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Biomedical subjects

A Fletcher

Publications and source records attributed to A Fletcher.

At least 91 records · Page 5Linked to original sources
PubMed1997

Does lowering the blood pressure improve the mood? Quality-of-life results from the Hypertension Optimal Treatment (HOT) study.

Nine-hundred-and-twenty-two hypertensive patients were included in a substudy to the Hypertension Optimal Treatment study, which aimed to investigate the impact on quality of life of lowering the pressure and of intensified therapy. Seven-hundred-and-eighty-one patients completed both baseline and follow-up questionnaires (intention-to-treat population), while 610 patients were included in a per protocol analysis. Patients were randomized to three diastolic BP levels (DBPs), i.e. < or =90 mmHg, < or =85 mmHg and < or =80 mmHg. Two self-administered validated questionnaires, the Psychological General Well-Being index and the Subjective Symptoms Assessment Profile (SSA-P) were completed at baseline and after 6 months. The lower the DBP achieved, the greater the improvement in well-being (p < 0.05). The increase in well-being from baseline to 6 months was significant in target groups < or =80 mmHg (p < 0.01) and < or =85 mmHg (p < 0.05). The SSA-P domains, cardiac symptoms and dizziness improved in all groups but the sex life score deteriorated in the < or =80 and < or =85 mmHg groups in male patients. In all target groups, headaches were reduced (p < 0.001), while swollen ankles (p < 0.001) and dry cough in the < or =80 mmHg group (p < 0.001) increased. Although more intensive antihypertensive therapy is associated with a slight increase in subjective symptoms, it is nonetheless still associated with improvements in patients' well-being.

Affect↗
PubMed1997

Influence of health status and the timing of surgery on mortality in hip fracture patients.

The purpose of the study was to determine the relationship of preoperative health status and time to surgery to mortality and late functional outcome in hip fracture patients. The records of 168 consecutive patients who had operations for 171 intertrochanteric or femoral neck fractures were reviewed retrospectively. Preoperative health status was assessed by the American Society of Anesthetists (ASA) classification. Postoperative outcome was determined by mortality and ambulatory status. The follow-up period for survivors averaged 33 months. The overall mortality was 14% at 1 year, which rose to 26% at 2 years, and 33% at 3 years. The 3-year mortality was significantly less for ASA I and II patients (23%) than for ASA III, IV, and V patients (39%). There was also a significant difference in mortality between patients having surgery within 24 hours of admission (20%) and those having surgery beyond 24 hours of admission (50%). Even when only the healthy subgroup of ASA I and II patients were considered, the relative risk of death was 4.5 times greater if surgery occurred after 24 hours from admission. These data support the concept that hip fracture patients are not a homogeneous group with respect to mortality and that the ASA classification is a good predictor of mortality. Patients who had surgery within 24 hours of admission had a significantly lower mortality rate than did patients having surgery beyond 24 hours of admission, regardless of their preoperative ASA classification.

Adult↗
PubMed1997

Thymoma-associated cutaneous graft-versus-host-like reaction.

A 47-year-old man presented with diarrhoea, acquired hypogammaglobulinaemia and a cutaneous graft-versus-host-like reaction in association with a spindle cell thymoma. Graft-versus-host reactions usually occur following allogeneic transplantation or transfusion of immunocompetent lymphoid cells but have been described rarely in the context of a thymoma.

Agammaglobulinemia↗
PubMed1996

Exquisite delineation of 5-HT1A receptors in human brain with PET and [carbonyl-11 C]WAY-100635.

