Two novel mutations in the POU1F1 gene generate null alleles through different mechanisms leading to combined pituitary hormone deficiency.

BACKGROUND: Mutations in the POU1F1 gene severely affect the development and function of the anterior pituitary gland and lead to combined pituitary hormone deficiency (CPHD). OBJECTIVE: The clinical and genetic analysis of a patient presenting with CPHD and functional characterization of identified mutations. PATIENT: We describe a male patient with extreme short stature, learning difficulties, anterior pituitary hypoplasia, secondary hypothyroidism and undetectable prolactin, growth hormone (GH) and insulin-like growth factor 1 (IGF1), with normal random cortisol. DESIGN: The POU1F1 coding region was amplified by PCR and sequenced; the functional consequence of the mutations was analysed by cell transfection and in vitro assays. RESULTS: Genetic analysis revealed compound heterozygosity for two novel putative loss of function mutations in POU1F1: a transition at position +3 of intron 1 [IVS1+3nt(A>G)] and a point mutation in exon 6 resulting in a substitution of arginine by tryptophan (R265W). Functional analysis revealed that IVS1+3nt(A>G) results in a reduction in the correctly spliced POU1F1 mRNA, which could be corrected by mutations of the +4, +5 and +6 nucleotides. Analysis of POU1F1(R265W) revealed complete loss of function resulting from severely reduced protein stability. CONCLUSIONS: Combined pituitary hormone deficiency in this patient is caused by loss of POU1F1 function by two novel mechanisms, namely aberrant splicing (IVS1+3nt (A>G) and protein instability (R265W). Identification of the genetic basis of CPHD enabled the cessation of hydrocortisone therapy without the need for further assessment for evolving endocrinopathy.

Carga epidemiológica y económica de la hipertensión arterial en pacientes con síndrome metabólico en España: un modelo basado en la prevalencia / Epidemiological and economic burden of arterial hypertension in patients with metabolic syndrome in spain: a prevalence-based model

Introducción: La presencia del síndrome metabólico en pacientes hipertensos aumenta significativamente el riesgo de enfermedades cardiovasculares, diabetes tipo 2 y mortalidad. El objetivo fue calcular la carga epidemiológica y económica del síndrome metabólico en pacientes hipertensos para el Sistema Nacional de Salud español en 2008 y 2020. Material y métodos: Modelo de coste de la enfermedad basado en la prevalencia según grupo de edad, sexo y riesgo. Se utilizaron datos publicados sobre prevalencia, patrones de tratamiento, incidencia de mortalidad y episodios cardiovasculares, prevalencia de diabetes tipo 2 y costes del manejo, estimaciones de población y grupos de riesgo y del crecimientofuturo. Resultados: La prevalencia de la hipertensión arterial con síndrome metabólico en la población general fue del 11% en 2008 y del 22% según la estimación para 2020. La proporción de hipertensos con síndrome metabólico fue del 23% en 2008 y del 45% en 2020. La incidencia de episodios cardiovasculares y mortalidad fue dos veces superior en pacientes hipertensos con síndrome metabólico frente a hipertensos sin SM y la prevalencia de diabetes tipo 2 fue casi seis veces superior. La carga económica en 2008 ascendió a 1.909 millones de euros en 2008para los pacientes con síndrome metabólico. Conclusión: Los pacientes con síndrome metabólico representan casi la cuarta parte de la población hipertensa, pero generan casi la mitad de los costes. La carga económica probablemente se incrementará en el futuro por el envejecimiento de la población y el aumento de la prevalencia de los componentes del síndrome metabólico (AU)

