Toxicity of non-abeta component of Alzheimer's disease amyloid, and N-terminal fragments thereof, correlates to formation of beta-sheet structure and fibrils.

Synucleins are small proteins that are highly expressed in brain tissue and are localised at presynaptic terminals in neurons. alpha-Synuclein has been identified as a component of intracellular fibrillar protein deposits in several neurodegenerative diseases, and two mutant forms of alpha-synuclein have been associated with autosomal-dominant Parkinson's Disease. A fragment of alpha-synuclein has also been identified as the non-Abeta component of Alzheimer's Disease amyloid. In this review we describe some structural properties of alpha-synuclein and the two mutant forms, as well as alpha-synuclein fragments, with particular emphasis on their ability to form beta-sheet on ageing and aggregate to form amyloid-like fibrils. Differences in the rates of aggregation and morphologies of the fibrils formed by alpha-synuclein and the two mutant proteins are highlighted. Interactions between alpha-synuclein and other proteins, especially those that are components of amyloid or Lewy bodies, are considered. The toxicity of alpha-synuclein and related peptides towards neurons is also discussing in relation to the aetiology of neurodegenerative diseases.

The validity of the MacNew Quality of Life Questionnaire in heart disease.

Background A previous review suggested that the MacNew Quality of Life Questionnaire was the most appropriate disease-specific measure of health-related quality of life among people with ischaemic heart disease. However, there is ambiguity about the allocation of items to the three factors underlying the MacNew and the factor structure has not been confirmed previously among the people in the UK. Methods The MacNew Questionnaire and the SF-36 were administered to 117 newly admitted patients to a tertiary referral centre in Northern Ireland. All patients had been diagnosed with ischaemic heart disease. Results A confirmatory factor analysis was conducted on the factor structure of the MacNew and the model was found to be an inadequate fit of the data. A quantitative and qualitative analysis of the items suggested that a five factor solution was more appropriate and this was validated by confirmatory factor analysis. This new structure also displayed strong evidence of concurrent validity when compared to the SF-36. Conclusion We recommend that researchers should submit scores obtained from items on the MacNew to secondary analyses after being grouped according to the factor structure proposed in this paper, in order to explore further the most appropriate grouping of items.

A comparative analysis of the SF-12 and the SF-36 among ischaemic heart disease patients.

This paper investigated whether the SF-12 could replace the SF-36 in the measurement of health status among ischaemic heart disease patients. The SF-36 and SF-12 were administered to 105 cardiac patients. The SF-36 summary scores were strongly correlated and similar to the SF-12 summary scores. Also, the SF-12 scores were as powerful as the SF-36 summary scores in discriminating between subgroups of patients categorized according to their self-reported health status or angina classification. It is suggested that when there is a need to collect routine information about cardiac patients' general physical and mental health, the SF-12 is preferable to the SF-36 because of its brevity and acceptability to patients.

Measuring the health-related quality of life of people with ischaemic heart disease.

Objectives—To inform researchers and clinicians about the most appropriate generic and disease specific measures of health related quality of life for use among people with ischaemic heart disease. Methods—MEDLINE and BIDS were searched for research papers which contained a report of at least one of the three most common generic instruments or at least one of the five disease specific instruments used with ischaemic heart disease patients. Evidence for the validity, reliability, and sensitivity of these instruments was critically appraised. Results—Of the three generic measures—the Nottingham health profile, sickness impact profile, and short form 36 (SF-36)—the SF-36 appears to offer the most reliable, valid, and sensitive assessment of quality of life. However, a few of the SF-36 subscales lack a sufficient degree of sensitivity to detect change in a patient’s clinical condition. According to the best available evidence, the quality of life after myocardial infarction questionnaire should be preferred to the Seattle angina questionnaire, the quality of life index cardiac version, the angina pectoris quality of life questionnaire, and the summary index. Overall, research on disease specific measures is sparse compared to the number of studies which have investigated generic measures. Conclusions—An assessment of the quality of life of people with ischaemic heart disease should comprise a disease specific measure in addition to a generic measure. The SF-36 and the quality of life after myocardial infarction questionnaire (version 2) are the most appropriate currently available generic and disease specific measures of health related quality of life, respectively. Further research into the measurement of health related quality of life of people with ischaemic heart disease is required in order to address the problems (such as lack of sensitivity to detect change) identified by the review.

