A novel pathway of levodopa metabolism by commensal Bifidobacteria.

The gold-standard treatment for Parkinson's disease is levodopa (L-DOPA), which is taken orally and absorbed intestinally. L-DOPA must reach the brain intact to exert its clinical effect; peripheral metabolism by host and microbial enzymes is a clinical management issue. The gut microbiota is altered in PD, with one consistent and unexplained observation being an increase in Bifidobacterium abundance among patients. Recently, certain Bifidobacterium species were shown to have the ability to metabolize L-tyrosine, an L-DOPA structural analog. Using both clinical cohort data and in vitro experimentation, we investigated the potential for commensal Bifidobacteria to metabolize this drug. In PD patients, Bifidobacterium abundance was positively correlated with L-DOPA dose and negatively with serum tyrosine concentration. In vitro experiments revealed that certain species, including B. bifidum, B. breve, and B. longum, were able to metabolize this drug via deamination followed by reduction to the compound 3,4-dihydroxyphenyl lactic acid (DHPLA) using existing tyrosine-metabolising genes. DHPLA appears to be a waste product generated during regeneration of NAD +. This metabolism occurs at low levels in rich medium, but is significantly upregulated in nutrient-limited minimal medium. Discovery of this novel metabolism of L-DOPA to DHPLA by a common commensal may help inform medication management in PD.

Perception of the risks of smoking in the general population and among general practitioners in Ireland.

BACKGROUND: Data on perception of smoking risk amongst the Irish population are sparse. AIMS: To study the accuracy and determinants of the perceived risk of premature death due to smoking in the general population and amongst general practitioners (GPs). METHODS: Telephone surveys of a representative sample of Irish adults (1,247) and GPs (171; 85% response rate) asked participants to estimate how many of 1,000 20-year-old life-long smokers would die from smoking-related disease before the age of 70 and to identify the main cause of death from a list of seven causes: smoking, road traffic accidents, accidents at work, AIDS, homicide, illicit drugs and alcohol misuse. RESULTS: In the population and GP samples, perception of the risk of smoking-related death was similar (median 200 and 150 deaths per 1,000 smokers respectively, epidemiological estimates 250/1000). Only 43% of the population identified smoking as the most important cause of death compared with 87% of GPs. Current smoking status, younger age, female gender, lower educational attainment and lower income were associated with failure to identify smoking as the main cause of death. CONCLUSION: Despite decades of health promotion, the general public underestimates the relative importance of smoking as a cause of death.

Established cardiovascular disease and CVD risk factors in a primary care population of middle-aged Irish men and women.

Contemporary Irish data on the prevalence of major cardiovascular disease (CVD) risk factors are sparse. The primary aims of this study were (1) to estimate the prevalence of major cardiovascular disease risk factors, including Type 2 Diabetes Mellitus, in the general population of men and women between the ages of 50 and 69 years; and (2) to estimate the proportion of individuals in this age group at high absolute risk of cardiovascular disease events on the basis of pre-existing cardiovascular disease or as defined by the Framingham equation. Participants were drawn from the practice lists of 17 general practices in Cork and Kerry using stratified random sampling. A total of 1018 people attended for screening (490 men, 48%) from 1473 who were invited, a response rate of 69.1%. Cardiovascular disease risk factors and glucose intolerance are common in the population of men and women aged between 50 and 69 years. Almost half the participants were overweight and a further quarter met current international criteria for obesity, one of the highest recorded prevalence rates for obesity in a European population sample. Forty per cent of the population reported minimal levels of physical activity and 19% were current cigarette smokers. Approximately half the sample had blood pressure readings consistent with international criteria for the diagnosis of hypertension, but only 38% of these individuals were known to be hypertensive. Eighty per cent of the population sample had a cholesterol concentration in excess of 5 mmol/l. Almost 4% of the population had Type 2 Diabetes Mellitus, of whom 30% were previously undiagnosed. A total of 137 participants (13.5%) had a history or ECG findings consistent with established cardiovascular disease. Of the remaining 881 individuals in the primary prevention population, a total of 20 high-risk individuals (19 male) had a risk of a coronary heart disease event > or = 30% over ten years according to the Framingham risk equation, giving an overall population prevalence of 2.0% (95% CI 1.3 - 3.0). At a risk level > or = 20% over ten years, an additional 91 individuals (8.9%) were identified. Thus a total of 24.4% of the population were at risk either through pre-existing CVD (13.5%) or an estimated 10-year risk exceeding 20% according to the Framingham risk equation (10.9%). Thus a substantial proportion of middle-aged men are at high risk of CVD. The findings emphasise the scale of the CVD epidemic in Ireland and the need for ongoing monitoring of risk factors at the population level and the need to develop preventive strategies at both the clinical and societal level.

