Sire selection and genetic improvement of dairy cattle assuming pure market competition.

Breeding companies and farmers rely on selection indices to identify sires they expect to improve production system profitability. Such indices combine estimates of genetic merit for individual traits with corresponding economic values that are fixed based on circumstances at a particular time. Perfect market competition has also been proposed as an economic basis to value alternative sires. The objective of this study was to propose an economic model and develop it for the evaluation of dairy sires. The pure competition model (PUC) was used to evaluate the relationship between a profitability index based on the PUC approach versus the traditional selection index approach for 330 dairy sires comprising Holstein-Friesians, Jerseys, and Ayrshires. The correlation between these 2 selection indices was only 0.56, indicating that the conventional selection index did not correlate well with an index based on the PUC model. In particular, the higher ranking bulls were overvalued using the conventional selection index. Our study concluded that the use of fixed economic values is problematic for the delivery of consistent rankings in selection indices. In contrast, sire rankings based on PUC are more reliable because the sires are evaluated on the basis of efficiency gains rather than production while accounting for market prices and marginal values of dairy outputs over time.

Protection Against Nephropathy in Diabetes with Atorvastatin (PANDA): a randomized double-blind placebo-controlled trial of high- vs. low-dose atorvastatin(1).

AIMS: To compare the renal effects of low- vs. high-dose atorvastatin in patients with Type 2 diabetes mellitus and optimally managed early renal disease. METHODS: We compared the 2-year progression of nephropathy in a double-blind randomized controlled trial of atorvastatin 80 mg/day (n = 60) vs. 10 mg/day (n = 59) in patients with Type 2 diabetes with microalbuminuria or proteinuria [mean (sd): age 64 years (10 years); HbA(1c) 7.7% (1.3%), 61 mmol/mol (10 mmol/mol); blood pressure 131/73 mmHg; renin-angiotensin system blocker use > 80%; dual blockade > 67%] recruited from diabetes clinics in Greater Manchester. RESULTS: Over (mean) 2.1 years of follow-up, the Modification of Diet in Renal Disease estimated glomerular filtration rate declined by 3 ml min(-1) 1.73 m(-2) in the combined group. The mean (95% CI) between-group difference during follow-up was not significant [2.2 ml min(-1) 1.73 m(-2) (-1.1 to 5.4 ml min(-1) 1.73: m(-2) ), P = 0.20] after adjusting for baseline differences in renal function; positive difference favours 80 mg dose. Similarly, there was no significant difference in creatinine clearance by Cockcroft and Gault [2.5 ml/min (-2.4 to 7.3 ml/min), P = 0.32]; serum creatinine/24-h urine collections [4.0 ml/min (-4.8 to 12.7 ml/min), P = 0.38]; cystatin C (P = 0.69); or 24-h urine protein or albumin excretion (P = 0.92; P = 0.93). We recorded no significant between-group differences in deaths or adverse events. CONCLUSIONS: In patients with Type 2 diabetes with early renal disease, we found no statistical difference in renal function between those taking high- or low-dose atorvastatin over 2 years. We cannot exclude a beneficial effect of < 1.6 ml min(-1) 1.73 m(-2) year(-1) on Modification of Diet in Renal Disease estimated glomerular filtration rate, or if blood pressure management or if renin-angiotensin system blocker use had not been optimized.

Stabilizing effect of exenatide in a patient with C-peptide-negative diabetes mellitus.