Introduction: The presence of metabolic syndrome in patients with hypertension significantly increases the risk of cardiovascular disease, type 2 diabetes and mortality. This study has aimed to estimate the epidemiological and economic burden of the metabolic syndrome in patients with hypertension in Spain in 2008 and 2020 for the Spanish National Health System. Material and methods: A model on the cost of the diseased based on prevalence according to age, sex and risk group was used. The data published on prevalence, treatment patterns, mortality incidence and cardiovascular events, prevalence of type 2 diabetes and cost of management as well as population and risk groups and future growth estimates were used. Results: The prevalence of arterial hypertension with metabolic syndrome in the general population was 11% in 2008 and a value of 22% has been estimated for 2020. The proportion of hypertensive population with metabolic syndrome was 23% in 2008 and 45% has been estimated for 2020. Incidence of cardiovascular events and mortality was two fold higher among hypertensive patients with metabolic syndrome compared to those without it and prevalence of type2 diabetes was nearly six times higher. The economic burden in 2008 was estimated at D1, 909 million in 2008 for patiens with metabolic syndrome. Conclusion: Patients with metabolic syndrome currently make up about one-fourth of the population with hypertension but account for nearly half the costs. The economic burden is likely to increase in the future due to an aging population and an increase in the prevalence of components of metabolic syndrome (AU)

Progress in Arabidopsis genome sequencing and functional genomics.

Arabidopsis thaliana has a relatively small genome of approximately 130 Mb containing about 10% repetitive DNA. Genome sequencing studies reveal a gene-rich genome, predicted to contain approximately 25000 genes spaced on average every 4.5 kb. Between 10 to 20% of the predicted genes occur as clusters of related genes, indicating that local sequence duplication and subsequent divergence generates a significant proportion of gene families. In addition to gene families, repetitive sequences comprise individual and small clusters of two to three retroelements and other classes of smaller repeats. The clustering of highly repetitive elements is a striking feature of the A. thaliana genome emerging from sequence and other analyses.

Sequence and analysis of chromosome 4 of the plant Arabidopsis thaliana.

The higher plant Arabidopsis thaliana (Arabidopsis) is an important model for identifying plant genes and determining their function. To assist biological investigations and to define chromosome structure, a coordinated effort to sequence the Arabidopsis genome was initiated in late 1996. Here we report one of the first milestones of this project, the sequence of chromosome 4. Analysis of 17.38 megabases of unique sequence, representing about 17% of the genome, reveals 3,744 protein coding genes, 81 transfer RNAs and numerous repeat elements. Heterochromatic regions surrounding the putative centromere, which has not yet been completely sequenced, are characterized by an increased frequency of a variety of repeats, new repeats, reduced recombination, lowered gene density and lowered gene expression. Roughly 60% of the predicted protein-coding genes have been functionally characterized on the basis of their homology to known genes. Many genes encode predicted proteins that are homologous to human and Caenorhabditis elegans proteins.

Patient satisfaction and acceptability of long-term treatment with quetiapine.

Satisfaction with, and subjective tolerability of, antipsychotic medication have emerged as important factors in determining treatment compliance and eventual outcome in the management of psychotic disorders. The acceptability of long-term treatment with quetiapine, an atypical antipsychotic agent with a lower incidence of extrapyramidal effects than standard therapy, was examined in this open-label, multicentre study of patient satisfaction. One hundred and twenty-nine patients with major psychiatric disorders, who had each been receiving quetiapine for at least 6 months in open-label extension studies, were asked to complete a 7-item questionnaire concerning subjective experience and satisfaction with treatment. Over 75% of respondents indicated that they were either "very" or "extremely" satisfied with their antipsychotic medication while 73.7% indicated that, over the last month, they regarded their antipsychotic medication to have been "very" or "extremely" helpful. Subjectively reported side-effects were uncommon, with 74.4% of patients reporting no side-effects, 23.3% mild side-effects and only 2.3% moderate side-effects. There were no unambiguous reports of extrapyramidal symptoms. An overwhelming majority of patients (114/118; 96.6%) reported that they preferred quetiapine to previous antipsychotic medications, the predominant reasons being their perceptions of better tolerability and greater efficacy. Patients also identified improvements in quality of life and their activities of daily living. These positive evaluations appeared to be reflected in the high proportion of respondents who indicated a readiness to continue quetiapine treatment. This study indicates that the combination of efficacy and a favourable tolerability profile shown by quetiapine may result in benefits that are evident to the patient and may be reflected in high levels of patient satisfaction and acceptance of treatment. By improving compliance with treatment, these benefits may also enhance clinical outcome.

Effects of urea on taurine efflux and cell volume in incubated rat cerebral cortical minislices.

