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K Zhou,
L Donnelly,
L Burch,
R Tavendale,
A S F Doney, G Leese,
A T Hattersley,
M I McCarthy,
A D Morris,
C C Lang,
C N A Palmer,
E R Pearson
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ABSTRACT: Sulfonylureas are metabolized mainly by the cytochrome p450 2C9 (CYP2C9) enzyme. Two CYP2C9 variants--*2 (Arg144Cys) and *3 (Ile359Leu)--are associated with reduced enzyme activity and impaired substrate metabolism. We identified 1,073 incident users of sulfonylureas in Tayside, Scotland, and assessed the impact of the combined CYP2C9*2 and CYP2C9*3 genotypes on early and sustained sulfonylurea response. We found that patients with two copies of a loss-of-function allele were 3.4 times (P = 0.0009) more likely to achieve a treatment hemoglobin A(1c) (HbA(1c)) level <7% than patients with two wild-type CYP2C9 alleles. This corresponds to a 0.5% (P = 0.003) greater reduction in HbA(1c) concentration. In addition, *2 and *3 allele carriers were less likely to experience treatment failure with sulfonylurea monotherapy (P = 0.04; per-allele hazard ratio 0.79; 95% confidence interval 0.63-0.99). In conclusion, CYP2C9 loss-of-function alleles are associated with greater response to sulfonylureas and decreased failure of therapy consistent with the pharmacokinetic role of CYP2C9.
Clinical Pharmacology & Therapeutics 09/2009; 87(1):52-6. · 6.04 Impact Factor
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ABSTRACT: Physical activity is a cornerstone of Type 2 diabetes management but is underutilized. Physical activity consultations increase physical activity in people with Type 2 diabetes but resources are often limited. Time2Act is a randomized control trial to study the 12-month effectiveness of a physical activity consultation delivered by a person or in written form, in contrast to standard care, for people with Type 2 diabetes.
A total of 134 inactive people with Type 2 diabetes in a contemplation or preparation stage were randomized to either intervention or standard care. Objective (accelerometer) and subjective (7-day recall) physical activity levels were measured over 1 week, along with physiological [blood pressure, body mass index (BMI), waist circumference] and biochemical [glycated haemoglobin (HbA(1c)), total and high-density lipoprotein (HDL) cholesterol] measures at baseline, 6 and 12 months.
Neither a physical activity consultation delivered by a person nor in written form was better than standard care at increasing physical activity levels or improving health outcomes in the full study cohort. Total and HDL cholesterol, waist circumference and both systolic and diastolic blood pressure improved over 12 months in all groups, whilst HbA(1c) improved over 6 months. In a subgroup (baseline pedometer steps < 5000/day), the physical activity consultation delivered by a person significantly increased physical activity over 12 months and the standard care group significantly decreased.
More research is needed which not only investigates the most economical and effective methods to promote physical activity, but also the best setting to conduct physical activity consultations and the participant factors affecting uptake of physical activity in Type 2 diabetes.
Diabetic Medicine 04/2009; 26(3):293-301. · 2.90 Impact Factor
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ABSTRACT: To determine whether Z scores can be used to predict the likelihood of patients having a secondary cause of low bone mineral density.
A retrospective cross sectional study was conducted among 136 consecutive patients with osteoporosis at Ninewells Hospital, Dundee, UK, between 1998-2002.
20.5% of female patients in this study were identified with previously unrecognised contributors to the low bone mineral density. In women, at a Z score cut-off of -1, the sensitivity of detecting a secondary cause for osteoporosis is 87.5% with a positive predictive value of 29.2%.
In women, a Z score of -1 would identify a majority of patients with a secondary cause for low bone mineral density and identifies patients who would especially benefit from a thorough history and clinical examination.
Postgraduate medical journal 02/2009; 85(999):38-9. · 1.38 Impact Factor
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ABSTRACT: Lymphocytic Hypophysitis (LH) is a rare and previously under-recognised disorder, most commonly affecting young females in the post-partum period. It presents clinically with symptoms and signs related to either a pituitary mass or hypopituitarism, frequently mimicking a pituitary adenoma; the diagnosis of LH can only be made histologically with the presence of a dense lymphocytic infiltration usually confined to the anterior pituitary. We present two case histories of patients who presented with symptoms suggestive of a functioning pituitary adenoma who also had concomitant LH confirmed histologically. The first case was a 39 year old lady, with a history of primary hypothyroidism, who presented with weight gain and hirsutism and clinical and biochemical features of Cushing's syndrome. The second case was a 61 year old male, also with a history of primary hypothyroidism, who presented with visual field loss and biochemically with hyperprolactinaemia. In both patients, magnetic resonance (MR) imaging of the pituitary demonstrated an enlarged partially cystic pituitary mass with slight suprasellar extension. Both patients were treated surgically with transphenoidal drainage and excision and histological examination of the surgical specimens demonstrated a mixture of pathologies with fragments of adenohypophyseal tissue (staining positive for ACTH and prolactin respectively) with a dense chronic inflammatory cell infiltrate suggestive of LH in nearby normal anterior pituitary. In both cases a joint diagnosis of a functioning pituitary adenoma with LH was made. There have been only several reported cases of this combination of pathologies but LH even in isolation is becoming increasingly recognised.
