A simple method for the induction of high levels of tyrosinase activity

A simple method for the induction of high levels of tyrosinase activit

Patients' experiences of deep brain stimulation for Parkinson's disease: a qualitative systematic review and synthesis.

Published onlineJournal ArticleThis is the final version of the article. Available from BMJ Publishing Group via the DOI in this record.OBJECTIVE: To review and synthesise qualitative research studies that have explored patients' experience of deep brain stimulation (DBS) in advanced Parkinson's disease (PD). DESIGN: Systematic review and meta-synthesis of 7 original papers, using metaethnography. SETTING: Studies conducted in Denmark, France and Sweden. PARTICIPANTS: 116 patients who had undergone DBS and 9 spouses of patients. RESULTS: Prior to surgery, the experience of advancing PD is one of considerable loss and a feeling of loss of control. There are significant hopes for what DBS can bring. Following surgery, a sense of euphoria is described by many, although this does not persist and there is a need for significant transitions following this. We suggest that normality as a concept is core to the experience of DBS and that a sense of control may be a key condition for normality. Experience of DBS for patients and spouses, and of the transitions that they must undertake, is influenced by their hopes of what surgery will enable them to achieve, or regain (ie, a new normality). CONCLUSIONS: There is a need for further qualitative research to understand the nature of these transitions to inform how best patients and their spouses can be supported by healthcare professionals before, during and after DBS. In assessing the outcomes of DBS and other treatments in advanced PD, we should consider how to capture holistic concepts such as normality and control. Studies that examine the outcomes of DBS require longer term follow-up.This work was part funded by the Medical Research Council Midland Hub for Trials Methodology Research (Grant Number: G0800808). RG is partially supported by the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care (CLAHRC) for the South West Peninsula (PenCLAHRC)

A practical method for optimum seismic design of friction wall dampers

Friction control systems have been widely used as one of the efficient and cost effective solutions to control structural damage during strong earthquakes. However, the height-wise distribution of slip loads can significantly affect the seismic performance of the strengthened frames. In this study, a practical design methodology is developed for more efficient design of friction wall dampers by performing extensive nonlinear dynamic analyses on 3, 5, 10, 15, and 20-story RC frames subjected to seven spectrum-compatible design earthquakes and five different slip load distribution patterns. The results show that a uniform cumulative distribution can provide considerably higher energy dissipation capacity than the commonly used uniform slip load pattern. It is also proved that for a set of design earthquakes, there is an optimum range for slip loads that is a function of number of stories. Based on the results of this study, an empirical equation is proposed to calculate a more efficient slip load distribution of friction wall dampers for practical applications. The efficiency of the proposed method is demonstrated through several design examples

Peroxisome Proliferator-Activated Receptor alpha (PPAR alpha) down-regulation in cystic fibrosis lymphocytes

Background: PPARs exhibit anti-inflammatory capacities and are potential modulators of the inflammatory response. We hypothesized that their expression and/or function may be altered in cystic fibrosis (CF), a disorder characterized by an excessive host inflammatory response. Methods: PPARα, β and γ mRNA levels were measured in peripheral blood cells of CF patients and healthy subjects via RT-PCR. PPARα protein expression and subcellular localization was determined via western blot and immunofluorescence, respectively. The activity of PPARα was analyzed by gel shift assay. Results: In lymphocytes, the expression of PPARα mRNA, but not of PPARβ, was reduced (-37%; p < 0.002) in CF patients compared with healthy persons and was therefore further analyzed. A similar reduction of PPARα was observed at protein level (-26%; p < 0.05). The transcription factor was mainly expressed in the cytosol of lymphocytes, with low expression in the nucleus. Moreover, DNA binding activity of the transcription factor was 36% less in lymphocytes of patients (p < 0.01). For PPARα and PPARβ mRNA expression in monocytes and neutrophils, no significant differences were observed between CF patients and healthy persons. In all cells, PPARγ mRNA levels were below the detection limit. Conclusion: Lymphocytes are important regulators of the inflammatory response by releasing cytokines and antibodies. The diminished lymphocytic expression and activity of PPARα may therefore contribute to the inflammatory processes that are observed in CF

Enhanced mechanical and thermal strength in mixed enantiomers based supramolecular gel

