Evaluating the fishery and ecological consequences of the proposed North Sea multi-annual plan.

The possible impacts of the European Commission's proposed North Sea Multi-Annual Plan are evaluated in terms of its likely outcomes to achieve management objectives for fishing pressure, species' biomass, fishery yield, the landed value of key species and ecosystem objectives. The method applies management strategy evaluation procedures that employ an ecosystem model of the North Sea and its fisheries as the operating model. Taking five key dimensions of the proposed plan, it identifies those areas that are key to its successful performance.

Endogenous Hot Spots of De Novo Telomere Addition in the Yeast Genome Contain Proximal Enhancers That Bind Cdc13.

DNA double-strand breaks (DSBs) pose a threat to genome stability and are repaired through multiple mechanisms. Rarely, telomerase, the enzyme that maintains telomeres, acts upon a DSB in a mutagenic process termed telomere healing. The probability of telomere addition is increased at specific genomic sequences termed sites of repair-associated telomere addition (SiRTAs).

Non-benzimidazole containing inhibitors of respiratory syncytial virus.

Several non-benzimidazole containing inhibitors of respiratory syncytial virus are described. Core template modification, analysis of antiviral activity, physicochemistry and optimisation of properties led to the thiazole-imidazole 13, that showed a good potency and pharmacokinetic profile in the rat.

An imidazopiperidine series of CCR5 antagonists for the treatment of HIV: the discovery of N-{(1S)-1-(3-fluorophenyl)-3-[(3-endo)-3-(5-isobutyryl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]propyl}acetamide (PF-232798).

Preventing entry of HIV into human host cells has emerged as an attractive approach to controlling viral replication. Maraviroc 1 is an approved antagonist of the human CCR5 receptor which prevents the entry of HIV. Herein, we report the design and discovery of a series of imidazopiperidine CCR5 antagonists which retain the attractive antiviral profile and window over hERG activity of maraviroc 1, combined with improved absorption profiles in rat and dog.

Design and optimisation of potent gp120-CD4 inhibitors.

The synthesis and structure-activity relationship of a series of novel gp120-CD4 inhibitors are described. Pharmacokinetic studies and antiviral spectrum assessment of lead compounds led to the identification of compound 36, a potent gp120-CD4 inhibitor which exhibited antiviral potency across a spectrum of 25 clade B isolates.

Discovery of a small molecule inhibitor through interference with the gp120-CD4 interaction.

A series of piperazine derivatives were designed and synthesised as gp120-CD4 inhibitors. SAR studies led to the discovery of potent inhibitors in a cell based anti viral assay represented by compounds 9 and 28. The rat pharmacokinetic and antiviral profiles of selected compounds are also presented.

The design and discovery of novel amide CCR5 antagonists.

The synthesis of a range of novel amine-containing structures and their primary potency as inhibitors of HIV-1 fusion via blocking of the CCR5 receptor is described. The development of the medicinal chemistry strategy and SAR's which led to the identification of the piperidine amide compounds 33 and 36 as excellent leads for further evaluation is described, along with key physicochemical data which highlighted their lead potential.

Novel selective inhibitors of neutral endopeptidase for the treatment of female sexual arousal disorder.

A series of substituted glutaramides were synthesised using Candoxatrilat 1 as a lead and evaluated for potency against neutral endopeptidase (NEP) as a potential treatment for female sexual arousal disorder (FSAD). In this paper, we describe studies in which we were able to increase NEP activity substantially over the levels reported for previous compounds from this programme by appropriate substitution in both the P(1)(') and P(2)(') regions. Optimisation led to the 4-chlorophenpropylamide S-30 which was selected as a candidate for further study.

Novel selective inhibitors of neutral endopeptidase for the treatment of female sexual arousal disorder. Synthesis and activity of functionalized glutaramides.