The 5-HT1A receptor antagonist, WAY-100635 [N-(2-(4-(2-methoxyphenyl)- 1-piperazinyl)ethyl)-N-(2-pyridyl) cyclohexanecarboxamide], was labelled in its carbonyl group with carbon-11 (t1/2 = 20.4 min), injected intravenously into healthy male volunteers and studied with positron emission tomography (PET). The acquired data provide exquisite delineation of 5-HT1A receptors in brain, with the ratio of radioactivity uptake in receptor-rich regions, such as medial temporal cortex, to that in receptor-devoid cerebellum reaching 25 by 60 min after radioligand injection. Application of biomathematical modelling to the data revealed high values (7.8) for binding potential, a measure of Bmax/Kp, in receptor-rich regions. Only very polar radioactive metabolites were present in plasma, a finding consistent with the low level of nonspecific binding seen in cerebellum. [carbonyl-11C]WAY-100635 is concluded to be far superior to the previously reported [0-methyl-11C]WAY-100635 as a radioligand for PET studies of 5-HT1A receptors in human brain.

Adult↗
PubMed1996

Symptoms of hypertrophic cardiomyopathy, with special emphasis on syncope and postprandial exacerbation of symptoms.

We undertook a prospective study of the symptoms of hypertrophic cardiomyopathy with the aim of profiling symptomatic morbidity in detail, determining the prevalence of anxiety and depression, and describing the prevalence and associations of syncope and postprandial symptom exacerbation. A questionnaire was administered to consecutive outpatients; 70 with hypertrophic cardiomyopathy, 43 with coronary artery disease, 32 with idiopathic dilated cardiomyopathy, and to 40 normal subjects. Hypertrophic cardiomyopathy patients underwent exercise testing, echocardiography, and Holter monitoring. Hypertrophic cardiomyopathy patients had a high frequency of cardiac symptoms and, on average, had a level of symptomatic morbidity equivalent to that of chronic stable angina and dilated cardiomyopathy. There was no evidence for an excess of anxiety (14%) or depression (6%) in patients with hypertrophic cardiomyopathy. Syncope and presyncope, especially provoked by exertion or posture change, were characteristic and common symptoms in hypertrophic cardiomyopathy. A history of syncope was associated with an abnormal blood pressure response to exercise in over 50% of cases that may be the mechanism of syncope in some. Postprandial exacerbation of symptoms occurred in over one-third of hypertrophic cardiomyopathy patients, half of coronary disease patients, and infrequently in dilated cardiomyopathy. Hypertrophic cardiomyopathy patients with postprandial symptoms had a greater frequency of angina, were more symptomatic, and had a reduced exercise capacity, suggesting that postprandial symptoms are a marker for more severe disease.

Adolescent↗
PubMed1996

Chemiluminescent enhanced CD47 detection on Western blotting.

CD47 is a leucocyte antigen of wide tissue distribution including platelets and erythrocytes. It has been found that anti-CD47 antibodies may cause platelet activation. Sensitive techniques are therefore needed for biochemical investigation of platelet glycoproteins including CD47. Conventional Western blotting techniques using horseradish peroxidase-conjugated antibody and 3,3'-diaminobenzidine (DAB) substrate resulted in unsatisfactory results with CD47 due to low sensitivity. When chemiluminescent detection with horseradish peroxidase-conjugated antibody was used in conjunction with Western blotting, detection of the CD47 molecule was greatly enhanced. A protein of 47--55 kDa was immunoblotted from platelets by anti-CD47 while the mAb immunoblotted a broader band (45--60 kDa) from erythrocyte membranes. Thus, there may be different forms of CD47 present on platelets and erythrocytes. The results indicate that Western blotting with the chemiluminescent detection technique is a useful and sensitive alternative for the study of human platelet antigens.

Antigens, CD↗
PubMed1996

Comparison of the effects of the 5-HT3 receptor antagonists WAY-100579 and ondansetron on spatial learning in the water maze in rats with excitotoxic lesions of the forebrain cholinergic projection system.