Endocrine Journal 06/2008; 55(4):729-35. · 2.03 Impact Factor
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ABSTRACT: To describe the relationship between fear of visual loss and dependent variables (visual acuity, retinopathy treatment, severity of retinopathy) in community-based diabetic patients.
Subjects were identified from the Diabetes Audit and Research in Tayside, Scotland (DARTS) diabetes register. From a total of 4825 individuals known to have diabetes and who were resident in Dundee and Perth (population 216 204; diabetes prevalence 2.23%), 586 persons with diabetes were randomly selected. Participants completed a self-administered questionnaire in Likert grade format which incorporated two items addressing presence and intensity of fear of visual loss.
Questionnaires were returned by 61.4% of the cohort. Fear of visual loss was 'often in mind' for 37% of respondents, and that fear was intense for 47.4%. Analysis by diabetes type revealed differences in reported fear of Type 1 and Type 2 patients in relation to disease and treatment variables. Linear regression highlighted the complexity of the issue with retinal status, acuity and treatment only partly explaining reported patient concern (r(2) range: 0.051-0.125 for presence of fear; 0.026-0.04 for intensity of fear, depending on diabetes type).
Fear of visual loss is preoccupying and intense for a substantial proportion of the diabetic population. Reasons for this are multiple and complex. Objective measures of visual impairment and retinal status are inadequate predictors of fear. Carers and researchers need to be mindful of this when approaching patients with diabetes.
Diabetic Medicine 11/2007; 24(10):1086-92. · 2.90 Impact Factor
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ABSTRACT: To describe the use of a validated diabetes register for sampling frame generation and assessment of the representative nature of participants in a fieldwork study of diabetic eye disease.
We performed an observational, cross-sectional fieldwork study of diabetic retinal disease using reference standard eye examination. We sampled the entire diabetic population using the Diabetes Audit and Research in Tayside Study (DARTS) diabetes register.
The study population comprised 4825 diabetic patients aged over 16 years registered with one of 166 general practitioners (GPs) in 41 practices in Tayside in October 1999. This represented 61.1% of the Tayside diabetic population (7903). A total of 586 (66%; 95% confidence interval 63, 70) patients were examined from a sampling frame of 882 living patients registered with a Tayside GP. Demographic and disease parameters recorded on the DARTS patient register allowed comparison between participants and non-participants.
This study shows the clear benefit of using a complete diabetic population as a sampling frame. This allows potential selection bias and external validity to be evaluated using routine data sources. Studies performed and reported in this way will aid the critical appraisal process.
Diabetic Medicine 01/2005; 21(12):1353-6. · 2.90 Impact Factor
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ABSTRACT: A National Screening Programme for diabetic eye disease in the UK is in development. We propose a grading and early disease management protocol to detect sight-threatening diabetic retinopathy and any retinopathy, which will allow precise quality assurance at all steps while minimizing false-positive referral to the hospital eye service.
Expert panel structured discussions between 2000 and 2002 with review of existing evidence and grading classifications. PROPOSALS: Principles of the protocol include: separate grading of retinopathy and maculopathy, minimum number of steps, compatible with central monitoring, expandable for established more complex systems and for research, no lesion counting, no 'questionable' lesions, attempt to detect focal exudative, diffuse and ischaemic maculopathy and fast track referral from primary or secondary graders. Sight-threatening diabetic retinopathy is defined as: preproliferative retinopathy or worse, sight-threatening maculopathy and/or the presence of photocoagulation. In the centrally reported minimum data set retinopathy is graded into four levels: none (R0), background (R1), preproliferative (R2), proliferative (R3). Maculopathy and photocoagulation are graded as absent (M0, P0) or present (M1, P1).
The protocol developed by the Diabetic Retinopathy Grading and Disease Management Working Party represents a new consensus upon which national guidelines can be based leading to the introduction of quality-assured screening for people with diabetes.
Diabetic Medicine 01/2004; 20(12):965-71. · 2.90 Impact Factor
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Diabetic Medicine 12/2001; 18(11):943. · 2.90 Impact Factor
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ABSTRACT: To evaluate whether diabetes mellitus is a risk factor for the development of primary open angle glaucoma or ocular hypertension (OHT).
