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J Charlton

Publications and source records attributed to J Charlton.

At least 37 records · Page 2Linked to original sources
PubMed1998

Potential for suicide prevention in primary care? An analysis of factors associated with suicide.

BACKGROUND: General practitioners (GPs) need to be aware of the risk factors for suicide. GP records may provide clues to identifying the relative importance of such risk factors. AIMS: To identify, in suicide cases and matched controls, the patterns of consultation, diagnosis, and treatment of mental illness, and recording of risk factors for suicide. To examine the usefulness of data routinely collected by GPs in computerized databases to investigate treatment of patients in general practice prior to suicide. METHOD: Case control study using GP records from the General Practice Research Database (GPRD). Three controls selected for each case, matched for age, sex, and duration of registration with practice. Information extracted of the prevalence of major disease; diagnosis of, and treatment, or referral for, mental illness; frequency of recording of recent life events; and consultations with the GP in the 12 months prior to death. RESULT: Of the 339 suicide cases recorded, 80% were male, which is similar to the national percentage for this age group. Females were more likely than males to have a history of mental illness and to have been diagnosed and treated for mental illness in the 12 months before death (59% versus 35%), and women were more likely to have previously attempted suicide (47% versus 27%). There was no significant difference between males and females in period of time since last contact with GP practice, but females consulted more frequently. Twenty-nine per cent of cases had not consulted their GP in the six months prior to death. In multivariate analysis, the following were identified as independent risk factors: history of attempted suicide; untreated serious mental illness (odds ratio > 20); recent (past 12 months) marital life event; alcohol abuse; frequent consultations with GP; and previous mental illness. Recording of life events by GPs was poor. CONCLUSIONS: Females at risk of suicide are more likely than males to have been diagnosed and treated for mental illness. It is likely that GPs are under-diagnosed and under-treating males at risk. Data from the GPRD give comparable results to those from other studies. The GPRD is a potentially useful tool for research into relatively uncommon events in general practice.

Adolescent↗
PubMed1997

Protective effects of an aptamer inhibitor of neutrophil elastase in lung inflammatory injury.

Neutrophils play an important part in the development of acute inflammatory injury. Human neutrophils contain high levels of the serine protease elastase, which is stored in azurophilic granules and is secreted in response to inflammatory stimuli. Elastase is capable of degrading many components of extracellular matrix [1-4] and has cytotoxic effects on endothelial cells [5-7] and airway epithelial cells. Three types of endogenous protease inhibitors control the activity of neutrophil elastase, including alpha-1 protease inhibitor (alpha-1PI), alpha-2 macroglobulin and secreted leukoproteinase inhibitor (SLPI) [8-10]. A disturbed balance between neutrophil elastase and these inhibitors has been found in various acute clinical conditions (such as adult respiratory syndrome and ischemia-reperfusion injury) and in chronic diseases. We investigated the effect of NX21909, a selected oligonucleotide (aptamer) inhibitor of elastase, in an animal model of acute lung inflammatory disease [11-14]. This inhibitor was previously selected from a hybrid library of randomized DNA and a small-molecule irreversible inhibitor of elastase (a valine diphenyl ester phosphonate, Fig. 1), by the blended SELEX process [15]. We show that NX21909 inhibits lung injury and neutrophil influx in a dose-dependent manner, the first demonstration of efficacy by an aptamer in an animal disease model.

Animals↗
PubMed1997

Highly potent irreversible inhibitors of neutrophil elastase generated by selection from a randomized DNA-valine phosphonate library.

We incorporated a phosphonate irreversible inhibitor of neutrophil elastase into a randomized DNA library and, using the SELEX process, iteratively selected these assemblies for the most potent elastase inhibitors. The inhibitors were selected against purified elastase and against secreted elastase in the presence of activated neutrophils. Very active aptamer inhibitors were obtained by both methods, with second-order rate constants for inactivation of human neutrophil elastase ranging (1-3) x 10(8) M(-1) min(-1). These rates exceed those of any reported irreversible inhibitor of elastase and exceed the previous best phosphonate inhibitors by 80-fold. The selected inhibitors are also significantly more potent than alpha-1 proteinase inhibitor in blocking degradation of elastin by activated neutrophils. In contrast to a previous experiment [Smith et al. (1995) Chem. Biol. 2, 741-750], a single-enantiomer form of the valyl phosphonate was used rather than a racemic mixture. Our analysis shows that this use of a chirally resolved valyl phosphonate results in selection of much more potent inhibitors and that these inhibitors specifically potentiate a single enantiomeric form of the phosphonate.

Cathepsin G↗
PubMed1997

Differences in traffic judgements between young and old adult pedestrians.