Ecological correlates of motor neuron disease mortality: a hypothesis concerning an epidemiological association with radon gas and gamma exposure.

This study investigates variations in motor neuron disease (MND) mortality rates between the counties of England and Wales from 1981 to 1989, and their relationship with gamma-ray dose rates, indoor radon gas concentrations and enhanced general life expectancy. A strong correlation was confirmed between age-adjusted rates of MND mortality and life expectancy. Weaker, but statistically significant, associations were observed between indoor radon gas concentrations, terrestrial gamma radiation and marginal variations in MND mortality. Life expectancy and radon gas concentrations were positively associated with MND mortality rates whilst gamma radiation was negatively associated. The negative correlation of gamma radiation with MND mortality may be understood with reference to its negative effects on overall population life expectancy. Radon gas concentrations seemingly account for a small elevation in MND mortality, amounting to at most 4% of total deaths. Further research is required to investigate this association.

Decline and rise of mortality from motor neuron disease in Spain, 1960-1989: demographic, environmental and competitive influences.

Mortality rates from motor neuron disease (MND) in Spain were analysed for the years 1960-1989, a period in which 3,530 deaths were recorded from the disease and during which the crude annual mortality rate ranged between 0.35 and 0.95 deaths per 100,000 persons. Whilst the crude mortality rate fell by 54% during the decade 1960-1969, there was a net increase of 26% over the entire period. The influence of three sets of variables-the increasing mean age of the population, changing environmental factors, and changing competition between diseases-upon mortality rates were investigated through Gompertzian analysis of crude and age-adjusted mortality rates. The increased mean age of the population contributed significantly to the overall rise in mortality from MND over the whole period, a feature that has previously been demonstrated to occur in the majority of industrialised countries. The unusual pattern of a decline and subsequent rise in mortality appears to be due to the influence of changing environmental factors on a sub-population susceptible to the disease.

Mortality from motor neuron disease in Japan, 1950-1990: association with radioactive fallout from atmospheric weapons testing.

Motor neuron disease (MND) is a progressive and invariably fatal disease affecting the nuclei of the pyramidal tract and anterior horn cells. Despite intensive research into environmental agents associated with the onset or course of the disease, there is no single factor that can be confidently linked over time with regional, national or international variations in mortality rates. However, unusual variations in MND mortality rate in Japan from 1950-1990 were found to correlate highly significantly with variations in radioactive fallout released by atmospheric weapons testing in the Pacific. This association could be explained by the ingestion of alpha-emitting radionuclides acting upon a pre-existing susceptible subpopulation, a hypothesis which is consistent with recent research on the epidemiology and pathology of MND. However, it is likely that radiation is only one of many factors that act singly or in combination to accelerate the condition in subpopulations susceptible to MND.

Rising mortality from motor neurone disease in Sweden 1961-1990: the relative role of increased population life expectancy and environmental factors.

Recent studies of mortality from motor neurone disease (MND) in Sweden have demonstrated rising levels of mortality from the disease, especially amongst older age groups. Case-control investigations have suggested that certain environmental factors are significantly related to variations in mortality from the disease, and are associated with a probable individual susceptibility to MND. This study applies an innovative epidemiological technique to longitudinal and cohort analysis of Swedish mortality from MND during the period 1961 to 1990. Survival modelling shows that a subpopulation susceptible to MND exists in Sweden, as has been demonstrated in other countries. The increased life expectancy of the Swedish population since 1961 has resulted in more of that susceptible population living to the ages at which MND is expressed, explaining the majority of the increase in mortality from the disease. However, environmental factors may play a role in accelerating the course of MND and may affect the timing of death within the susceptible sub-population.

