Methylphenidate Exposure Induces Dopamine Neuron Loss and Activation of Microglia in the Basal Ganglia of Mice

Background: Methylphenidate (MPH) is a psychostimulant that exerts its pharmacological effects via preferential blockade of the dopamine transporter (DAT) and the norepinephrine transporter (NET), resulting in increased monoamine levels in the synapse. Clinically, methylphenidate is prescribed for the symptomatic treatment of ADHD and narcolepsy; although lately, there has been an increased incidence of its use in individuals not meeting the criteria for these disorders. MPH has also been misused as a cognitive enhancer and as an alternative to other psychostimulants. Here, we investigate whether chronic or acute administration of MPH in mice at either 1 mg/kg or 10 mg/kg, affects cell number and gene expression in the basal ganglia. Methodology/Principal Findings: Through the use of stereological counting methods, we observed a significant reduction (~20%) in dopamine neuron numbers in the substantia nigra pars compacta (SNpc) following chronic administration of 10 mg/kg MPH. This dosage of MPH also induced a significant increase in the number of activated microglia in the SNpc. Additionally, exposure to either 1 mg/kg or 10 mg/kg MPH increased the sensitivity of SNpc dopaminergic neurons to the parkinsonian agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Unbiased gene screening employing Affymetrix GeneChip® HT MG-430 PM revealed changes in 115 and 54 genes in the substantia nigra (SN) of mice exposed to 1 mg/kg and 10 mg/kg MPH doses, respectively. Decreases in the mRNA levels of gdnf, dat1, vmat2, and th in the substantia nigra (SN) were observed with both acute and chronic dosing of 10 mg/kg MPH. We also found an increase in mRNA levels of the pro-inflammatory genes il-6 and tnf-α in the striatum, although these were seen only at an acute dose of 10 mg/kg and not following chronic dosing. Conclusion: Collectively, our results suggest that chronic MPH usage in mice at doses spanning the therapeutic range in humans, especially at prolonged higher doses, has long-term neurodegenerative consequences

Expectations of Consumers of Store Brand Apparels in Chennai City of India

The growth of store brands in India presents an interesting opportunity for the retailer to understand the motivations of consumers behind choice of store brands. Since, Chennai is not a saturated market, and with an expected growth of 10-12% over the next 10 years. Chennai is under-branded and under penetrated in many categories of apparels. Clearly, Chennai market has scope for more brands and all brands can co exist. Hence, among the four major metropolises in India, The data and information have been collected from 500 consumers of store brand apparels in Chennai city by adopting multi stage random sampling technique through pre-tested, structured interview schedule through direct interview method pertains to the year 2009-2010. The results shows that more than one third of consumers belong to the middle age group and nearly two third of them are married. About of half of the consumers are graduates and majority of consumers belong to middle income group. The results show that more than half of the consumers are employed in private sector and nearly two third of them visit the apparel store once in a month followed by every two months. The spouse and children are highly influencing the purchasing decision and most of them suggest the price of apparel store brands and nearly half of them purchase store brand apparels worth of Rs..2001-3000 per visit. The discriminant analysis indicates that lift/elevator, price tag, lighting and accessories discriminate best among age groups while comfortable, courtesy, convenience and quick delivery discriminate best among income groups. Hence, it is suggested that styling should be specific and sensitive to the large-size male consumers taking into account fashion ability and uniqueness. To remain competitive, apparel stores must continue low pricing and weekly sale advertisements. In addition, stores must continue to promote their store labels and brands as well as focus on small niche markets. Without a combination of low price and high quality, store brands will not succeed. Low price store brands end up eliminating price competition, which intensifies consumer price sensitivity, satisfaction and loyalty. Keywords: Store Brands, Consumers Expectations, Discriminant Analysi

In silico and in vitro validation of some benzimidazole derivatives as adenosine deaminase inhibitors

