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Background Recent studies have demonstrated the possibility of negative associations between prior influenza vaccines and subsequent influenza vaccine effectiveness (VE), depending on season and strain. We investigated this association over 4 consecutive influenza seasons (2011–2012 through 2014–2015) in Canada. Methods Using a matched test-negative design, laboratory-confirmed influenza cases and matched test-negative controls admitted to hospitals were enrolled. Patients were stratified into 4 groups according to influenza vaccine history (not vaccinated current and prior season [referent], vaccinated prior season only, vaccinated current season only, and vaccinated both current and prior season). Conditional logistic regression was used to estimate VE; prior vaccine impact was assessed each season for overall effect and effect stratified by age ( Results Overall, mainly nonsignificant associations were observed. Trends of nonsignificant decreased VE among patients repeatedly vaccinated in both prior and current season relative to the current season only were observed in the A/H3N2-dominant seasons of 2012–2013 and 2014–2015. Conversely, in 2011–2012, during which B viruses circulated, and in 2013–2014, when A/H1N1 circulated, being vaccinated in both seasons tended to result in a high VE in the current season against the dominant circulating subtype. Conclusions Prior vaccine impact on subsequent VE among Canadian inpatients was mainly nonsignificant. Even in circumstances where we observed a trend of negative impact, being repeatedly vaccinated was still more effective than not receiving the current season’s vaccine. These findings favor continuation of annual influenza vaccination recommendations, particularly in older adults. Clinical Trials Registration NCT01517191.

This paper investigates and argues the modes of self-presentation established and kept by Guru Gobind Singh in the late seventeenth century not only defied Mughal convention and law, but also came to influence regional styles of dress and other aspects of courtly fashion in the Jammu court during the eighteenth and nineteenth centuries, closely attending the changes in the art historical record of both the Sikh and Dogra court during this two hundred year period, as well as the travelogues of several important Europeans who visited the area during Maharaja Ranjit Singh. In doing so, this study will seek to rethink how the conventions of Sikh culture, while initially ignored and censured by surrounding powers, spread and reshaped the styles of dress, and ultimately the art historical record of surrounding, Mughal strongholds.

Background Consideration of cost determinants is crucial to inform delivery of public vaccination programs. Objectives To estimate the average total cost of laboratory-confirmed influenza requiring hospitalization in Canadians prior to, during, and 30 days following discharge. To analyze effects of patient/disease characteristics, treatment, and regional differences in costs. Methods Study utilized previously recorded clinical characteristics, resource use, and outcomes of laboratory-confirmed influenza patients admitted to hospitals in the Serious Outcomes Surveillance (SOS), Canadian Immunization Research Network (CIRN), from 2010/11 - 2012/13. Unit costs including hospital overheads were linked to inpatient/outpatient resource utilization before and after admissions. Results Dataset included 2,943 adult admissions to 17 SOS Network hospitals, 24 Toronto Invasive Bacterial Disease Network hospitals. Mean age was 69.5 years. Average hospital stay was 10.8 days (95% CI: 10.3, 11.3), general ward stays were 9.4 days (95% CI: 9.0, 9.8) and ICU stays were 9.8 days (95% CI: 8.6, 11.1) for the 14% of patients admitted to the ICU. Average cost per case was $14,612 CAD (95% CI: $13,852, $15,372) including $133 (95% CI: $116, $150) for medical care prior to admission, $14,031 (95% CI: $13,295, $14,768) during initial hospital stay, $447 (95% CI: $271, $624) post-discharge, including readmission within 30 days. Conclusion The cost of laboratory-confirmed influenza was higher than previous estimates, driven mostly by length of stay and analyzing only laboratory-confirmed influenza cases. The true per patient cost of influenza-related hospitalization has been underestimated and prevention programs should be evaluated in this context. This article is protected by copyright. All rights reserved.