The effects of urea on the rate of efflux of preloaded taurine and volume regulation have been examined in incubated minislices from rat superficial cerebral cortex. As external urea was increased in the range 0-100 mmol/L, there was a concentration-dependent slowing of cellular taurine efflux. Cell volumes progressively increased over the range 0-50 mmol/L urea, but decreased slightly in 100 mmol/L. Urea had no effect on cell volume in the absence of taurine. Retardation of efflux, and cell swelling in the presence of 50 mmol/L urea were entirely abolished by trimethylamine (100 mumol/L). TMA had no effect on either variable in the absence of urea. It is suggested that impaired loss of taurine and accompanying cell swelling may be factors contributing to the neurological disturbances accompanying uremia.

The cardiac waiting game: are patients prioritized on the basis of clinical need?

Waiting lists for coronary artery bypass grafting (CABG) have been a recurring problem for many hospitals, putting pressure on hospitals to manage waiting lists more effectively. In this study, we audited the records of 1594 patients who had coronary artery bypass surgery in 1992 and 1993 in three London hospitals, to assess their waiting time experience. Patients' actual waiting times were compared with an appropriate waiting time defined using an adapted version of a Canadian urgency scoring system. Influence of other factors (sex, age, smoking, hypertension, diabetes and obesity) on actual waiting time was assessed. A comparison of patients' actual waiting times with an appropriate waiting time, defined by the urgency score, showed that only 38% were treated within the appropriate period. Thirty-four per cent were treated earlier than their ischaemic risk indicated, and 28% with high ischaemic risk were delayed. Actual waiting time was associated with a patient's sex and smoking status but not with the other factors studied. The current system of prioritizing patients awaiting CABG is not concordant with a measure of appropriate waiting time. This could have arisen due to a number of factors, including the contracting process, waiting list initiatives, and methods of waiting list administration and patient pressures. The use of a standard method for prioritizing patients would enable a more appropriate use of resources.

Impact of the 1991 NHS reforms on the availability and use of coronary revascularisation in the UK (1987-1995)

OBJECTIVE: To describe changes in the availability, utilisation, and waiting times for coronary artery bypass grafting (CABG) and percutaneous transluminal coronary angioplasty (PTCA) between 1987/88 and 1994/95 and to review commissioning of these services. DESIGN: A series of cross sectional surveys and interviews with purchasers and providers. SETTING: Four health regions in the United Kingdom. PATIENTS: All residents aged 25 years or more who underwent coronary revascularisation. RESULTS: There has been little change in the availability of consultants in cardiology in specialist centres, while the number of non-consultant cardiologists has risen significantly. The availability of consultant surgeons more than doubled in some regions, while non-consultant surgical staff increased by 40-90%. The NHS rate of use of both CABG and PTCA has increased steadily since 1987/88. In 1994/95, only two districts had CABG rates of less than 300 per million population. The additional contribution of privately funded cases varied between 14-23% for CABG and 7-30% for PTCA. Regional rates varied 1.3-fold for CABG and threefold for PTCA in 1994/95, while district rates of CABG varied 3.6-fold and PTCA 18-fold. Revascularisation rates were higher in districts with least need in 1991/92 and this persisted over the following three years. The overall waiting time for CABG (214 days) was largely unchanged from 1992/93 (234 days). The overall waiting time for PTCA (138 days) was 25% shorter than in 1992/93 (185 days). Prioritisation of patients waiting over a year had not yet adversely affected the waiting time of more urgent patients. Commissioning has faced a complex web of interconnected problems which, in general, caused more problems for purchasers than providers initially but which appear to be of increasing concern to providers. CONCLUSIONS: The 1991 NHS reforms had had no observable impact on the availability and use of coronary revascularisation by 1995. Continued monitoring is necessary to detect any delayed effect.

Costs and cost effectiveness of health checks conducted by nurses in primary care: the Oxcheck study.