BACKGROUND: Exenatide is an incretin mimetic licensed for treatment of Type 2 diabetes poorly controlled despite maximally tolerated doses of oral therapy. Similar in structure to the natural incretin hormone glucagon-like peptide 1 (GLP-1), it helps restore underlying pathophysiological abnormalities. CASE REPORT: We report the successful use of exenatide, combined with insulin, in a 66-year-old woman initially diagnosed with Type 2 diabetes in 1989 but now exhibiting a Type 1 phenotype. Diet, lifestyle advice and oral glucose-lowering agents were commenced but persisting poor control necessitated insulin therapy in 2005. She later presented twice in diabetic ketoacidosis, suggesting conversion to a Type 1 phenotype (postprandial C-peptide < 94 pmol/l). Despite differing insulin regimens, control remained poor with frequent hyperglycaemic and hypoglycaemic excursions, severely impairing quality of life. Whilst an inpatient in 2007 [glycated haemoglobin (HbA(1c)) 10.2%, body mass index (BMI) 31.5 kg/m(2)] exenatide was commenced in an attempt to stabilize glycaemic control. Dramatic improvements were seen and continued. Eight months later, HbA(1c) had fallen by 2% with an 8-kg weight loss and 10-unit reduction in daily insulin dose. Quality of life dramatically improved. C-peptide remains undetectable. CONCLUSIONS: This patient with features of both Type 1 and Type 2 diabetes benefited greatly from exenatide with insulin therapy. The improvement seen in glycaemic control could not be attributable to enhanced insulin secretion but could be as a result of a combination of the other incretin effects (postprandial glucagon suppression, delayed gastric emptying and weight loss secondary to increased satiety) all improving insulin sensitivity, reducing insulin dose and smoothing control.

A pilot randomized trial in primary care to investigate and improve knowledge, awareness and self-management among South Asians with diabetes in Manchester.

AIMS: To investigate whether a secondary-primary care partnership education package could improve understanding of diabetes care among South Asians. METHODS: In a pilot randomized controlled trial, in the setting of eight general practices randomized to intervention or control, patients were invited to four or more rotating visits per year by one of a diabetes specialist nurse, dietician or chiropodist working with general practice staff. Participants were from lists of South Asian patients with known Type 2 diabetes in each (general) practice. RESULTS: Patients and practice scores at baseline and 1-year follow-up, from an interview using a questionnaire on knowledge, awareness and self-management of diabetes. Responses were developed into educational packages used during intervention. Of the 411 patients listed at baseline only 211 were traced for interview (refusal only 4%). Mean age was 55.4 years, age of diabetes onset 47.1 years. Fourteen percent were employed and 35% were able to communicate in English fluently. Only 118 could be traced and interviewed at 1 year, although there was no significant difference in demography between those who completed the study and those who did not. Despite a mean of four visits/patient, intervention had no impact on scores for diabetes knowledge, or awareness [score change 0.14, 95% confidence interval (CI) -0.20, 0.49] or self-management (-0.05, 95% CI -0.48, 0.39) between baseline and 1 year. CONCLUSIONS: This form of secondary/primary care support did not transfer information effectively, and we suspect similar problems would arise in other similar communities. Different methods of clinician/patient information exchange need to be developed for diabetes in this South Asian group.

Diabetic ketoacidosis precipitated by thyrotoxicosis.

We report two patients with type 1 diabetes mellitus, previously well controlled with good compliance, presenting with unexplained diabetic ketoacidosis. Following initial correction of the metabolic disorder, persisting tachycardia lead to the diagnosis of thyrotoxicosis. In both cases, treatment with propranolol and carbimazole helped in the stabilization of their metabolic states. Although thyrotoxicosis is known to destabilize diabetes control, we can find no reports of it precipitating diabetic ketoacidosis.

Thyrotoxicosis in old age: a different clinical entity?

Thyrotoxicosis generally presents with classic signs and symptoms in younger people. Among the elderly population atypical presentation is recognized, although this has not been well quantified or characterized. To avoid misdiagnosis or delay in diagnosis, clinical suspicion needs to remain high.

Routine analysis of proteins by Kjeldahl and Dumas methods: review and interlaboratory study using dairy products.

The Kjeldahl and Dumas (combustion) methods were compared in 11 laboratories analyzing samples of milk, skim milk powder, whole milk powder, whey protein concentrate, infant formula, casein, caseinate, 2 reference compounds (glycine and EDTA), and a secondary reference skim milk powder. The comparison was conducted by using international standards where applicable. Overall means were 8.818 g N/100 g by the Kjeldahl method and 8.810 g N/100 g by the Dumas method. No evidence was found for a consistent bias between methods that may be of concern in the trading of dairy produce. A review of more than 10 related trials revealed a lack of consensus in the bias between the 2 methods, suggesting that differences in methodology and sources of systematic error may be contributors. For samples containing > 2 g N/100 g, the Dumas relative repeatability and reproducibility standard deviations were consistently about 0.35 and 0.75%, respectively, whereas the corresponding Kjeldahl values declined generally with N content and were significantly larger. The Dumas precision characteristics may be due to the dominance of Leco analyzers in this trials, and in most other recent trials, rather than an inherent method attribute. Protein determination methods for dairy products need to be reviewed and updated. The Dumas method needs Codex Alimentarius status as a recognized test method.

