiple bending peaks which is not desirable for fluid flow. Following the extensive numerical analysis, actual fabrication and performance characterization of the micropump is presented. The performance of the micropump is characterized in terms of piezoelectric actuator deflection and micropump flow rate at different operational parameters. The set of multifield simulations and experimental measurement of deflection and flow rate at varying voltage and excitation frequency is a significant advance in the study of the electric-solid-fluid coupled field effects as it allows transient, three dimensional piezoelectric and fluid analysis of the micropump thereby facilitating a more realistic multifield analysis. The results of the present study will also help to conduct relevant strength duration tests of integrated drug delivery device with micropump and microneedle array in future.     

Ventricular fibrillation in a left ventricular assist device patient: Can the echocardiogram be misleading?

Sustained ventricular tachycardia and ventricular fibrillation (VF) are life-threatening arrhythmias which remain highly prevalent in patients with advanced heart failure. These ventricular arrhythmias may impair the support provided by continuous-flow left ventricular assist devices (CF-LVADs) and lead to frequent hospitalizations, antiarrhythmic medication use, external defibrillations, and need for heart transplantation. We report a case in which a patient with a CF-LVAD and an implantable cardioverter defibrillator at end of life presented with asymptomatic low-flow alarms and was found to have VF of unknown duration. Unique in our case was the presence of apparent organized contractility and rhythmic opening of the mitral valve on echocardiogram despite VF on electrocardiogram.     

Tat Peptide Is Capable of Importing Large Nanoparticles Across Nuclear Membrane in Digitonin Permeabilized Cells

Understanding the capabilities and limitations of nuclear import is crucial to efficient delivery of macromolecules and nanoparticles for diagnosis and targeted therapy of diseases. Here we report the Tat peptide-mediated import of different cargos into cell nucleus, including dye-labeled streptavidin protein, 43 and 90 nm fluorescent beads, as well as ~20 nm quantum dots for kinetic measurements. Our results revealed significant differences between Tat- and NLS-mediated nuclear import: unlike delivery with the NLS, Tat peptide-based delivery is not inhibited by WGA blockage nor does it require ATP. Surprisingly, Tat peptide was able to import 90 nm beads into the nuclei of digitonin-permeabilized cells, suggesting that its interaction with the nuclear envelope follows a mechanism different from that of NLS. The import kinetics was quantified using Tat peptide-conjugated QDs, yielding a kinetic constant of 0.0085 s⁻¹. Taken together, our results suggest that, compared with NLS, Tat peptide-mediated nuclear import is faster, follows a different pathway, and is capable of importing large nanoparticles. These results have significant implications for the development of new approaches for delivery of cargo into the nuclei of living cells.     

Posterior capsule opacification after cataract surgery in remote Australian Aboriginal patients

Purpose: The aim of this retrospective study was to determine the rate of visually significant posterior capsular opacification formation after cataract surgery for Australian Aborigines living in rural or remote areas in the ‘Top End’ of the Northern Territory, Australia, and then to assess these patients’ outcomes after capsulotomy. Methods: Aboriginal patients living in remote areas of the Top End of the Northern Territory who underwent cataract surgery between 1994 and 1999 were identified from records at the three major hospitals in the region. The presence of posterior capsular opacification (PCO) was determined by clinical examination. The primary endpoint for this study was the presence of axial opacification of the posterior capsule and the need for subsequent Nd:YAG posterior capsulotomy to improve sight. Linear regression analysis of the time from surgery to follow up and the number of eyes requiring Nd:YAG capsulotomy was performed. Operated eyes were grouped according to the interval between surgery and follow up (Group 1: follow up within 1 year of surgery, n= 25; Group 2: follow up 1?3 years after surgery, n= 42; Group 3: follow up 3?5 years after surgery, n= 51). Results: One hundred and eighteen operated eyes were examined. Eyes in Group 3 were found to have the highest incidence of visually significant PCO (27.5%). There were more eyes requiring capsulotomy after 3 years than after 1 year following surgery. Linear regression analysis revealed an odds ratio of 1.4 (P = 0.07). All nine eyes in the 1?3 year group that had developed visually significant PCO had undergone extra‐capsular cataract extraction. Conclusions: For the remote Aboriginal patient who has undergone cataract surgery, there is a relatively minor chance of developing PCO within the first postoperative year regardless of the type of surgery undertaken. This study illustrates that the longer the time after surgery the greater the chance of developing visually significant PCO. For the remote Aboriginal patient there is a high chance (approximately 28%) of developing visually significant PCO within 5 years after cataract surgery. These figures are lower than those reported from other parts of Australia.     