Wall decoration and architecture have strong relations with each other. This relationship has been seen during the evaluation of wall decorations in the Mughal period and contemporary period. The Mughal period covers the fifteenth century up to the seventeenth century, and the contemporary period belongs to the twentieth century. There is a gap between the two periods. In present time, the concept, theme, and style have been affected by Western culture. The artist, without innovative ideas of Westernization or modernization in art, is being neglected by the society. At present, among the other changes, the impulses have dispelled from natural representation. The impact of abstraction may be seen in art forms, which has been broken by the tendency of making the natural things and converting them into abstract. This is the main theme for decorating a building in the present scenario. Except from all innovations, Indian art has its roots into its cultural and religious diameter. The present paper is an analytical study to explore the trend and trendies of present-time mural decoration in Jaipur architecture. This paper will also focus on the impact of Mughal art on contemporary wall decorations and also make clear if contemporary wall decorations have any impact from Mughal wall decorations or not.

Melatonin has multiple roles including neuroprotection. Melatonin signaling involves diverse targets including two G-protein-coupled receptors, MT(1) and MT(2), which have both been localized to the nigrostriatal pathway. Previous studies in our laboratory demonstrated preservation of tyrosine hydroxylase immunoreactivity, following chronic treatment with a physiological dose of melatonin, in the 6-hydroxydopamine rat model of Parkinson's disease. Additionally, we reported the presence of the melatonin MT(1) receptor subtype in cultured C17.2 neural stem cells (NSCs). In the present study, we examined the effects of C17.2 NSC transplantation on dopaminergic denervation following 6-hydroxydopamine lesioning in the rat striatum. Moreover, based on our detection of the MT(1) in these cells, we examined the effects of combined C17.2 NSC transplantation and melatonin treatment, following striatal lesioning. Behavioral studies indicated a marked inhibition of apomorphine-induced rotations in lesioned animals that received C17.2 NSC transplantation, melatonin, or the combined regimen. In addition, these treatments resulted in a significant protection of tyrosine hydroxylase immunoreactivity in the striatum and substantia nigra of lesioned animals, when compared with untreated controls. Lesioned animals treated with C17.2 NSCs, melatonin or a combination of both agents exhibited no significant differences in the number of tyrosine hydroxylase-positive cells in the substantia nigra or ventral tegmental area ipsilateral or contralateral to the lesioned striatum. These findings suggest that stem cell therapy and concomitant use of neuroprotective agents such as melatonin could be a viable approach in Parkinson's disease.

We have previously reported in vivo preservation of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis, following treatment with physiological doses of melatonin, in a 6-hydroxydopamine model of Parkinson's disease. Based on these findings, we postulated that melatonin would similarly modulate the expression of TH in vitro. Therefore, using human SH-SY5Y neuroblastoma cells which can differentiate into dopaminergic neurons following treatment with retinoic acid, we first examined whether these cells express melatonin receptors. Subsequently, the physiological dose-dependent effects of melatonin on TH expression were examined in both undifferentiated and differentiated cells. The novel detection of the G protein-coupled melatonin MT(1) receptor in SH-SY5Y cells by RT-PCR was confirmed by sequencing and Western blotting. In addition, following treatment of SH-SY5Y cells with melatonin (0.1-100 nM) for 24h, Western analysis revealed a significant increase in TH protein levels. A biphasic response, with significant increases in TH protein at 0.5 and 1 nM melatonin and a reversal at higher doses was seen in undifferentiated cells; whereas in differentiated cells, melatonin was effective at doses of 1 and 100 nM. These findings suggest a physiological role for melatonin in modulating TH expression, possibly via the MT(1) receptor.