OBJECTIVE: To measure the costs and cost effectiveness of the Oxcheck cardiovascular risk factor screening and intervention programme. DESIGN: Cost effectiveness analysis of a randomised controlled trial using clinical and economic data taken from the trial. SETTING: Five general practices in Luton and Dunstable, England. SUBJECTS: 2205 patients who attended a health check in 1989-90 and were scheduled for re-examination in 1992-3 (intervention group); 1916 patients who attended their initial health check in 1992-3 (control group). Participants were men and women aged 35-64 years. INTERVENTION: Health check conducted by nurse, with health education and follow up according to degree of risk. MAIN OUTCOME MEASURES: Cost of health check programme; cost per 1% reduction in coronary risk. RESULTS: Health check and follow up cost 29.27 pounds per patient. Estimated programme cost per 1% reduction in coronary risk per participant was between 1.46 pounds and 2.25 pounds; it was nearly twice as much for men as women. CONCLUSIONS: The cost to the practice of implementing Oxcheck-style health checks in an average sized practice of 7500 patients would be 47,000 pounds, a proportion of which could be paid for through staff pay reimbursements and Band Three health promotion target payments. This study highlights the considerable difficulties faced when calculating the costs and benefits of a health promotion programme. Economic evaluations should be integrated into the protocols of randomised controlled trials to enable judgments to be made on the relative cost effectiveness of different prevention strategies.

What can be concluded from the Oxcheck and British family heart studies: commentary on cost effectiveness analyses.

OBJECTIVES: To provide a commentary on the economic evaluations of the Oxcheck and British family heart studies: direct comparison of their relative effectiveness and cost effectiveness; comparisons with other interventions; and consideration of problems encountered. DESIGN: Modelling from cost and effectiveness data to estimate of cost per life year gained. SUBJECTS: Middle aged men and women. INTERVENTIONS: Screening for cardiovascular risk factors followed by appropriate lifestyle advice and drug intervention in general practice, and other primary coronary risk management strategies. MAIN OUTCOME MEASURES: Life years gained; cost per life year gained. RESULTS: Depending on the assumed duration of risk reduction, the programme cost per discounted life year gained ranged from 34,800 pounds for a 1 year duration to 1500 pounds for 20 years for the British family heart study and from 29,300 pounds to 900 pounds for Oxcheck. These figures exclude broader net clinical and cost effects and longer term clinical and cost effects other than coronary mortality. CONCLUSIONS: Despite differences in underlying methods, the estimates in the two economic analyses of the studies can be directly compared. Neither study was large enough to provide precise estimates of the overall net cost. Modelling to cost per life year gained provides more readily interpretable measures. These estimates emphasise the importance of the relatively weak evidence on duration effect. Only if the effect lasts at least five years is the Oxcheck programme likely to be cost effective. The effect must last for about 10 years to justify the extra cost associated with the British family heart study.

The carrot, the stick and the general practitioner: how have changes in financial incentives affected health promotion activity in general practice?

BACKGROUND: Financial incentives for increasing health promotion activity in primary care, introduced with the 1990 contract for general practitioners, were amended in 1993 and are now focused on cardiovascular disease. Payments for health promotion clinics were abolished and target payments were introduced. AIM: The study aimed to evaluate the effect of the change, in June 1993, in financial incentives for health promotion activity in primary care on the distribution of health promotion payments in two family health services authorities. METHOD: A retrospective study was undertaken in which data from two family health services authorities were used to determine the annual level of health promotion payments per 1000 practice population before and after the contractual amendment. Health promotion clinic payment data were analysed for 78 practices in Bedfordshire Family Health Services Authority and 85 practices in Kensington, Chelsea and Westminster Family Health Services Authority. Changes in health promotion payments were calculated and related to two measures of relative need: all cause standardized mortality ratios, for patients aged 74 years or less, of the electoral ward in which the practice is located; and the Jarman underprivileged area score. High relative need was defined as a standardized mortality ratio of over 100 or more than 25% of the practice population living in electoral wards with a Jarman score of over 30. RESULTS: Health promotion payments were more evenly distributed after the change in June 1993 than before between the two family health services authorities and between general practices. Single-handed practices were carrying out more clinics in 1992 than multi-partner practices and consequently were one of the greatest financial losers as a result of the change. In addition, practices located in electoral wards with high relative needs lost proportionally more than those in electoral wards with lower needs. CONCLUSION: Changes in the general practitioner health promotion contract have created new financial winners and losers. It now appears that health promotion payments are more evenly distributed but that the distribution is unrelated to need or treatment given. More evidence on the effectiveness of health promotion interventions is required before policies aimed at promoting better health through primary care can be fully evaluated.