The adaptations of a quality of life questionnaire for routine use in clinical practice: the Chronic Respiratory Disease Questionnaire in Cystic Fibrosis.

The assessment of quality of life (QOL) is necessary to monitor the course of disease and to assess the effect of new and existing interventions in clinical practice. This will only be achieved if QOL can be measured accurately and routinely. The aim of this study was to demonstrate the methodology involved in the adaptation and shortening of the Chronic Respiratory Disease Questionnaire (CRDQ) in a population of adults with cystic fibrosis (CF). A single interviewer administered the CRDQ to a sample of 45 adult patients (32 males) with CF prior to assessment of spirometric measures of lung function. Those patients whose lung function was stable at the time of study, and who could attend for a retest within 14 days, were asked to complete the questionnaire at a subsequent visit (n=10). The average interval between visits was 7 days (range 5-14 days). Correlations between spirometry and CRDQ dimensions ranged from -0.003 to 0.426. The fatigue, emotion and mastery dimensions showed high internal consistency, and adequate construct validity. In the small number of patients suitable for retest, the results indicated that the dimensions exhibited adequate test retest reliability. In contrast low internal consistency was demonstrated for the dyspnoea dimension. The fatigue, emotion and mastery dimensions could be reduced, in terms of their number of items without a substantial loss in explanatory power. This study suggests that QOL measurement can be made convenient, and so more easily accessible for routine clinical assessment.

Generic, disease-specific and individualised approaches to measuring health-related quality of life among people with heart disease - a comparative analysis.

Increasing emphasis is being placed on the evaluation of health-related quality of life. However, there is no consensus on the definition of this concept and as a result there are a plethora of existing measurement instruments. Head-to-head comparisons of the psychometric properties of existing instruments are necessary to facilitate evidence-based decisions about which instrument should be chosen for routine use. Therefore, an individualised instrument (the modified Patient Generated Index), a generic instrument (the Short Form 36) and a disease-specific instrument (the Quality of Life after Myocardial Infarction questionnaire) were administered to patients with ischaemic heart disease (n=117) and the evidence for the validity, reliability and sensitivity of each instrument was examined and compared. The modified Patient Generated Index compared favourably with the other instruments but none of the instruments examined provided sound evidence for sensitivity to change. Therefore, any recommendation for the use of the individualised approach in the routine collection of health-related quality of life data in clinical practice must be conditional upon the submission of further evidence to support the sensitivity of such instruments.

Family-based investigation of the C677T polymorphism of the methylenetetrahydrofolate reductase gene in ischaemic heart disease

Background: Elevated homocysteine is associated with ischaemic heart disease (IHD). The C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene results in reduced MTHFR enzyme activity and reduced methylation of homocysteine to methionine resulting in mild hyperhomocysteinaemia. Case-control association studies of the role of the C677T MTHFR polymorphism in IHD have produced conflicting results. We therefore used newly described family-based association tests to investigate the role of this polymorphism in IHD, in a well-defined population. Methods: A total of 352 individuals from 129 families (discordant sibships and parent-child trios) were recruited. Linkage disequilibrium between the polymorphism and IHD was tested for using the combined transmission disequilibrium test (TDT)/sib-TDT and pedigree disequilibrium test (PDT). Homocysteine levels were measured. Results: Both the TDT/sib-TDT and PDT analyses found a significantly reduced transmission of the T allele to affected individuals (P=0.016 and P=0.021). There was no significant difference in homocysteine levels between affected and unaffected siblings. TT homozygotes had mean homocysteine levels significantly higher than those of TC heterozygotes (P

Lack of association between the-2518G/A polymorphism of the MCP-1 gene and ischaemic heart disease: a family-based investigation

Using two recently described family-based tests of association, the possible role of the functional -2518G/A polymorphism in the promoter region of the monocyte chemoattractant protein-1 (MCP-1) gene in the susceptibility to ischaemic heart disease (IHD) was investigated in a well-defined Irish population. One thousand and twelve individuals from 386 families with at least one member prematurely affected with M were, genotyped for the MCP-1 -2518G/A polymorphism. Using the combined transmission disequilibriurn test and the pedigree disequilibriurn test, no association between the MCP-1 -2518G/A polymorphism and M was found. g Our data demonstrate that, in an Irish population, the MCP-1 -2518G/A polymorphism is not strongly associated with M.