There is considerable evidence that pharmacological doses of the pineal hormone, melatonin, are neuroprotective in diverse models of neurodegeneration including Parkinson's disease. However, there is limited information about the effects of physiological doses of this hormone in similar models. In this study, rats were chronically treated with melatonin via drinking water following partial 6-hydroxydopamine lesioning in the striatum. The two doses of melatonin (0.4 microg/ml and 4.0 microg/ml) were within the reported physiological concentrations present in the serum and cerebrospinal fluid respectively. At 2 weeks after surgery, the higher dose of melatonin significantly attenuated rotational behavior in hemi-parkinsonian rats compared to similarly lesioned animals receiving either vehicle (P < 0.001) or the lower dose of melatonin (P < 0.01). Animals were perfused or sacrificed 10 weeks after commencing melatonin treatment for immunohistochemical or mRNA studies. Animals treated with 4.0 microg/ml melatonin exhibited normal tyrosine hydroxylase (TH) immunoreactivity in the lesioned striatum, whereas little or no TH immunofluorescence was visible in similarly lesioned animals receiving vehicle. In contrast, semiquantitative RT-PCR analysis revealed no group differences in TH mRNA, suggesting spontaneous recovery of this transcript as observed previously in partially lesioned animals. There were no significant differences in striatal GDNF mRNA levels between sham and lesioned animals. However, there was a significant (P < 0.01) increase in GDNF mRNA expression in the intact contralateral striata of lesioned animals treated with vehicle. Interestingly, melatonin treatment attenuated this novel compensatory contralateral increase in striatal GDNF expression, presumably due to its neuroprotective effect. These findings support a physiological role for melatonin in protecting against parkinsonian neurodegeneration in the nigrostriatal system.

Background Recent controversy has arisen from observational studies suggesting a potential negative association between prior influenza vaccination and subsequent influenza vaccine effectiveness (VE). As immunologic theories suggest this impact could vary by season/strain, we investigated this association over 4 influenza seasons in Canada. Methods The CIRN SOS Network prospectively enrolled laboratory-confirmed influenza cases and influenza-negative controls admitted to participating hospitals. Using a test-negative control design, matched conditional logistic regression modeling stratifying participants into 4 groups (not vaccinated current or prior season [referent], vaccinated prior season only, vaccinated current season only, and vaccinated both current and prior season) was used to calculate odds ratios (OR) to estimate the effect of vaccination status on influenza-related hospitalization (VE= 1-OR x100). We assessed VE overall and stratified by strain (A/H3N2, A/H1N1, and influenza B) for 4 influenza seasons in Canada: 2011/2012–2014/2015. Results Although impact of prior vaccination varied, the largest strain-specific impacts were observed in the H3N2 dominant seasons 2012/2013 and 2014/2015, seasons where the H3N2 vaccine component was matched, and mismatched, respectively, to the circulating strain. In 12/13, adjusted VE against influenza H3N2 hospitalization was 58.6% (95% Confidence Interval [CI]: 32.5–74.7%) for patients vaccinated in current season only, relative to 30.9% (10.8–46.5%) among those vaccinated in both prior and current season; VE against influenza B hospitalization in 12/13 was 83.2% (18.9–96.5%) in current season only vaccinees and 54.1% (-6.0–80.2%) in both seasons vaccinees. In 14/15, H3N2 VE was 35.3% (-32.6–68.5%) in current season only vaccinees and -8.3% (-56.7–25.1%) in both seasons vaccinees. Conclusion While our findings support a possible negative association between prior influenza vaccination and subsequent season VE against some strains in certain seasons, non-statistically significant reductions in VE were observed. Future prospective studies, using varying methodology to examine this association and to explore contributing biological/immunological mechanisms, are critical to inform immunization policy. Disclosures M. K. Andrew, GSK: Grant Investigator, Research grant; Pfizer: Grant Investigator, Research grant; Sanofi-Pasteur: Grant Investigator, Research grant; T. Hatchette, GSK: Grant Investigator, Grant recipient; Pfizer: Grant Investigator, Grant recipient; Abbvie: Speaker for a talk on biologics and risk of TB reactivation, Speaker honorarium; G. Dos Santos, GSK: Employee, Salary; Business and Decision Life Sciences (Contractor for GSK Vaccines): Independent Contractor, Salary; M. Elsherif, Canadian Institutes of Health Research: Investigator, Research grant; Public Health Agency of Canada: Investigator, Research grant; GSK: Investigator, Research grant; F. Haguinet, GSK: Employee, Salary; J. Mcelhaney, GSK: Scientific Advisor, Honorarium to institution; sanofi pasteur: Scientific Advisor, Honorarium to institution; A. Mcgeer, Hoffman La Roche: Investigator, Research grant; GSK: Investigator, Research grant; sanofi pasteur: Investigator, Research grant; J. Powis, Merck: Grant Investigator, Research grant; GSK: Grant Investigator, Research grant; Roche: Grant Investigator, Research grant; Synthetic Biologicals: Investigator, Research grant; M. Semret, GSK: Investigator, Research grant; Pfizer: Investigator, Research grant; R. Sharma, GSK: Employee and Shareholder, Salary; V. Shinde, Novavax: Employee, Salary; GSK: Shareholder, Stocks; GSK: Employee, Salary; S. Trottier, Canadian Institutes of Health Research: Investigator, Research grant; S. McNeil, GSK: Contract Clinical Trials and Grant Investigator, Research grant; Merck: Contract Clinical Trials and Speaker’s Bureau, Speaker honorarium; Novartis: Contract Clinical Trials, No personal renumeration; sanofi pasteur: Contract Clinical Trials, No personal renumeration