Older pedestrians have been shown to be over-involved in casualty crashes, compared to younger pedestrians, in recent reports. This study set out to investigate whether older pedestrians' road crossing behaviour might render them more vulnerable to crashes because of declines in their physical, sensory, perceptual or cognitive abilities. An initial 'blackspot' accident analysis highlighted the types of crashes in which older (and younger) adult pedestrians were involved and likely crossing actions. Road crossing behaviour was then systematically measured from unobtrusive video recordings of individual road crossings for a sample of younger and older pedestrians at several urban locations. On two-way undivided roads, older pedestrians crossed more frequently when there was closer moving traffic and generally adopted less safe road crossing strategies than their younger counterparts. On one-way divided roads, their crossing behaviour was considerably more safe and similar to that of younger pedestrians. The findings suggest that age-related perceptual and cognitive deficits may play a substantial role in many of the crashes involving older pedestrians.

Accidents, Traffic↗
PubMed1997

In vivo imaging of inflammation using an aptamer inhibitor of human neutrophil elastase.

BACKGROUND: We previously reported the isolation of aptamer irreversible inhibitors of human neutrophil elastase. We now report on the application of aptamer technology to the field of diagnostic imaging. RESULTS: The enzyme elastase has been reported to bind to the surface of activated neutrophils. Using a fluorescent flow cytometry assay, we showed that an aptamer inhibitor of elastase also binds preferentially to activated neutrophils. We then tested the ability of the aptamer to image inflammation in vivo in a rat reverse passive Arthus reaction model. The aptamer achieved a peak target-to-background (T/B) ratio of 4.3 +/- 0.6 in 2 hours. IgG, which is used clinically to image inflammation, took a longer time to achieve a lower T/B: 3.1 +/- 0.1 at 3 hours. The difference in T/B values is due to the faster clearance of the aptamer signal from the blood pool. CONCLUSIONS: It is feasible to apply aptamer ligands for use in diagnostic imaging, where they may offer significant advantages over monoclonal antibodies and other reagents.

Animals↗
PubMed1997

Methylation of genomes and genes at the invertebrate-vertebrate boundary.

Patterns of DNA methylation in animal genomes are known to vary from an apparent absence of modified bases, via methylation of a minor fraction of the genome, to genome-wide methylation. Representative genomes from 10 invertebrate phyla comprise predominantly nonmethylated DNA and (usually but not always) a minor fraction of methylated DNA. In contrast, all 27 vertebrate genomes that have been examined display genome-wide methylation. Our studies of chordate genomes suggest that the transition from fractional to global methylation occurred close to the origin of vertebrates, as amphioxus has a typically invertebrate methylation pattern whereas primitive vertebrates (hagfish and lamprey) have patterns that are typical of vertebrates. Surprisingly, methylation of genes preceded this transition, as many invertebrate genes have turned out to be heavily methylated. Methylation does not preferentially affect genes whose expression is highly regulated, as several housekeeping genes are found in the heavily methylated fraction whereas several genes expressed in a tissue-specific manner are in the nonmethylated fraction.

Animals↗
PubMed1996

The capture of socioeconomic data in general practice.

BACKGROUND: It is common practice to record the reasons why patients have an encounter with the practice, but the collection of socioeconomic data with which to link this morbidity data is less easy to achieve. AIM: To describe the social enquiry used in the Fourth National General Practice-based morbidity study (1991-1992) and to consider its effectiveness for use in practice. METHOD: Socioeconomic data were collected suing a structured questionnaire administered by a trained interviewer. Data were provided by both consulting and non-consulting registered patients. RESULTS: The interview technique proved to be acceptable to patients, interviewers and general practitioners, simple to administer, and inexpensive to collect. Eighty-three per cent of the 502,000 people included in the study provided social and occupational data. Less than 1.5% of patients refused to be interviewed. Fifty-four of the 60 practices achieved the target level of 90% of registered patients being successfully interviewed. CONCLUSION: A method of socioeconomic data collection based on that used in the 1991-1992 study would be of benefit for health care planning, allocation of resources, design of performance indicators and epidemiological research.

England↗
PubMed1996

Which areas are healthiest?

This article compares mortality rates by geography and over time. This is done by analysing, for England and Wales, mortality data from 1981 to 1992 by cause, local authority, and ward, using the new OPCS area classifications, and the urban/rural categorisation of 1991 Census enumeration districts based on land use. The proportion of babies who in 1990-92 were lightweight at birth was also examined. Urban areas (particularly purpose-built inner city estates and deprived industrial areas) tend to be the least healthy. Rural and prosperous areas are the most healthy, and the biggest health gains have been made in these. Based on 1992 mortality rates, out of every 100 boys born in 'Ports and industry' areas, 16 would survive to age 85 whereas 24 would do so in the 'Most prosperous' areas. The corresponding figures for girls were 33 and 43. The 'Most prosperous' areas also had the most similar male and female life expectancies, with the difference narrowing throughout the period 1981-1992. In 1990-92 people in 'Ports and industry' areas had the highest male mortality levels for malignant neoplasms, lung cancer, circulatory diseases, ischaemic heart disease and cerebrovascular disease. People in 'Inner London' had the highest levels for respiratory diseases and injury and poisoning.

