A reinforcing circuit action of extrasynaptic GABAA receptor modulators on cerebellar granule cell inhibition.

GABAA receptors (GABARs) are the targets of a wide variety of modulatory drugs which enhance chloride flux through GABAR ion channels. Certain GABAR modulators appear to acutely enhance the function of δ subunit-containing GABAR subtypes responsible for tonic forms of inhibition. Here we identify a reinforcing circuit mechanism by which these drugs, in addition to directly enhancing GABAR function, also increase GABA release. Electrophysiological recordings in cerebellar slices from rats homozygous for the ethanol-hypersensitive (α6100Q) allele show that modulators and agonists selective for δ-containing GABARs such as THDOC, ethanol and THIP (gaboxadol) increased the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) in granule cells. Ethanol fails to augment granule cell sIPSC frequency in the presence of glutamate receptor antagonists, indicating that circuit mechanisms involving granule cell output contribute to ethanol-enhancement of synaptic inhibition. Additionally, GABAR antagonists decrease ethanol-induced enhancement of Golgi cell firing. Consistent with a role for glutamatergic inputs, THIP-induced increases in Golgi cell firing are abolished by glutamate receptor antagonists. Moreover, THIP enhances the frequency of spontaneous excitatory postsynaptic currents in Golgi cells. Analyses of knockout mice indicate that δ subunit-containing GABARs are required for enhancing GABA release in the presence of ethanol and THIP. The limited expression of the GABAR δ subunit protein within the cerebellar cortex suggests that an indirect, circuit mechanism is responsible for stimulating Golgi cell GABA release by drugs selective for extrasynaptic isoforms of GABARs. Such circuit effects reinforce direct actions of these positive modulators on tonic GABAergic inhibition and are likely to contribute to the potent effect of these compounds as nervous system depressants

Changes in Purkinje cell firing and gene expression precede behavioral pathology in a mouse model of SCA2.

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominantly inherited disorder, which is caused by a pathological expansion of a polyglutamine (polyQ) tract in the coding region of the ATXN2 gene. Like other ataxias, SCA2 most overtly affects Purkinje cells (PCs) in the cerebellum. Using a transgenic mouse model expressing a full-length ATXN2(Q127)-complementary DNA under control of the Pcp2 promoter (a PC-specific promoter), we examined the time course of behavioral, morphologic, biochemical and physiological changes with particular attention to PC firing in the cerebellar slice. Although motor performance began to deteriorate at 8 weeks of age, reductions in PC number were not seen until after 12 weeks. Decreases in the PC firing frequency first showed at 6 weeks and paralleled deterioration of motor performance with progression of disease. Transcription changes in several PC-specific genes such as Calb1 and Pcp2 mirrored the time course of changes in PC physiology with calbindin-28 K changes showing the first small, but significant decreases at 4 weeks. These results emphasize that in this model of SCA2, physiological and behavioral phenotypes precede morphological changes by several weeks and provide a rationale for future studies examining the effects of restoration of firing frequency on motor function and prevention of future loss of PCs

Optimal Siting of Distributed Generators in a Distribution Network using Artificial Immune System

Distributed generation (DG) sources are being installed in distribution networks worldwide due to their numerous advantages over the conventional sources which include operational and economical benefits. Random placement of DG sources in a distribution network will result in adverse effects such as increased power loss, loss of voltage stability and reliability, increase in operational costs, power quality issues etc. This paper presents a methodology to obtain the optimal location for the placement of multiple DG sources in a distribution network from a technical perspective. Optimal location is obtained by evaluating a global multi-objective technical index (MOTI) using a weighted sum method. Clonal selection based artificial immune system (AIS) is used along with optimal power flow (OPF) technique to obtain the solution. The proposed method is executed on a standard IEEE-33 bus radial distribution system. The results justify the choice of AIS and the use of MOTI in optimal siting of DG sources which improves the distribution system efficiency to a great extent in terms of reduced real and reactive power losses, improved voltage profile and voltage stability. Solutions obtained using AIS are compared with Genetic algorithm (GA) and Particle Swarm optimization (PSO) solutions for the same objective function