In humans, beta-hexosaminidase A (alphabeta) is required to hydrolyze GM2 ganglioside. A deficiency of either the alpha- or beta-subunit leads to a severe neurological disease, Tay-Sachs or Sandhoff disease, respectively. In mammals beta-hexosaminidase B (betabeta) and S (alphaalpha) are other major and minor isozymes. The primary structures of the alpha- and beta-subunits are 60% identical, but only the alpha-containing isozymes can efficiently hydrolyze beta-linked GlcNAc-6-SO(4) from natural or artificial substrates. Hexosaminidase has been grouped with glycosidases in family 20. A molecular model of the active site of the human hexosaminidase has been generated from the crystal structure of a family 20 bacterial chitobiase. We now use the chitobiase structure to identify residues close to the carbon-6 oxygen of NAG-A, the nonreducing beta-GlcNAc residue of its bound substrate. The chitobiase side chains in the best interactive positions align with alpha-Asn(423)Arg(424) and beta-Asp(453)Leu(454). The change in charge from positive in alpha to negative in beta is consistent with the lower K(m) of hexosaminidase S, and the much higher K(m) and lower pH optimum of hexosaminidase B, toward sulfated versus unsulfated substrates. In vitro mutagenesis, CHO cell expression, and kinetic analyses of an alphaArg(424)Lys hexosaminidase S detected little change in V(max) but a 2-fold increase in K(m) for the sulfated substrate. Its K(m) for the nonsulfated substrate was unaffected. When alphaAsn(423) was converted to Asp, again only the K(m) for the sulfated substrate was changed, increasing by 6-fold. Neutralization of the charge on alphaArg(424) by substituting Gln produced a hexosaminidase S with a K(m) decrease of 3-fold and a V(max) increased by 6-fold for the unsulfated substrate, parameters nearly identical to those of hexosaminidase B at pH 4.2. As well, for the sulfated substrate at pH 4.2 its K(m) was increased 9-fold and its V(max) decreased 1.5-fold, values very similar to those of hexosaminidase B obtained at pH 3.0, where its betaAsp(453) becomes protonated.