Female sexual arousal disorder (FSAD) is a highly prevalent sexual disorder affecting up to 40% of women. We describe herein our efforts to identify a selective neutral endopeptidase (NEP) inhibitor as a potential treatment for FSAD. The rationale for this approach, together with a description of the medicinal chemistry strategy, lead compounds, and SAR investigations are detailed.

Metabolic cost of over ground gait in younger stroke patients and healthy controls.

Purpose: Locomotor impairment, such as that which may occur following a stroke, results in increased energy expenditure during walking. Previous research quantifying this increased metabolic demand has focused on older people; thus, the aim of this study was to investigate the physiological cost of walking in younger patients following stroke.

Methods: Thirteen stroke patients (mean age of 40.

The discovery of small molecule inhibitors of neutral endopeptidase. Structure-activity studies on functionalized glutaramides.

A series of small molecule glutaramides were synthesized and evaluated for potency against canine and human neutral endopeptidase using target criteria of molecular weight <400 and log P between 2 and 4.5 to maximize the likelihood of achieving good oral absorption. The structure-activity relationship (SAR) investigations described in this paper led to the identification of an ethyl 1,3,4-thiadiazole glutaramide which demonstrated good neutral endopeptidase potency, selectivity and excellent oral absorption in the rat.

Regulation of telomere length by an N-terminal region of the yeast telomerase reverse transcriptase.

Telomerase is a reverse transcriptase that maintains chromosome integrity through synthesis of repetitive telomeric sequences on the ends of eukaryotic chromosomes. In the yeast Saccharomyces cerevisiae, telomere length homeostasis is achieved through negative regulation of telomerase access to the chromosome terminus by telomere-bound Rap1 protein and its binding partners, Rif1p and Rif2p, and positive regulation by factors such as Ku70/80, Tel1p, and Cdc13p. Here we report the identification of mutations within an N-terminal region (region I) of the yeast telomerase catalytic subunit (Est2p) that cause telomere lengthening without altering measurable catalytic properties of the enzyme in vitro.

Estimating a preference-based index for a menopause specific health quality of life questionnaire.

Background: The aim of the study was to develop a menopause-specific, preference-based health-related quality-of-life (HRQoL) index reflecting both menopausal symptoms and potential side-effects of Hormone Replacement Therapy (HRT).

Methods: The study had three phases: the development of a health state classification, a prospective valuation survey and the estimation of a model to interpolate HRQoL indices for all remaining health states as defined by the classification. A menopausal health state classification was developed with seven dimensions: hot flushes, aching joints/muscles, anxious/frightened feelings, breast tenderness, bleeding, vaginal dryness and undesirable androgenic signs.

Health-related quality of life and cost impact of irritable bowel syndrome in a UK primary care setting.

Objectives: To identify the impact of irritable bowel syndrome (IBS) on health-related quality of life (HR-QOL), time off work and the utilisation and cost of health services.

Design: A case-control study was undertaken matching patients with IBS and controls. Quality-of-life information was collected using the Medical Outcomes Study 36-item Short Form (SF-36) health survey, EuroQOL instrument (EQ-5D) and IBS Quality-of-Life (IBS-QOL) instruments.

Some medical syndromes encountered in nineteenth-century French literature.

The medical content of a hundred selected French novels written between 1815 and 1914 has been examined. These books reflect contemporary public interest in medicine and disease. By means of translated quotations, the spectrum of diseases common at the time, including conditions nowadays rarely or never observed, such as smallpox and diphtheria, are graphically described, along with the effects of treatment of syphilis with mercury and the ravages of tuberculosis including lupus vulgaris.

Patients' perceptions of primary health care in an inner-city practice.

Background: The 1978 Alma Ata declaration by the World Health Organization emphasized the importance of primary health care, which includes social services and participation, as well as primary medical care. In the UK, primary medical care is based on general practice, increasingly working from purpose-built premises with primary care teams. However, this does not usually include social services or involve patient participation.

5-Fluorouracil related toxic myocarditis: case reports and pathological confirmation.