A comparison of qualitative and quantitative research methods used to assess knowledge of foot care among people with diabetes.

Many diabetes-related pathologies, especially among neuropathic patients, are potentially avoidable. Prevention, however, requires appropriate knowledge and understanding. To assess our ability to effect change in behaviour we need adequate tools to measure not only knowledge but also understanding and change of behaviour. To assess individuals' knowledge and beliefs towards diabetic footcare, we used both quantitative and qualitative methods: a structured questionnaire composed of 20 questions was completed by the respondent, followed by a semi-structured interview conducted by the chiropodist. Results from the structured questionnaire were inconsistent with those from the interviews (Wilcoxon test, p < 0.008). The former demonstrated an average knowledge score of 45% while performance during the interview generated data which suggested poorer knowledge levels. Respondents who correctly identified a series of statements regarding diabetic footcare within the questionnaire could not then apply this knowledge meaningfully when interviewed. A structured questionnaire may not be the best means of assessing patients' knowledge and understanding. We need not only to improve patient education regarding footcare, but also to improve our means of measuring patient knowledge and understanding, more accurately to assess the success or otherwise of our interventions.

Cushing's syndrome: still a potential killing disease.

When Harvey Cushing described his syndrome in 1932 he named it the killing disease because of its cardiovascular complications. Heart failure is rarely reported as a presenting feature. We report a case in which left ventricular failure (LVF) was the predominant feature, associated with gross left ventricular hypertrophy (LVH) which regressed after treatment.

Fluoxetine in the treatment of obese type 2 diabetic patients.

In a 12-month randomly allocated double-blind trial in 19 obese Type 2 diabetic patients, fluoxetine 60 mg daily compared to placebo produced a significant fall in median body weight after 3 months (3.8 kg), 6 months (6.5 kg), 9 months (7.1 kg) and at 1 year (5.8 kg). Median fasting blood glucose and HbA1c levels fell significantly after 3 months (1.9 mmol l-1) and 1.7%, respectively) and 6 months (1.8 mmol l-1 and 1.7%) but neither showed a significant difference to placebo after 9 or 12 months therapy with fluoxetine. There were no significant changes in serum cholesterol levels in the year but patients on fluoxetine showed a significant fall in serum triglyceride level (0.5 mmol l-1) after 3 months therapy but not thereafter. Compared to placebo there was a significant fall in median energy intake on fluoxetine after 3 months (257 kcal day-1) and 6 months (199 kcal day-1) but this difference was not significant at 9 or 12 months. There was also a significant fall in carbohydrate intake after 3 months (30 g day-1) and 6 months (23 g day-1) on fluoxetine as well as a significant fall in carbohydrate intake expressed as a percentage of the total daily energy intake; 5.9% at 3 months, 6.1% at 6 months, and 4.0% at 9 months. There were no significant effects on protein or fat intake except a significant increase in the intake of fat expressed as a percentage of daily energy intake, 5.9% after 6 months. Two of the nine patients on fluoxetine dropped out of the study due to gastrointestinal side-effects. Fluoxetine might prove to be a useful adjunct therapy in obese Type 2 diabetic patients where short-term weight loss and fall in carbohydrate intake and an improvement in glycaemia are indicated.

The degree of day-to-day variation in food intake in diabetic patients.

A prospective study of food intake using 7 day food diaries was undertaken in 92 diabetic men and women aged 17-81 years. The median individual day-to-day coefficients of variation for energy intake were: in insulin treated patients 12.0%, in non-insulin treated patients 13.7%; for carbohydrate intake 14.5% and 13.8% and for fat 20.7% and 20.8%, respectively. The median individual differences between the minimum and maximum daily intake of energy in insulin treated patients was 787 kcal, in non-insulin treated patients 649 kcal, for carbohydrate intake 89g and 77g and fat 50g and 43g, respectively. Only 39% patients ate within 20% of their prescribed carbohydrate diet. In non-insulin treated patients on prescribed calorie controlled diets, calorie consumption was on average 46% in excess of that prescribed. Although the variation in dietary intake in diabetic patients is large, it is smaller than that reported in non-diabetic subjects in the UK. This variation is likely to make the manipulation of other antidiabetic therapy both difficult and somewhat arbitrary.