Assessment of patients undergoing re-restoration after class ii amalgam

Amalgam is a restorative material especially suitable for class I and class II restoration in teeth that encounter heavy chewing forces. Amalgam restorations may also present degradation in the intra oral environment due to secondary caries, fracture and marginal breakdown and wear. The aim of the study is the number of patients undergoing re restoration after class II amalgam. It is a retrospective study. Data collection was done and entered in the excel sheet. Parameters assessed were age, gender, teeth no. and re restoration after class II amalgam. The data collection was tabulated in excel and data analysis was done using SPSS software. The association between study variables was calculated using the chi-square test. The result showed 940 individuals with re restoration after class II amalgam. The frequency was seen to be 39.2%%. The chi square test showed positive correlation between gender and amalgam restoration (P value <0.05). It may be concluded that amalgam longevity is an important issue for patients, governments and dentists to define the court of dental treatment. The re-restoration and other types of local defect increases the longevity of the amalgam restoration

Finite-temperature behavior of the Bose polaron

We consider a mobile impurity immersed in a Bose gas at finite temperature. Using perturbation theory valid for weak coupling between the impurity and the bosons, we derive analytical results for the energy and damping of the impurity for low and high temperatures, as well as for temperatures close to the critical temperature $T_c$ for Bose-Einstein condensation. These results show that the properties of the impurity vary strongly with temperature. In particular, the energy exhibits a non-monotonic behavior close to $T_c$, and the damping rises sharply close to $T_c$. We argue that this behaviour is generic for impurities immersed in an environment undergoing a phase transition that breaks a continuous symmetry. Finally, we discuss how these effects can be detected experimentally.Comment: 10 pages and 6 figure

A positive feedback loop linking enhanced mGluR function and basal calcium in spinocerebellar ataxia type 2

Metabotropic glutamate receptor 1 (mGluR1) function in Purkinje neurons (PNs) is essential for cerebellar development and for motor learning and altered mGluR1 signaling causes ataxia. Downstream of mGluR1, dysregulation of calcium homeostasis has been hypothesized as a key pathological event in genetic forms of ataxia but the underlying mechanisms remain unclear. We find in a spinocerebellar ataxia type 2 (SCA2) mouse model that calcium homeostasis in PNs is disturbed across a broad range of physiological conditions. At parallel fiber synapses, mGluR1-mediated excitatory postsynaptic currents (EPSCs) and associated calcium transients are increased and prolonged in SCA2 PNs. In SCA2 PNs, enhanced mGluR1 function is prevented by buffering [Ca 2+ ] at normal resting levels while in wildtype PNs mGluR1 EPSCs are enhanced by elevated [Ca 2+ ]. These findings demonstrate a deleterious positive feedback loop involving elevated intracellular calcium and enhanced mGluR1 function, a mechanism likely to contribute to PN dysfunction and loss in SCA2

Effect of patent law changes on the innovation strategy of Chinese and Indian Life Science companies as reflected in US patent filings

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2010.Cataloged from PDF version of thesis.Includes bibliographical references (p. 34-35).In this paper we evaluate how harmonization of patent laws in China and India to developed world standards has affected innovative research and development activity in the life sciences industry of those countries. The patents listed in the United States Patent and Trademark Office were used as a proxy to measure innovative activity. The number and types of patents filed over the period from 1976 through 2008 were analyzed for trends towards innovation. At a high level, we found that 'Drugs and Medical' account for only 6% of Chinese patents but make up 20% of the universe of Indian patents. When evaluating patent activity over time, we found that filings rose exponentially in the mid-nineties corresponding to the creation and implementation of product patent laws in both countries. India exhibited a much higher and steeper increase, likely due to its previously established capabilities as a generics manufacturer. When segmenting the data based on type of firms (academic, foreign multinationals and local private) we found that post product patent laws, local private firms exhibit more activity in India whereas local firms and multinationals show similar amounts of activity in China. In both countries, academic institutions show the greatest amount of activity compared to the multinationals and local private companies. We conclude that stronger IP laws have resulted in greater innovative activity as seen in the exponential rise in patent filings in the life sciences industry in both China and India. Although India has shown greater activity compared to China possibly due to its established capabilities in the generics space as a result of its protective patent regime prior to the harmonization.by Meera S. Gupta.S.M

ANTIOXIDANT, ANTI-LIPID PEROXIDATIVE AND ANTIMICROBIAL PROPERTIES OF THE EPIPHYTIC FERN, PYRROSIA HETEROPHYLLA (L.) M. G. PRICE