Intranuclear inclusions in a case of pigmented villonodular synovitis of the ankle

Pigmented villonodular synovitis (PVNS) is a proliferative disorder of the synovial lining of the joints. Although the cytological findings of this disorder have been described in the literature, there is no mention of intranuclear cytoplasmic inclusions in this entity. A 65-yr-old woman presented with a painful swelling on the ankle. In addition to other characteristic findings of PVNS, we found the presence of intranuclear cytoplasmic inclusions in the fine-needle aspiration (FNA) smears. The characteristic cytological findings of abundant mononuclear cells occurring singly and in papillary clusters, multinucleated giant cells, and hemosiderin deposition should aid in the diagnosis of PVNS and in its differentiation from melanoma and other soft tissue sarcomas, even in the presence of uncommon features such as intranuclear inclusions.     

Clozapine-induced akathisia in children with schizophrenia

Akathisia is a relatively rare side effect with the newer atypical antipsychotic agents, particularly clozapine, and is easily misdiagnosed in children. As children are often unable to describe their symptoms verbally, their akathisia can be misdiagnosed as worsening of their psychosis, prompting an unnecessary increase in their neuroleptic dose. Two cases of childhood-onset schizophrenia associated with clozapine-induced akathisia responsive to beta-blocker treatment are described. Akathisia should be considered in all cases of apparent nonresponse to atypical antipsychotics.     

Preventive efficacy of receptor class selective retinoids on HER-2/neu oncogene expressing preneoplastic human mammary epithelial cells

Aberrant proliferation is an early-occurring event in vitro prior to tumorigenesis in vivo in the multistep process of carcinogenesis. Inhibition of aberrant proliferation therefore may represent a useful biomarker to evaluate the efficacy of chemopreventive agents. Retinoids have exhibited preventive efficacy in vitro and in vivo predominantly through the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). Clinically relevant biochemical and cellular mechanistic endpoints for chemopreventive effects of retinoids should provide novel biomarkers. The present study was designed to examine the preventive efficacy of natural retinoids, all-trans-retinoic acid (ATRA) and 9-cis-retinoic acid (9cisRA), and to identify the possible mechanisms for their effects using the HER-2/neu oncogene expressing preneoplastic human mammary epithelial 184-B5/HER cells. Seven-day treatment with ATRA and 9cisRA exhibited a dose-dependent growth inhibition. Long-term (21 days) treatment with IC20 doses of 50 nM ATRA and 100 nM 9cisRA inhibited anchorage-dependent colony forming efficiency by about 75.4% (p<0.01) and 84.9% (p<0.01), respectively. Cell cycle analysis revealed that a 24-h treatment with IC90 doses of 2 microM ATRA and 3 microM 9cisRA accumulates cells in the G0/G1 phase and inhibit S and/or G2/M phase of the cell cycle. ATRA and 9cisRA induced an 11-fold (p=0.03) and a 9-fold (p=0.04) increase in subG0/G1 (apoptotic) population relative to the solvent control, respectively. ATRA and 9cisRA induced 77% (p=0.01) and 51% (p=0.02) decrease in tyrosine kinase immunoreactivity, respectively. Similarly, the two retinoids caused almost a 50% (p=0.01) down-regulation of Bcl-2 immunoreactivity. Western blot analysis revealed that ATRA induced an increase in RARbeta expression and a decrease in RARgamma expression, while 9cisRA down-regulated RXRalpha expression. These data demonstrate that ATRA and 9cisRA may inhibit HER-2/neu induced aberrant proliferation in part by retarding cell cycle progression, down-regulating HER-2/neu-mediated signal transduction and inducing Bcl-2-dependent apoptosis through a retinoid receptor-mediated mechanism.