We have reported the induction of glial cell line-derived neurotrophic factor, a potent survival factor for dopaminergic neurons, in the C17.2 neural stem cell line following in vitro treatment with melatonin. Furthermore, we have detected the melatonin MT(1) receptor in these cells. Given these findings and recent evidence that melatonin may play a role in cellular differentiation, we examined whether this indoleamine induces morphological and transcriptional changes suggestive of a neuronal phenotype in C17.2 cells. Moreover, in order to extend preliminary evidence of a potential role for melatonin in epigenetic modulation, its effects on the mRNA expression of several histone deacetylase (HDAC) isoforms and on histone acetylation were examined. Physiological concentrations of melatonin (nanomolar range) increased neurite-like extensions and induced mRNA expression of the neural stem cell marker, nestin, the early neuronal marker beta-III-tubulin and the orphan nuclear receptor nurr1 in C17.2 cells. The indoleamine also significantly increased mRNA expression for various HDAC isoforms, including HDAC3, HDAC5, and HDAC7. Importantly, treatment with melatonin for 24 hr caused a significant increase in histone H3 acetylation, which is associated with chromatin remodeling and gene transcription. Since the melatonin MT(2) receptor was not detected in C17.2 cells, it is likely that the MT(1) receptor is involved in mediating these physiological effects of melatonin. These findings suggest novel roles for melatonin in stem cell differentiation and epigenetic modulation of gene transcription.

Human beta-hexosaminidase A (Hex A) (alphabeta) is composed of two subunits whose primary structures are approximately 60% identical. Deficiency of either subunit results in severe neurological disease due to the storage of GM2 ganglioside; Tay-Sachs disease, alpha deficiency, and Sandhoff disease, beta deficiency. Whereas both subunits contain active sites only the alpha-site can efficiently bind negatively charged 6-sulfated hexosamine substrates and GM2 ganglioside. We have recently identified the alphaArg(424) as playing a critical role in the binding of 6-sulfate-containing substrates, and betaAsp(452) as actively inhibiting their binding. To determine if these same residues affect the binding of the sialic acid moiety of GM2 ganglioside, an alphaArg(424)Gln form of Hex A was expressed and its kinetics analyzed using the GM2 activator protein:[3H]-GM2 ganglioside complex as a substrate. The mutant showed a approximately 3-fold increase in its K(m) for the complex. Next a form of Hex B (betabeta) containing a double mutation, betaAspLeu(453)AsnArg (duplicating the alpha-aligning sequences), was expressed. As compared to the wild type (WT), the mutant exhibited a >30-fold increase in its ability to hydrolyze a 6-sulfated substrate and was now able to hydrolyze GM2 ganglioside when the GM2 activator protein was replaced by sodium taurocholate. Thus, this alpha-site is critical for binding both types of negatively charge substrates.

Background In order to optimize the potential benefits of neural stem cell (NSC) transplantation for the treatment of neurodegenerative disorders, it is necessary to understand their biological characteristics. Although neurotrophin transduction strategies are promising, alternative approaches such as the modulation of intrinsic neurotrophin expression by NSCs, could also be beneficial. Therefore, utilizing the C17.2 neural stem cell line, we have examined the expression of selected neurotrophic factors under different in vitro conditions. In view of recent evidence suggesting a role for the pineal hormone melatonin in vertebrate development, it was also of interest to determine whether its G protein-coupled MT1 and MT2 receptors are expressed in NSCs.

The 2014/15 influenza season in Canada has been characterised to date by early and intense activity dominated by influenza A(H3N2). A total of 99.0% (593/599) hospitalisations for laboratory-confirmed influenza with a known influenza virus type enrolled in sentinel hospitals of the Serious Outcomes Surveillance Network of the Canadian Immunization Research Network were due to influenza A. Of the 216 with a known subtype, influenza A(H3N2) accounted for 99.1% (n=214). Interim unmatched vaccine effectiveness (VE) estimates adjusted for age and presence of one or more medical comorbidities were determined by test-negative case-control design to be ?16.8% (90% confidence interval (CI): ?48.9 to 8.3) overall and ?22.0% (90% CI: ?66.5 to 10.7) for laboratory-confirmed influenza A(H3N2). Among adults?aged under?65 years, the overall VE was 10.8% (90% CI: ?50.2 to 47.0) while in adults?aged 65 years or older, the overall VE was ?25.4% (90% CI: ?65.0 to 4.6). .