Objective: The present study was aimed at establishing the antioxidant, free radical scavenging, anti-lipid peroxidative and antimicrobial properties of the plant Pyrrosia heterophylla (L.) M. G. PRICE.Methods: Standard protocols were used to estimate the antioxidant potential of the hexane, ethyl acetate and methanolic extracts of the plant. Radical scavenging ability of the extracts was assayed for 2, 2'-azino-bis (3-ethylbenzothiazoline-6-sulphonicacid) (ABTS), 1,1-diphenyl-2-picryl-hydrazil (DPPH) and hydroxyl radicals. Total antioxidant activity assay was done following the phospho- molybdenum method. The reductive potential was measured by ferric reducing antioxidant power (FRAP) assay. Lipid peroxidation assay was done in vitro. Total phenolic content was measured by the Folin-Ciocalteu method. Antimicrobial activity was identified by well diffusion method, and minimum inhibitory concentration (MIC) was determined by serial dilution method.Results: Results revealed that the ethyl acetate extract (PHE) exhibited the highest antioxidant capacity followed by the methanolic extract (PHM) whereas the hexane extract (PHH) had the lowest activity. The percentage radical scavenging by PHE was found to be 86.63±0.85, 89.48±2.08 and 70.89±1.46 for DPPH, ABTS and hydroxyl radicals respectively, at a concentration of 800μg/ml. The total antioxidant activity of PHE, PHM and PHH was found to be 538.33±3.51, 283.33±7.57and 13.76±3.95 ascorbic acid equivalents/g of extract respectively. Phenolic content of PHE was the highest (207.22±1.95 gallic acid equivalents (GAE)/g of extract), followed by PHM and PHH (197.92±2.00 and 37.50±2.18 GAE/g respectively). Total reducing power was also found to be the highest in PHE followed by PHM and PHH as per the FRAP assay. All the extracts were found to possess inhibitory activity against the tested microorganisms. MIC50 value of all the extracts was below 40 µg/ml.Conclusion: The results of this study confirmed the antioxidant, antimicrobial and anti-lipid peroxidation potentials of the plant P. heterophylla (L.) M. G. PRICE

"A Comparitive Study on the Assessment of Neuro Protective Effect of Citicoline Vs Citicoline with Piracetam and Health Related Quality of Life in Post Stroke Patients"

AIM: To assess the neuroprotective effects of Citicoline versus Citicoline with Piracetam combination and health related quality of life in post stroke patients. METHODS: A hospital based prospective observational study was done at a tertiary care hospital located in Thiruvananthapuram over a period of 6 months. The neuroprotective effect of citicoline against a combination of drugs, citicoline with piracetam was compared by the use of two groups. One group of patients treated with citicoline and the other group with citicoline and piracetam combination. The neuroprotective effect was compared by the use of National Institute of Health Stroke Scale (NIHSS). The quality of life of the patients was evaluated before and after the treatment by using Barthel Index Scale (BIS) to detect whether the QOL has improved.The treatment with citicoline and piracetam combination gives better neuroprotection than that of individual treatment with citicoline.The result shows that the treatment with the combination of citicoline and piracetam gives better neuroprotective effect and also shows superiority in upgrading the quality of life

Women’s Experiences in Religious Tourism: An Investigation into Women’s Involvement in Sabarimala Pilgrimage, Kerala

Preparations for the Sabarimala pilgrimage involves devotees observing a 41 day period of austerity (vrata) during which they practice an ascetic life. Women between the age of 10 and 50 do not visit the shrine at Sabarimala due to long-established customs. However, women do play an important role during the 41-day austerity observed by family members preparing for the pilgrimage, which could be described as a non-participant involvement in the pilgrimage. While there have been many studies on the spiritual and secular experiences of pilgrims, research on this unique form of non-participant involvement in pilgrimages is not found especially in the Indian context. This study explores the religious experience of female family members, who do not join the pilgrimage but participate by assisting family members going on the Sabarimala pilgrimage. The study aims to identify their unique experience from multiple perspectives such as personal, interpersonal, and societal through a constructivist approach. Adopting qualitative research methods, interviews were carried out among female members of Sabarimala pilgrims’ families in the states of Kerala, Tamil Nadu and Andhra Pradesh to get insight into their experiences and their involvement in the pilgrimage process. The findings of the study propose Sabarimala pilgrimage as a very important social process which cements and strengthens family relationships and togetherness