The effects of the 5-HT3 receptor antagonists. WAY-100,579 and ondansetron (both at doses of 0.001, 0.01 and 0.1 mg/kg s.c.) and the muscarinic receptor agonist arecoline (1.0 mg/kg s.c.), on spatial learning and memory in the water maze were examined in rats after combined S-AMPA lesions to the nucleus basalis and medial septal brain regions. Lesioned rats showed substantially increased latency to find the submerged platform, and spent less time searching in the correct quadrant, and more time circling the periphery of the pool, relative to controls. Lesioned rats treated with WAY-100,579, ondansetron and arecoline exhibited marked improvement in these parameters of learning relative to lesioned animals, with arecoline-treated animals showing the most substantial recovery. Linear dose-related trends of improvement were seen with both of the 5-HT3 antagonists. In probe trials, testing retention of the platform position 24 and 72 h after the end of training, control rats exhibited substantial superiority relative to lesioned rats in accuracy of search in the training quadrant and former platform area, matched by rats treated with arecoline on the first, and by rats treated with the two higher doses of WAY-100,579 and ondansetron on the second probe trial. These results are consistent with our previous studies which demonstrated that another selective 5-HT3 receptor antagonist. WAY-100,289, significantly reversed the cognitive deficits in water maze performance induced by ibotenic acid lesions of forebrain cholinergic projection system. Therefore, selective 5-HT3 receptor antagonists may provide a novel effective therapy for treating cognitive deficits associated with degeneration of central cholinergic neurones, such as Alzheimer's disease or age-associated memory impairment.

Animals↗
PubMed1996

Electrophysiological, biochemical, neurohormonal and behavioural studies with WAY-100635, a potent, selective and silent 5-HT1A receptor antagonist.

Although considerable progress has been made in characterising the 5-HT1A receptor using agonists, partial agonists or non-selective antagonists, further studies of 5-HT1A receptor function have been hindered by the lack of highly selective antagonists. The term 'silent' antagonist has been used for such compounds in order to distinguish them unequivocally from several 5-HT1A receptor partial agonists which were initially designated 'antagonists'. In this report we provide a comprehensive review of the biochemical, pharmacological and behavioural properties of the first potent, selective and silent 5-HT1A receptor antagonist, WAY-100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl)-N-(2- pyridinyl)cyclohexanecarboxamide trihydrochloride). WAY-100635 had an IC50 (displacement of specific [3H]8-OH-DPAT binding to 5-HT1A receptors in the rat hippocampus) of 1.35 nM and was > 100-fold selective for the 5-HT1A site relative to a range of other CNS receptors. [3H]WAY-100635 was also characterised as the first 5-HT1A antagonist radioligand, displaying the same regional distribution of binding sites as [3H]8-OH-DPAT in rat brain. As would be expected for the binding of an antagonist to a G-protein-coupled receptor, the Bmax of [3H]WAY-100635 specific binding was consistently 50-60% greater than that of the agonist radioligand, [3H]8-OH-DPAT. Mn2+, but not guanine nucleotides, inhibited [3H]WAY-100635-specific binding. [3H]WAY-100635 was also shown to bind selectively to brain 5-HT1A receptors in vivo, following intravenous administration to mice. In vitro electrophysiological studies demonstrated that WAY-100635 had no 5-HT1A receptor agonist actions, but dose-dependently blocked the effects of agonists at both the postsynaptic 5-HT1A receptor in the CA1 region of the hippocampus, and the somatodendritic 5-HT1A receptor located on dorsal raphe 5-HT neurones. In vivo, WAY-100635 also dose-dependently blocked the ability of 8-OH-DPAT to inhibit the firing of dorsal raphe 5-HT neurones, and to induce the '5-HT syndrome', hypothermia, hyperphagia and to elevate plasma ACTH levels. In the mouse light/dark box anxiety model, WAY-100635 induced anxiolytic-like effects. WAY-100635 had no intrinsic effect on cognition in the delayed-matching-to-position model of short-term memory in the rat, but reversed the disruptive effects of 8-OH-DPAT on motor motivational performance. These data clearly demonstrate that WAY-100635 is the first potent, selective and silent 5-HT1A receptor antagonist. Furthermore, [3H]WAY-100635 is the first antagonist radioligand to become available for 5-HT1A receptor binding studies both in vitro and in vivo. The positive effects of WAY-100635 in an anxiety model also indicate that a postsynaptic 5-HT1A receptor antagonist action may contribute to the anxiolytic properties of 5-HT1A receptor partial agonists.