Rising amyotrophic lateral sclerosis mortality in France 1968-1990: increased life expectancy and inter-disease competition as an explanation.

Gompertzian analysis is a statistical technique which has been successfully applied to the analysis of amyotrophic lateral sclerosis (ALS) mortality in England and Wales, Japan and the United States. This paper analyses the consistent trend of rising ALS mortality in France over the years 1968-1990, a period during which crude mortality rose from 400 deaths in 1968 to 950 deaths in 1990. The findings indicate that age-specific mortality rates have risen at ages older than 54 years for men and 53 years for women and decreased slightly at younger ages. The evolving ALS mortality pattern is attributable to changing inter-disease competition resulting from the increased life expectancy of the French population, rather than to changing environmental aetiopathogenic factors or to substantial artefact effects.

Longitudinal analysis of amyotrophic lateral sclerosis mortality in Norway, 1966-1989: evidence for a susceptible subpopulation.

Mortality from amyotrophic lateral sclerosis (ALS) in Norway has increased substantially over the last two or three decades, as it has in other Western nations. The reasons for this general increase are not clear, but the rise has been attributed to increasing exposure to a broad range of environmental agents. Our previous research has indicated that another explanation for the substantial rise in ALS mortality is more likely to be valid. In particular, the mortality rate curve for ALS is consistent with deaths being confined to an inherently susceptible subpopulation. The size of susceptible subpopulations and mortality rates within them have been shown to be consistent in England and Wales, Japan and the United States. The same methods have been used to analyse Norwegian mortality data. The analysis demonstrates that the rise in ALS mortality is real and that the cause of the increase is almost entirely attributable to the increasing life expectancy of the Norwegian population. Increased life expectancy, a consequence of decreasing general mortality, allows ALS susceptible individuals to survive to the ages at which ALS is expressed. As in other national populations, it is expected that mortality from the disease will continue to increase with continuing increases in life expectancy.

Reinterpreting mortality statistics: some uses of Gompertzian analysis in epidemiological research.

Gompertzian analyses of mortality data have recently been undertaken for a number of individual conditions (Riggs JE. Mech Ageing Dev 1990; 55: 207-220 [1]; Neilson S et al. Mech Ageing Dev 1992; 64: 201-216 [2]; Neilson S et al. Acta Neurol Scand 1993; 87: 184-191 [3]). Such analyses are in principle of particular epidemiological value in circumstances where demographic change is occurring and where the balance between mortality from different conditions is subject to change. However, the extent to which a Gompertzian relationship between age and mortality holds for particular conditions has been subject to debate. In this analysis it is demonstrated that even some conditions which do not superficially hold to a Gompertz relationship do in fact do so, if such conditions are considered to be restricted to small, inherently susceptible subpopulations. By analysing mortality from a range of neurological conditions within the context of general mortality in England and Wales, conditions with different aetiologies such as Huntington's chorea, amyotrophic lateral sclerosis and multiple sclerosis can be shown to have a Gompertzian mortality rate distribution. Such analyses are of substantial value in indicating how demographic change affects the balance of mortality between conditions, as well as directing interest to revised aetiological possibilities.

The functional and psychological status of patients with amyotrophic lateral sclerosis: some implications for rehabilitation.

Amyotrophic lateral sclerosis (ALS), known as motor neurone disease (MND) in Britain, poses special problems in rehabilitation by virtue of its nature, trajectory and the age of patients with the disease. Many practical difficulties of ALS are well known, but there has been little research on the psychological parameters of the disease. This study of 181 ALS patients, from a national register in England and Wales, indicates that, contrary to some previous research, psychological distress (measured by the General Health Questionnaire) is widespread among patients at all stages of the disease. Severity of functional impairment is significantly related to psychological distress, but explains only a small part of the variance. Rehabilitation in relation to ALS must take account of the high incidence of psychological difficulties, as well as the considerable functional problems associated with the disease.