This report describes two cases of cardiotoxicity associated with the use of 5-fluorouracil (5-FU) in the treatment of neoplastic disease, and reviews the literature to date. The manifestations of cardiac toxicity were significant ventricular dysfunction during continuous infusion of 5-FU, accompanied by symptoms resembling cardiac ischemia in one case and irreversible cardiogenic shock in another. Detailed cardiac investigations and pathological findings provide convincing evidence that the development of acute myocarditis is the likely mechanism of 5-FU cardiotoxicity, rather than coronary insufficiency as has commonly been postulated.

The provision and use of medical services during the 1991 World Student Games in Sheffield.

This paper describes the provision and use of medical services organized by Sheffield during the World Student Games in 1991. A descriptive study of medical and physio-therapy records, together with minor incident logs and hospital referrals, was carried out. It was found that 571 medical records and 357 physiotherapy records were completed, of which 83 per cent were generated at the Games Village.

Practice organization before and after the new contract: a survey of general practices in Sheffield.

In order to assess the effects of the new contract on practice organization, all general practices in Sheffield were surveyed just before the new contract came into effect in April 1990, and again one year later. Of the 120 practices, 57% responded in 1990 and 61% in 1991, with 47% responding in both years. There were significant increases in the mean number of clinics and employed staff for the practices responding to both questionnaires and in the proportion of these practices which had a computer.

Workload of general practitioners before and after the new contract.

Objective: To assess changes in general practitioners' workload associated with the new contract introduced in April 1990.

Design: Weekly workload diary completed during four weeks in February-March 1990 and during the same period in 1991.

Setting: Sheffield, United Kingdom.

Sociocultural correlates of eating disorders among Asian schoolgirls in Bradford.

A survey of 204 south-Asian and 355 Caucasian schoolgirls was conducted in Bradford using the EAT-26 and the BSQ. At interview, seven Asian girls and two Caucasian girls met DSM-III-R criteria for bulimia nervosa, yielding a prevalence of 3.4% and 0.

Rheumatic disease in the Nuu-Chah-Nulth native Indians of the Pacific Northwest.

The Nuu-Chah-Nulth are a tribe of 2,300 Pacific Northwest native Indians. A retrospective study has identified 157 requiring referral to rheumatologists over 15 years. Rheumatoid arthritis (RA) was found in 23, systemic lupus erythematosus (SLE) in 8, sacroiliitis 5, and Reiter's syndrome 1.

An interactive computerized protocol for the management of hypertension: effects on the general practitioner's clinical behaviour.

This paper reports an experimental study of general practitioners' use of an interactive computerized protocol for the management of hypertension, focussing particularly on the protocol's effects on doctors' clinical behaviour. Prior to its computerization a paper-based version of the protocol was used enabling a comparison of the alternative forms. Doctors' delivery of care was assessed from video recordings of 89 consultations and from the records made during these consultations.

Anaphylactoid reactions during haemodialysis are due to ethylene oxide hypersensitivity.

Anaphylactoid reactions during haemodialysis are unusual, but increasingly recognised. It has recently been reported that there is a significant association between such reactions and the presence of IgE to albumin exposed to ethylene oxide (ETO). Review of the clinical features and epidemiology of dialysis anaphylaxis in the light of this new data suggests that these reactions are due to ETO hypersensitivity.

Spleen size in chronic renal failure.

To investigate the cause of clinically detectable splenomegaly, which is common in patients receiving regular haemodialysis, splenic volume was assessed by isotopic scanning using intravenously injected technetium-99m microspheres in 34 controls and 149 patients with chronic renal failure. Of the patients, 16 had never received dialysis, 10 were undergoing continuous peritoneal dialysis, 94 were undergoing regular haemodialysis, and 29 had undergone successful renal transplantation more than nine months previously. Mean splenic volume was increased only in the patients who were receiving haemodialysis.