Challenges in detecting disease modification in Parkinson's disease clinical trials.

Despite the wealth of encouraging data from numerous compounds that demonstrate "neuroprotection" in pre-clinical studies of Parkinson's disease, and despite numerous clinical trials, to date, no intervention has been demonstrated to able to modify the course of disease progression. While this "failure to translate" is likely due to numerous factors including our incomplete understanding of the pathogenic mechanisms underlying PD together with excessive reliance on data from the toxin-based animal models of PD, here we will discuss the "structural issues" pertaining to inadequate clinical trial design, selection of inappropriate endpoints and poor patient selection which are often not addressed following failed disease modification trials. Future directions to overcome these challenges such as reducing the heterogeneity of patient cohorts, identifying and utilising a pre-diagnostic population, embracing a personalised medicine approach and utilising novel trial designs may be required to ultimately fulfil the goal of conclusively demonstrating evidence of disease modification

The glucagon-like peptide 1 (GLP) receptor as a therapeutic target in Parkinson's disease: mechanisms of action

Growing evidence suggests that agonists of the glucagon-like peptide 1 (GLP-1) receptor provide neuroprotection across a range of experimental models of Parkinson's disease (PD) and, recently, a small proof-of-concept, open-label human trial of exenatide in the treatment moderate severity PD appeared to show persistent improvements in motor and cognitive function. The underlying mechanisms of action remain unclear, but as evidence for the potential use of GLP-1 agonists in treating several neurodegenerative disease mounts, and with several clinical trials of GLP-1 analogues in PD and Alzheimer's disease (AD) currently underway, here we review the molecular mechanisms underlying the neuroprotective effects of GLP-1 analogues in the laboratory and their potential therapeutic utility with particular relevance to PD and PD dementia (PDD)

Insulin resistance and Parkinson's disease: A new target for disease modification?

There is growing evidence that patients with Type 2 diabetes have an increased risk of developing Parkinson's disease and share similar dysregulated pathways suggesting common underlying pathological mechanisms. Historically insulin was thought solely to be a peripherally acting hormone responsible for glucose homeostasis and energy metabolism. However accumulating evidence indicates insulin can cross the blood-brain-barrier and influence a multitude of processes in the brain including regulating neuronal survival and growth, dopaminergic transmission, maintenance of synapses and pathways involved in cognition. In conjunction, there is growing evidence that a process analogous to peripheral insulin resistance occurs in the brains of Parkinson's disease patients, even in those without diabetes. This raises the possibility that defective insulin signalling pathways may contribute to the development of the pathological features of Parkinson's disease, and thereby suggests that the insulin signalling pathway may potentially be a novel target for disease modification. Given these growing links between PD and Type 2 diabetes it is perhaps not unsurprising that drugs used the treatment of T2DM are amongst the most promising treatments currently being prioritised for repositioning as possible novel treatments for PD and several clinical trials are under way. In this review, we will examine the underlying cellular links between insulin resistance and the pathogenesis of PD and then we will assess current and future pharmacological strategies being developed to restore neuronal insulin signalling as a potential strategy for slowing neurodegeneration in Parkinson's disease

Advances in Molecular Subclassification of Colorectal Cancer

This chapter will highlight the advances made in our understanding of the molecular landscape of colorectal cancer (CRC) via the development of molecular subclassification systems and their potential predictive and prognostic utility. Firstly, the comprehensive integrative analysis of 224 colorectal cancer samples performed by The Cancer Genome Atlas (TCGA) Research Network will be described highlighting the potential therapeutic targets identified. The development of molecular subclassification systems primarily via gene expression profile analysis by independent groups will also be described, and their potential clinical and prognostic associations will also be discussed. The chapter will then go on to describe the four consensus molecular subtypes of colorectal cancer which were proposed by an international consortium who applied unsupervised clustering techniques to the independent classification systems previously described. The clinical and prognostic associations of these four subtypes have been explored, and these findings will be discussed. Finally, the utility of molecular subclassification in colorectal cancer will be briefly explored

Does worker alcohol addiction directly influence the productivity of tea plantation workers of Sri Lanka?

The Sri Lankan tea industry plays a major role in contributing significant amount to government revenue as well as gross domestic product of Sri Lanka. The quality and the undeniable flavor of Sri Lankan tea had been able to attract more markets though the prices of Sri Lankan tea are higher compared to the other nations. Today Sri Lanka shows the signs of reaping competitive disadvantages due to low labor productivity and high cost of production. Alcohol addiction has not still taken into account as a major problem, even though it is a social problem which is exists highly in plantation sector. This paper examines the association between alcohol addiction and labour productivity. The information on worker socio economic background and alcohol consumption of workers was collected using a pre-tested questionnaire. Data collected from 60 workers of tea plantations were analysed using Chi-square test to see the association between alcohol addictions, labour productivity and socio economic factors. The results revealed that among the socio-economic factors, sex and excess money has an impact on alcohol addiction. There is no direct association between alcohol addiction and labour productivity. Highly effective factor that reduces the overall productivity of the plantations was identifies as alcohol related absenteeism. It also shown that the over expense on alcohol consumption would influence workers to out migrate from estates and they consider alcohol as a basic need of their lives and as a motivator

A distributed secure mechanism for resource protection in a digital ecosystem environment

The dynamic interaction and collaboration of the loosely coupled entities play a pivotal role for the successful implementation of a Digital Ecosystem environment. However, such interaction and collaboration can only be promoted when information and resources are effortlessly shared, accessed, and utilized by the interacting entities. A major requirement to promote an intensive sharing of resources is the ability to secure and uphold the confidentiality, integrity and non-repudiation of resources. This requirement is extremely important in particular when interactions with the unfamiliar entities occur frequently. In this paper, we present a distributed mechanism for improving resource protection in a Digital Ecosystem environment. This mechanism can be used not only for any secure and reliable transaction, but also for encouraging the collaborative efforts by the Digital Ecosystem community members to play a major role in securing the environment. Public Key Infrastructure is also employed to provide a strong protection for its access workflows

Designing User Interfaces for the Elderly: A Systematic Literature Review

This paper discusses the issues of implied trust in ethical hacking. Ethical hackers are considered to be professionals and experts in their field. It is well documented that there is an implied trust toward professionals who are entrusted to undertake a task. Like many similar professions, such as ICT and computer forensics, there is no uniform or mandated code of ethics that an ethical hacker must adhere to. Given the nature of hacking and the potential for misuse and access to sensitive and confidential information, the need to ensure professionalism is maintained through ensuring competence and ethical behaviour is critical

Data Mining Applications: Promise and Challenges

Data mining is an emerging field gaining acceptance in research and industry. This is evidenced by an increasing number of research publications, conferences, journals and industry initiatives focused in this field in the recent past. Data mining aims to solve an intricate problem faced by a number of application domains today with the deluge of data that exists and is continually collected, typically, in large electronic databases. That is, to extract useful, meaningful knowledge from these vast data sets. Human analytical capabilities are limited, especially in its ability to analyse large and complex data sets. Data mining provides a number of tools and techniques that enables analysis of such data sets. Data mining incorporates techniques from a number of fields including statistics, machine learning, database management, artificial intelligence, pattern recognition, and data visualisation