A new analysis of mortality from motor neurone disease in Japan, 1950-1990: rise and fall in the postwar years.

Recent studies have demonstrated a worldwide rise in mortality from motor neurone disease (MND). However, in Japan mortality appears to have fallen significantly since the late 1960s, especially amongst women. Studies of the cause of both the worldwide rise, and the unique decline in MND mortality in Japan, have largely failed to substantiate the role of any single factor, or group of factors in these phenomena. Modelling the relationship between age and mortality using gompertzian analysis has already shown that the rise in MND mortality in England and Wales, and the United States, is mainly the result of increased longevity and decreasing competition from other causes of death amongst a susceptible subpopulation. Employing the same techniques on Japanese mortality data from 1950 to 1990 demonstrates that an unusual and accelerated increase of mortality occurred in the 1950s and 1960s, probably caused by an earlier unknown but extremely potent environmental agent or agents. This premature depletion of the susceptible subpopulation resulted subsequently in a lower than expected mortality rate. Mortality is now rising slowly to expected levels as the size of the susceptible subpopulation recovers to reach the ages at which MND is normally expressed. Further substantial rises in mortality are anticipated in future decades.

Cross-sectional Gompertzian analysis: the development of a Gompertz mortality ratio (GMR) and its applicability.

Many conventional epidemiological analyses of the distribution and aetiology of disease employ standardised mortality ratios (SMRs) as a basis upon which to evaluate comparative studies of disease in populations. However SMRs, whilst constructed to control for age and sex, are not capable of incorporating other variables such as life expectancy which has been demonstrated to be of crucial importance in understanding the changing relationships between mortality from different causes. The development of a Gompertz mortality ratio (GMR) and its application to recent mortality from amyotrophic lateral sclerosis (ALS) in the Counties of England and Wales illustrates the value of substituting GMRs for SMRs in the analysis of competitive relationships between conditions, especially those associated with enhanced life expectancy.

Rising mortality from motor neurone disease: an explanation.

There is considerable debate about the increasing mortality from motor neurone disease (MND). However, examination of the relationship between increased life expectancy (through decreased general mortality) and increased mortality in both England and Wales and the United States indicates a close association between the two variables. Using a statistical model, defined sub-populations susceptible to MND can be identified in both countries. The size of such a sub-population has been estimated from the 1989 mortality data to be approximately 160,000 people in England and Wales. The proportion of this sub-population dying from MND has increased over the last 30 years, rather than, as previously, dying at an earlier age from other conditions. On this basis, deaths from MND are expected to increase by a further 20% in this sub-population between 1991-2021 because of continuing changes in life expectancy. MND is a condition made increasingly visible in mortality statistics through decreased general mortality, rather than one in which the underlying population at risk has substantially changed. Aetiological extrapolations from the data indicate that susceptibility to the disease is acquired early in life, and that it is unlikely, given the relative stability of the underlying sub-population, that either changed environmental circumstances or artifactual factors can account in themselves for the rise in mortality.

Static and dynamic models of interdisease competition: past and projected mortality from amyotrophic lateral sclerosis and multiple sclerosis.

Longitudinal Gompertzian analysis is an effective method for determining both the pure probability of death for a given condition and the size of inherently susceptible subpopulations [1]. Gompertzian analysis has been used in this study to provide the parameters necessary to construct a stationary population lifetable (static model) of mortality for amyotrophic lateral sclerosis (ALS) and for multiple sclerosis (MS). The static model demonstrates the relative effect of changing general mortality upon the mortality from each specific disease in a situation where interdisease competition is continuously changing. In order to represent mortality in a real population more closely (where age structure is not the result of mortality rates alone) a dynamic model was constructed for both conditions using the age distributions of the population of England and Wales. The quality of the model was verified by comparison of estimated mortality with historical data from the last three decades. The dynamic model has then been used to estimate mortality from each condition over the next three decades on the basis of population projections made by the Central Statistical Office [2], assuming no major change in the factors which lead to either condition. This analysis demonstrates both the theoretical applicability and practical capabilities of Gompertz-derived mortality models for analysing changing mortality patterns.