Adrenocorticotropic Hormone↗
PubMed1996

Characterization of the radioactive metabolites of the 5-HT1A receptor radioligand, [O-methyl-11C]WAY-100635, in monkey and human plasma by HPLC: comparison of the behaviour of an identified radioactive metabolite with parent radioligand in monkey using PET.

N-(2-(4-(2-Methoxy-phenyl)-1-piperazin-1-yl)ethyl)-N-(2-pyridyl) cyclohexanecarboxamide (WAY-100635), labelled in the O-methyl group with carbon-11 (t1/2 = 20.4 min), is a promising radioligand for application with positron emission tomography (PET) to the study of 5-HT1A receptors in living human brain. An understanding of the metabolism of this new radioligand is crucial to the development of a biomathematical model for the interpretation of the kinetics of radioactivity uptake in brain in terms of receptor-binding parameters. After intravenous injection of [O-methyl-11C]WAY-100635 into humans, radioactivity was found to clear rapidly from blood and plasma. By using established methods for the analysis of radioactivity in plasma, it was found that intravenously injected [O-methyl-11C]WAY-100635 is rapidly metabolised to more polar radioactive compounds in a cynomolgus monkey and in humans. Thus, at 60 min postinjection, parent radioligand represented 40% and 5% of the radioactivity in monkey and human plasma, respectively. In monkey and human, one of the radioactive metabolites was identified as the descyclohexanecarbonyl analogue of the parent radioligand, namely [O-methyl-11C]WAY-100634. This compound is known to have high affinity for 5-HT1A receptors and alpha 1-adrenoceptors. In a PET experiment it was demonstrated that, after IV injection of [O-methyl-11C]WAY-100634 into a cynomolgus monkey, radioactivity was avidly taken up by brain. Uptake of radioactivity was higher in 5-HT1A receptor-rich frontal cortex than in cerebellum, which is devoid of 5-HT1A receptors. Polar radioactive metabolites appeared in plasma. The results suggest that the use of WAY-100635 labelled with carbon-11 in its cyclohexanecarbonyl moiety may provide enhanced signal contrast in PET studies and a possibility to develop a simple biomathematical model for regional brain radioactivity uptake.

Animals↗
PubMed1996

Reversibility of cerebral ventricular enlargement in anorexia nervosa, demonstrated by quantitative magnetic resonance imaging.

OBJECTIVE: To determine the reversibility of the loss of brain parenchyma and ventricular enlargement in patients with anorexia nervosa after refeeding. STUDY DESIGN: Quantitative magnetic resonance imaging was performed on three groups of subjects: (1) 12 female adolescents hospitalized with anorexia nervosa, (2) the same 12 patients after nutritional rehabilitation, a mean of 11.1 months later, and (3) 12 healthy age-matched control subjects. Sixty-four contiguous coronal magnetic resonance images, 3.1 mm thick, were obtained. With a computerized morphometry system, lateral and third ventricular volumes were measured by a single observer unaware of the status of the patient. RESULTS: On admission, patients were malnourished and had lost an average of 11.7 kg (body mass index, 14.3 +/- 2.0 kg/m2). After refeeding, they gained an average of 9.7 kg (body mass index, 17.9 +/- 1.5 kg/m2). Total ventricular volume decreased from 17.1 +/- 5.5 cm3 on admission to 12.4 +/- 3.0 cm3 after refeeding (p < 0.01) and returned to the normal range. The degree of enlargement of the third ventricle was greater than that of the lateral ventricles. There was a significant inverse relationship between body mass index and total ventricular volume (r = -0.63; p < 0.05). CONCLUSION: In patients with anorexia nervosa, cerebral ventricular enlargement correlates with the degree of malnutrition and is reversible with weight gain during long-term follow-up.