A historical cohort study of an unselected population comprising all residents of the Tayside region of Scotland was performed using record linkage techniques followed by case note review. Ascertainment of prevalent diabetes was achieved using the Diabetes Audit and Research in Tayside Study (DARTS) validated regional diabetes register. Glaucoma and treated OHT were defined by encashment of community prescriptions and the statutory surgical procedure coding database.
The study population comprised 6631 diabetic subjects and 166 144 non-diabetic subjects aged >40 years without glaucoma or OHT at study entry. 65 patients with diabetes and 958 without diabetes were identified as new cases of glaucoma or treated OHT during the 24 month study period, yielding a standardised morbidity ratio of 127 (95% CI, 96-158). Case note review demonstrated non-differential misclassification of prevalent glaucoma and OHT as incident disease (diabetic cohort 20%, non-diabetic cohort 24%; p=0.56) primarily as a result of non-compliance in medically treated disease. Removing misclassified cases and adjusting for age yielded an incidence of primary open angle glaucoma in diabetes of 1.1/1000 patient years (95% CI, 0.89-1. 31) compared to 0.7/1000 patient years (95% CI, 0.54-0.86) in the non-diabetic cohort; RR 1.57 (95% CI, 0.99-2.48).
This study failed to confirm an association between diabetes mellitus and primary open angle glaucoma and ocular hypertension. A non-significant increase in diagnosed and treated disease in the diabetic population was observed, but evidence was also found that detection bias contributes to this association.
British Journal of Ophthalmology 12/2000; 84(11):1218-24. · 2.90 Impact Factor
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ABSTRACT: Hyponatraemia is a common bio-chemical abnormality, occurring in about 15% of hospital inpatients. It is often associated with severe illness and relatively poor outcome. Pathophysiologically, hyponatraemia may be spurious, dilutional, depletional or redistributional. Particularly difficult causes and concepts of hyponatraemia are the syndrome of inappropriate antidiuresis and the sick cell syndrome, which are discussed here in detail. Therapy should always be targeted at the underlying disease process. 'Hyponatraemic symptoms' are of doubtful importance, and may be more related to water overload and/or the causative disease, than to hyponatraemia per se. Artificial elevation of plasma sodium by saline infusion carries the risk of induction of osmotic demyelination (central pontine myelinolysis).
Postgraduate Medical Journal 10/1998; 74(875):516-23. · 1.94 Impact Factor
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ABSTRACT: A patient with a pituitary adenoma secreting follicle-stimulating hormone with co-existent primary hyperaldosteronism is described. After his second transsphenoidal surgery, the patient developed a Staphylococcus aureus pituitary abscess. Symptoms improved after abscess drainage. Subsequent cabergoline therapy arrested the deterioration of symptoms. and decreased serum follicle-stimulating hormone concentrations. Cabergoline may be a useful treatment for aggressively growing non-prolactin-secreting pituitary adenomas.
Postgraduate Medical Journal 09/1997; 73(862):507-8. · 1.94 Impact Factor
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ABSTRACT: The purpose of this study was to determine whether a short period (5 days) of night-shift work affected the pituitary-adrenal responses to CRH. Ten nurses (8 female and 2 male; age 28.1 +/- 1.7 yr: mean +/- SEM) working at the Royal Liverpool University Hospital, and who regularly undertook periods of night and day shift work were enrolled. Measurements were made of basal ACTH and cortisol concentrations, and their responses to iv ovine CRH (1 microgram.kg-1). Basal ACTH concentrations were higher during the night shift than during the day shift (12.9 +/- 5.1 pmol.L-1 vs. 4.7 +/- 1.2 pmol.L-1, P < 0.01) whereas cortisol concentrations were lower (551 +/- 48 nmol.L - 1 vs. 871 +/- 132 nmol.L - 1, P < 0.01). After CRH injection, ACTH concentrations remained consistently higher during the night shift, but the integrated increase in ACTH concentration was lower (P < 0.05) than during the day shift. Conversely, the increase in cortisol concentration was greater during the night shift than the day shift (283 +/- 53 nmol.L-1 vs. 134 +/- 41 nmol.L-1, P < 0.05). We conclude that the pituitary-adrenal responses to CRH are markedly disrupted after only 5 days of nighttime work. These abnormalities mimic those previously observed in patients with chronic fatigue syndrome. Neuroendocrine abnormalities reported to be characteristic of chronic fatigue syndrome may be merely the consequence of disrupted sleep and social routine.
Journal of Clinical Endocrinology & Metabolism 05/1996; 81(5):1867-70. · 6.50 Impact Factor
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BMJ 12/1995; 311(7014):1230-1. · 14.09 Impact Factor
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Injury 04/1993; 24(3):212-3. · 1.98 Impact Factor