Coronary revascularisation: why do rates vary geographically in the UK?

OBJECTIVE: To explain the reasons for geographical variation in the use of coronary revascularisation in the United Kingdom. DESIGN: This was a cross sectional ecological study. SETTING: NHS and independent hospitals performing coronary revascularisation for the 11.6 million residents of the south east Thames, East Anglian and north western health regions in England plus Greater Glasgow, Lanarkshire, Ayr and Arran health boards in Scotland were included. SUBJECTS: All residents aged > or = 25 years in 1992-93 who underwent coronary artery bypass grafting (CABG) or percutaneous transluminal coronary angioplasty (PTCA) in either the public or private sector were included. MAIN MEASURES: Crude and age-sex standardised intervention rates for residents of the 42 constituent districts and boards were determined. Variation was measured using the systematic component of variation. RESULTS: Considerable systematic variations in district rates of CABG and PTCA existed. These variations mostly arose from differences in supply factors. Higher rate districts were characterised by being close to a regional revascularisation centre and having a local cardiologist. Demand factors such as the level of need in the population (measured by coronary heart disease mortality) and the lack of use of alternative treatments not only failed to explain the observed variation but were inversely associated with the rate of intervention--an example of the inverse care law. The finding that the residents of more socially deprived districts experienced higher intervention rates was probably subject to confounding due to their close proximity to specialist centres. CONCLUSIONS: If greater geographical equity of use for the same level of need is to be achieved, attention must be paid to the supply factors that determine levels of utilisation. As responsibility for purchasing these procedures is decentralised, utilisation might become even more unequal.

Trends in the age and sex of patients undergoing coronary revascularisation in the United Kingdom 1987-93.

OBJECTIVES: To describe how coronary revascularisation rates in the United Kingdom (in the public and private sectors) vary by age and sex; how these relations have changed between 1987 and 1993; whether significant differences exist between geographical areas, public and private sectors, and hospitals; and to make comparisons with trends in North America. DESIGNS: Secondary analysis of data on the age, sex, procedure, NHS/private, and health district of residence of patients. SETTING: Resident population of South East Thames, East Anglian, and North Western health regions and Greater Glasgow, Lanarkshire, and Ayr/Arran health boards (11.6 million; 20% United Kingdom population). PATIENTS: All 19,665 residents who underwent either coronary artery bypass grafting or percutaneous coronary angioplasty without any concomitant procedure during 1987-8, 1989-90, 1991-2 and 1992-3 in either NHS or independent hospitals. MAIN MEASURES: Population based rates of revascularisation by age, sex, area of residence, and NHS/private treatment. Secular trends in the age (mean, standard deviation, range), and sex ratio (male to female) of patients. RESULTS: Revascularisation rates in men were about four times higher than in women (1992-3: 1340 v 362/10(6) aged 25 years or more). The highest rates were in those aged 55-64 years (for men) and 55-64 and 65-74 years (for women). In 1992-3 the mean age of female patients was three years older than that for men (61.2 v 58.3) and that for coronary artery grafting was over two years older than for angioplasty (59.4 v 56.9). Between 1987-8 and 1992-3 the male to female ratio decreased (4.2:1 to 3.55:1) and the mean age of patients increased steadily by about six months each year. Intervention rates for the older groups increased faster than those for the younger, particularly in high rate regions. The age and sex mix of patients varied between regions and districts/boards. The mean age of patients varied by nine years and the sex ratio varied twofold between NHS hospitals. The male to female ratio was higher in private than NHS patients (1992-3: 5.5:1 v 3.6:1), suggesting greater access to care for men than women in the private sector. The trends observed in the United Kingdom are similar to those that have occurred in North America, with the exception of a decrease in the male to female ratio, which has not previously been reported. CONCLUSION: The increase in the revascularisation rate has been accompanied by an increasing proportion of women and older people. The extent of these changes varies between geographical areas. The change in the sex ratio has occurred despite an increasing contribution by the private sector, to which women have less access than men.