Adolescent↗
PubMed1996

Coordinator's report on the flow cytometric analysis of the Rh antibodies.

One hundred and four IgG monoclonal antibodies with specificity within the Rh Blood Group System were evaluated by flow cytometry as part of the Third International Workshop. Standardisation of data to permit interlaboratory comparison of antibody binding was achieved by adherence to a standard red blood cell staining protocol, defined control cells and a standard FITC-labelled antibody. In addition, calibration standards were provided to permit the calculation of Molecules of Equivalent Soluble Fluorochrome (MESF) values from the mean channel fluorescence. For the majority of anti-D antibodies mean MESF values obtained with D positive cells were far higher than with the negative controls (D negative cells), with D variants having intermediate although very varied MESFs. In general MESF values obtained with non anti-D antibodies were less than for the anti-D antibodies although some of the anti-E antibodies were very strong. The highest MESF values were obtained with an anti-CD antibody.

Antibodies, Monoclonal↗
PubMed1996

The evaluation of diagnostic and prognostic criteria and the terminology of thin cutaneous malignant melanoma by the CRC Melanoma Pathology Panel.

Sections from 95 skin lesions excised at pigmented lesion clinics in England and Scotland were studied by eight histopathologists in order to evaluate consistency in the use of histopathological terms for features of diagnostic and prognostic importance for cutaneous malignant melanoma. The level of agreement (kappa) amongst the panel improved after discussion and re-definement of criteria for several features. These included, architectural and nuclear atypia, pagetoid infiltration and radial and vertical growth phases. A high level of agreement was achieved for an overall benign or malignant diagnosis (kappa = 0.77) but use of more specific terms such as benign naevi with atypia and melanoma < or = 0.76 mm thickness, was associated with only an intermediate level of agreement. Of the original diagnosis of melanoma, 17% were re-classified by the panel as benign with atypia and 2% reported to be benign were judged to be melanoma. This reflected the high proportion of borderline lesions in the study. The use of standardized diagnostic criteria with precise definitions has been shown to improve consistency in diagnosis and it is recommended for general application. From this should emanate more reliable incidence figures for thin melanoma, and improved understanding of the nature of these early lesions, to the benefit of patient and clinician alike. The poor concordance in distinguishing severe dysplasia in the junctional component of melanocyte proliferations from melanoma in situ and superficial dermal invasion improved only modestly despite intensive efforts. Since melanoma in situ and severe dysplasia cannot be distinguished by objective measurements and since their clinical management is the same, the panel suggests that attempts to separate them in diagnostic reports should be discontinued and they could both be referred to as melanocytic intraepidermal neoplasia (MIN). If it becomes accepted that dermal invasion without a vertical growth component can also be managed identically to MIN, then this invasive radial phase may be appropriately referred to as microinvasion and linked to MIN for the purposes of clinical management.

Biopsy↗
PubMed1996

Identification of a new plasma alpha(1,3)fucosyltransferase (FUT6) allele requires an extended genotyping strategy.

Screening the FUT6 gene of 40 Swedish individuals, originally selected for genotyping of FUT3, revealed an unexpected high frequency of mutations. Four were originally typed as homozygous for the enzyme lethal mutation G739A by Taq alpha I restriction pattern, but only one lacked plasma alpha(1,3)fucosyltransferase activity. Cloning and sequencing of FUT6 from 2 of them revealed a new allele, without the G739A mutation, but with two new point mutations C738T and G977A. Segregation of this allele was confirmed in Swedish and Indonesian families. Since G739A and C738T mutations are only one nucleotide apart and induce the same modification of Taq alpha I cleavage, a new screening strategy for FUT6 was adopted. The homozygous inactivating G739A mutation was for the first time identified in Caucasian and Polynesian individuals, both lacking plasma enzyme activity. The mutation C370T was present in 25 of the 40 Swedish individuals and the inactivating mutation C945A was not found at all. These findings stress the dangers of transferring restriction enzyme genotype strategies from one population to another and of inferring phenotypes from genotypes without phenotyping and/or performing confirmatory cloning and sequencing.