Mixing supramolecular gels based on enantiomers leads to re-arrangement of gel fibers at the molecular level, which results in more favorable packing and tuneable properties. Bis(urea) compounds tagged with a phenylalanine methyl ester in racemic and enantiopure forms were syn-thesized. Both enantiopure and racemate compounds formed gels in a wide range of solvents and the racemate (1-rac) formed a stronger gel network compared to the enantiomers. The gel (1R+1S) obtained by mixing equimolar amount of enantiomers (1R and 1S) showed enhanced mechanical and thermal stability compared to enantiomers and racemate gels. The preservation of chirality in these compounds was analyzed by circular dichroism and optical rotation measurements. Analysis of the SEM and AFM images revealed that the network in the mixed gel is a combination of enantiomers and racemate fibers, which was further supported by solid state NMR. The analysis of the packing in xerogels by solid state NMR spectra and the existence of twisted-tape morphology in SEM and AFM images confirmed the presence of both self-sorted and co-assembled fibers in mixed gel. The enhanced thermal and mechanical strength may be attributed to the enhanced intermolecular forces between the racemate and enantiomer and the combination of both self-sorted and co-assembled enantiomers in the mixed gel.We thank University of Iceland Research Fund for financial support. D.G. thanks University of Iceland for the Doctoral Research grant and Z.K. thanks University of Ljubljana for the Erasmus exchange program. We thankfully acknowledge Dr. A. Rawal, The Mark Wainwright Analytical Centre, UNSW for solid state NMR studies and Dr. Sigrídur Jónsdóttir, University of Iceland for solution NMR and Mass spectroscopy. P.T. thanks the Australian Research Council for an ARC Centre of Excellence grant (CE140100036) and A.D.M. thanks the National Health and Medical Research Council for a Dementia Development Research Fellowship (APP1106751). L.F. and A.V. thank the FCT (UID/BIO/04469/2013), COMPETE 2020 (POCI-01-0145-FEDER-006684), and Norte2020 Programa Operacional Regional do Norte (BioTecNorte operation, NORTE-01-0145-FEDER-000004) for rheological studies. The rheological study was supported by a STSM Grant from COST Action CM1402 Crystallize.info:eu-repo/semantics/publishedVersio

Alignment of European Regulatory and Health Technology Assessments: A Review of Licensed Products for Alzheimer's Disease

Aims: To facilitate regulatory learning, we evaluated similarities and differences in evidence requirements between regulatory and health technology assessment (HTA) bodies of Alzheimer's disease (AD) approved products.Methods: The European marketing authorisation application dossiers and European public assessment reports (EPARs) of the licensed AD drugs were screened to identify the phase III randomised controlled trials (RCTs) and outcomes used. We also screened the assessment reports of the National Institute of Health and Care Excellence (NICE, England) and the National Health Care Institute (ZiN, the Netherlands) to identify the studies and outcomes used in HTA assessments.Results: The application dossiers of donepezil, galantamine, rivastigmine, and memantine contained 16 phase III RCTs in total. These trials were also included in HTA assessments except that NICE excluded studies that were not published (n = 2) or trials that included patients with other types of dementia (n = 3). In the regulatory assessments the focus was on cognitive and global outcomes, and to some extent on function. In the HTA assessments of clinical effectiveness other domains were also covered including: function, behaviour and mood, and, occasionally, quality of life. In the economic analyses of NICE the domains cognition, function, and quality of life were included.Conclusion: There was a large overlap in inclusion of trials in regulatory and HTA assessments, although the focus on specific outcomes slightly differed. Understanding the methods and perceptions of both authorities can stimulate regulatory and HTA cross-talk and further alignment, and therefore more rapid patient access to new treatments

Large-scale pathways-based association study in amyotrophic lateral sclerosis

Sporadic amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease, most likely results from complex genetic and environmental interactions. Although a number of association studies have been performed in an effort to find genetic components of sporadic ALS, most of them resulted in inconsistent findings due to a small number of genes investigated in relatively small sample sizes, while the replication of results was rarely attempted. Defects in retrograde axonal transport, vesicle trafficking and xenobiotic metabolism have been implicated in neurodegeneration and motor neuron death both in human disease and animal models. To assess the role of common genetic variation in these pathways in susceptibility to sporadic ALS, we performed a pathway-based candidate gene case-control association study with replication. Furthermore, we determined reliability of whole genome amplified DNA in a large-scale association study. In the first stage of the study, 1277 putative functional and tagging SNPs in 134 genes spanning 8.7 Mb were genotyped in 822 British sporadic ALS patients and 872 controls using whole genome amplified DNA. To detect variants with modest effect size and discriminate among false positive findings 19 SNPs showing a trend of association in the initial screen were genotyped in a replication sample of 580 German sporadic ALS patients and 361 controls. We did not detect strong evidence of association with any of the genes investigated in the discovery sample (lowest uncorrected P-value 0.00037, lowest permutation corrected P-value 0.353). None of the suggestive associations was replicated in a second sample, further excluding variants with moderate effect size. We conclude that common variation in the investigated pathways is unlikely to have a major effect on susceptibility to sporadic ALS. The genotyping efficiency was only slightly decreased (∼1%) and genotyping quality was not affected using whole genome amplified DNA. It is reliable for large scale genotyping studies of diseases such as ALS, where DNA sample collections are limited because of low disease prevalence and short survival time. © 2007 The Author(s)