1175-1182Benzimidazole nucleus considered as an important scaffold for developing drug candidates against a wide spectrum of diseases. Adenosine deaminase (ADA), an enzyme present in purine metabolic pathway, has a significant role in inflammatory and malignant diseases and hence it is considered as a major target for drug development. The present study investigates ADA inhibitory potential of selected benzimidazole derivatives by using in silico and in vitro methods. Molecular docking and dynamics simulations have been carried out to identify potential ADA activesite binders from benzimidazole derivatives. Compounds having strong binding affinities were selected for enzyme inhibition assays and fluorescent binding studies. The results showed that the pyridinyl and butyl derivatives of benzimidazole possess significant ADA inhibitory potential.The study proposes these compounds can be used as potent candidates for developing ADA inhibitor drugs

In silico and in vitro validation of some benzimidazole derivatives as adenosine deaminase inhibitors

Benzimidazole nucleus considered as an important scaffold for developing drug candidates against a wide spectrum of diseases. Adenosine deaminase (ADA), an enzyme present in purine metabolic pathway, has a significant role in inflammatory and malignant diseases and hence it is considered as a major target for drug development. The present study investigates ADA inhibitory potential of selected benzimidazole derivatives by using in silico and in vitro methods. Molecular docking and dynamics simulations have been carried out to identify potential ADA activesite binders from benzimidazole derivatives. Compounds having strong binding affinities were selected for enzyme inhibition assays and fluorescent binding studies. The results showed that the pyridinyl and butyl derivatives of benzimidazole possess significant ADA inhibitory potential.The study proposes these compounds can be used as potent candidates for developing ADA inhibitor drugs

Simulation of flow diversion in cerebral aneurysms

Intracranial aneurysms are abnormal focal enlargements of the vascular walls that necessitate surgical intervention once detected. Emerging stent technology involves an innovative type of finely-braided stents, called flow diverters, which abruptly impede the arterial flow into the aneurysm, upon deployment, and induce thrombosis, vascular remodelling and complete aneurysm occlusion in under a year [1]. The understanding of the dynamics of blood flow within this radically modified environment is thought to be pivotal in increasing the efficacy of both stent design and prolonged treatment. The aim of this study is to numerically simulate the blood flow within stented arterial segments and to evaluate critical hemodynamic factors around the aneurysm neck, validated with clinical and experimental data [1,2]. These objectives create many geometric challenges around the flow diverter due to the tessellation and resolution of features with very large ratio (artery-to-stent) in the input i.e., medical images and stent models. Following a novel Body-Centric Cubic (BCC) mesh generation method [2], high-fidelity tetrahedral meshes of aneurysmal dilatations that incorporate flow diverters across the aneurysm neck are now possible with an accurate image- to-mesh (I2M) conversion scheme from micro-CT images (Fig. 1a,b). Preliminary results involve arterial segments both with and without flow diverters (Fig.1c), utilising the CFD software OpenFOAM® to solve the incompressible Navier-Stokes equations, under steady and physiologically-correct pulsatile flow conditions

Photon Beam Asymmetry Σ for η and η′ Photoproduction From the Proton

Measurements of the linearly-polarized photon beam asymmetry Σ for photoproduction from the proton of η and η ′ mesons are reported. A linearly-polarized tagged photon beam produced by coherent bremsstrahlung was incident on a cryogenic hydrogen target within the CEBAF Large Acceptance Spectrometer. Results are presented for the γ p → η p reaction for incident photon energies from 1.070 to 1.876 GeV, and from 1.516 to 1.836 GeV for the γ p → η ′ p reaction. For γ p → η p , the data reported here considerably extend the range of measurements to higher energies, and are consistent with the few previously published measurements for this observable near threshold. For γ p → η ′ p , the results obtained are consistent with the few previously published measurements for this observable near threshold, but also greatly expand the incident photon energy coverage for that reaction. Initial analysis of the data reported here with the Bonn–Gatchina model strengthens the evidence for four nucleon resonances – the N (1895) 1/2− , N (1900) 3/2+ , N(2100) 1/2+ and N (2120) 3/2− resonances – which presently lack the four-star status in the current Particle Data Group compilation, providing examples of how these new measurements help refine models of the photoproduction process