Adolescent↗
PubMed1995

In vitro selection of RNA-based irreversible inhibitors of human neutrophil elastase.

INTRODUCTION: We describe a new approach to drug discovery which joins the technologies of medicinal and combinatorial chemistry, allowing selection of the most active variant of a lead compound from a large (> 10(12)) pool. A small-molecule covalent inhibitor of elastase was coupled to a randomized pool of RNA, and this assembly was iteratively selected for oligonucleotide sequences that promote the covalent reaction of the inhibitor with the human neutrophil elastase (hNE) active site. RESULTS: Incorporation of the covalent inhibitor into the randomized pool increases the second-order rate of inactivation of hNE by approximately 15-fold; sequences selected from this pool show an additional approximately 20-fold increase in activity. The relative rate of cross-reaction with another serine protease, cathepsin G, was reduced > 100-fold. Low doses of the inhibitor were found to prevent lung damage inflicted by human neutrophils in an isolated rat lung model of acute respiratory distress syndrome (ARDS). CONCLUSIONS: This result supports the hypothesis that neutrophil elastase is a significant effector of inflammatory disease. More generally, our findings demonstrate that blending small molecules into combinatorial libraries is a feasible method of drug discovery.

Animals↗
PubMed1995

Trends and patterns in suicide in England and Wales.

BACKGROUND: Suicides among young men have been rising since the early 1970s while at the same time the rates for women of all ages and for men over age 44 been falling. Byu 1992 the highest risk group was men aged 25-44. In all age groups female rates have declined relative to those for men. METHODS: A case-control analysis was undertaken comparing suicide death with deaths from natural causes fo the years 1990-1992, based on data collected on the death certificate, and 1991 census data relating to the ward of residence of the person who died. Data for men and women aged 16-64 were analysed separately, with allowance for the fact that the effects of the factors analysed could be different above and 45. RESULTS: For men, different models were necessary for the two age groups, but or women a single model sufficed. For men and women occupations with access to effective methods of suicide, such as veterinarians, medical practitioners, nurses and pharmacists had much higher risks than other professions. Being widowed/divorced or marital status not stated was also an important risk factor, as was being single for men aged 45 and over and women of all ages. Country of birth was also significantly related to suicide risk. For older men, living in a ward with unemployment rates below 5% was a risk factor, as was living in a ward with high own occupancy rates. Younger men living in wards with owner occupancy rates below 55% were at reduced risk. For women owner occupancy and unemployment rates had little association with suicide rates.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1995

Studies of DNA methylation in animals.

We have been studying the evolution and function of DNA methylation in vertebrate animals using three related approaches. The first is to further characterise proteins that bind to methylated DNA. Such proteins can be viewed as 'receptors' of the methyl-CpG 'ligand' that mediate downstream consequences of DNA modification. The second approach involves CpG islands. These patches of non-methylated DNA coincide with most gene promoters, but their origin and functional significance have only recently become the subject of intensive study. The third approach is to trace the evolution of DNA methylation. Genomic methylation patterns of vertebrates are strikingly different from those of invertebrates. By studying methylation in animals that diverged from common ancestors near to the invertebrate/vertebrate boundary, we will assess the possibility that changes in DNA methylation contributed causally to the evolution of the complex vertebrate lineage.

Animals↗
PubMed1995

The new OPCS area classifications.

This article introduces the OPCS area classifications based on the 1991 Census. It illustrates the methodology and results in terms of local authority districts. It follows earlier articles in Population Trends that described the production of similar classifications after the 1971 and 1981 Censuses. Each district in Great Britain is classified as both the centre of a small cluster of districts which correspond closely to it and as a member of a cluster within a division of all districts. The list of corresponding districts is set out in full. Information is also given on how to obtain further details of the classification.

Data Interpretation, Statistical↗
PubMed1995

Suicide deaths in England and Wales, 1982-92: the contribution of occupation and geography.

Following two previous articles which described changes that are occurring in suicide rates and trends in factors known to be associated with suicides, this article examines in greater depth the effect of occupation and geography on suicide mortality. For both men and women the highest risk occupations are mostly in Social Class I or II. The occupations at highest risk, which include several medical-related professions, and the method of suicide they choose, suggest that easy access to means of suicide is an important factor. Suicide rates for men aged 15-44 are generally higher in Inner London, rural areas, resort and retirement areas, and urban manufacturing areas.

Adolescent↗