Alleles↗
PubMed1996

Effect of blood donation on the establishment of normal ranges of lymphocyte subsets.

BACKGROUND: Absolute counts of CD4+ T-lymphocytes are used in the management of patients with human immunodeficiency virus infection. Low absolute counts of CD3+CD4+ cells have also been observed in healthy people--a phenomenon called idiopathic CD4 lymphocytopenia. It is common practice for normal ranges for lymphocyte subsets to be derived from samples taken from blood donors. STUDY DESIGN AND METHODS: A sample of EDTA blood was taken through the donation line tubing, after donation from 565 blood donors in Sydney, Australia, who were selected from a range of age groups. An additional 12 donors provided a predonation sample as well as a postdonation sample. Hematologic assays were performed on two analyzers. Samples were stained for CD3, CD4, CD8, CD19, and CD56 and analyzed on a flow cytometer. RESULTS: Three donors were found to have absolute CD3+CD4+ counts < 300 cells per microL. The percentage of CD3+CD4+ cells was found to increase with age. Both the percentage and the absolute count of CD3+CD8+ cells decreased with age, which resulted in an increased CD4:CD8 ratio with age. Men had consistently higher absolute counts of CD3-CD56+ cells than women. The 12 additional donors all had greater percentages of CD3+CD4+ cells and lower absolute counts for CD3+, CD3+CD4+, CD3+CD8+, CD19+ and CD3-CD56+ cells after donation than they had before donation (p < 0.001). CONCLUSION: It is not satisfactory to base normal ranges for lymphocyte subsets on donor blood, from which the blood sample has been obtained after donation.

Adolescent↗
PubMed1996

Effects of 8-OHDPAT and 5-HT1A antagonists WAY100135 and WAY100635, on guinea-pig behaviour and dorsal raphe 5-HT neurone firing.

1. The effects of 5-HT1A antagonists on guinea-pig behaviour and dorsal raphe neuronal activity were investigated. 2. WAY100135 (10 mg kg-1, s.c.) and WAY100635 (1 mg kg-1, s.c.) significantly reduced the behaviours induced by 8-hydroxy-2-(di-n-propylamino) tetralin (8-OHDPAT) (1 mg kg-1, s.c.) indicative of post-synaptic 5-HT1A receptor antagonism. WAY100635 (10 mg kg-1, s.c.) alone induced ear twitches, which were antagonized by ketanserin (1 mg kg-1, s.c.), but no other overt behaviours. 3. WAY100635 (0.125 mg kg-1, i.v.) produced a right-ward shift in the dose-related inhibition of neuronal firing by 8-OHDPAT (5-100 micrograms kg-1, i.v.) but did not affect the maximum inhibition induced by 8-OHDPAT indicating competitive antagonism between 8-OHDPAT and WAY100635 at the 5-HT1A somato-dendritic autoreceptor in the dorsal raphe nucleus of the guinea-pig. WAY100635 also produced a dose-related increase in the basal firing of 5-HT neurones in the dorsal raphe nucleus and restored the firing of dorsal raphe neurones previously inhibited by 8-OHDPAT (10 micrograms kg-1, i.v.). 4. The results indicate that WAY100635 is a competitive 5-HT1A antagonist in the guinea-pig. Furthermore WAY100635 can increase 5-HT neuronal firing, suggesting that it blocks a 5-HT1A receptor-mediated inhibitory tone acting on guinea-pig 5-HT neurones resulting in increased 5-HT release and 5-HT2 receptor-mediated behaviours.

8-Hydroxy-2-(di-n-propylamino)tetralin↗