Diabetic diets and nutritional recommendations: what happens in real life?

Prospective 7-day estimated weight food records were computer analysed in 92 diabetic patients, 45 men and 47 women, 25 with Type 1 and 67 Type 2 diabetes, attending a hospital-based diabetic clinic. The nutrient intakes were compared with a national survey in non-diabetic British adults (OPCS) and the current EASD recommendations for the diabetic diet. Only three diabetic patients achieved the recommended 50-60% energy intake as carbohydrate, four achieved less than 30% energy as fat, one patient less than 10% saturated fat and 20 ate greater than 30 g fibre per day. The overall nutrient intakes of these diabetic patients reflected those of non-diabetic subjects except for a greater intake of protein and smaller intakes of sugar and alcohol. These findings reinforce the problems currently faced in achieving the present recommendations for the diabetic diet.

Early loss of neurogenic inflammation in the human diabetic foot.

1. Neurogenic inflammation, mediated by nociceptor C fibres, is part of the acute neurovascular response to injury producing the axon reflex flare. Laser Doppler flowmetry was used to measure the flare response induced by the electrophoresis, at various current strengths, of a ring of acetylcholine solution into dorsal foot skin. 2. Nineteen control subjects and 52 long-duration insulin-dependent (Type 1) diabetic patients of similar age (20 without complications; 19 with laser-treated retinopathy; 13 with reduced vibration perception and retinopathy) were studied in order to investigate the possible attenuation of this defence mechanism in diabetes. 3. The maximal (1 mA) flare response [control median (interquartile range): 1.55 (1.16-2.06) arbitrary units] was reduced greatly in neuropathic patients [0.37 (0.24-0.66) arbitrary units; P less than or equal to 0.001 with respect to all other groups], especially those with a previous history of foot ulceration. The flare was also reduced in some patients with retinopathy alone [1.06 (0.56-1.27) arbitrary units; P less than 0.005 with respect to control subjects]. 4. No rightward shift of the curve of hyperaemic response plotted against current strength was found, suggesting that the abnormal response was due to axonal loss rather than to dysfunction. 5. Neurogenic inflammation, mediated by small pain fibres, was markedly impaired in a group of diabetic patients at risk of foot ulceration. Furthermore, impairment of this nociceptor C fibre response can develop before clinical large-fibre neuropathy and could itself predispose to foot complications.

Vibration perception threshold: influence of age, height, sex, and smoking, and calculation of accurate centile values.

Vibration perception threshold (VPT) is increasingly used as a measure of large nerve fibre function in studies of patients with diabetes and in other disorders. In order to establish the influence of age, height, sex, and smoking on VPT values in the normal population and to allow the calculation of accurate age-related percentile charts, 1365 healthy volunteers were studied using a biothesiometer. Measurements were made bilaterally on thumbs, great toes, and over medial malleoli. Multivariate regression analysis confirmed age to be the major determinant of VPT levels at all sites (p less than 0.001). Height was a significant factor for toes and ankles (p less than 0.001) but not thumbs. Sex had no overall effect at toe or thumb but there were differences regarding ankle VPT (p less than 0.01). Log transformation of VPT data produced a linear relationship with age at all sites except at the thumbs in elderly females where there was significant deviation from this model (p less than 0.001) and inverse square root transformation was more appropriate. Smoking had no effect on VPT levels. Age-related centile charts were produced for each site and an easy-to-use computer program was developed to calculate centile values based on raw VPT data, age, height, and sex.

Reactive hyperaemia in skin of the human foot measured by laser Doppler flowmetry: effects of duration of ischaemia and local heating.

The effect of duration of ischaemia and of local heating on reactive hyperaemia in dorsal foot skin was determined in normal subjects using laser Doppler flowmetry. In the nine subjects studied, peak post-ischaemic blood flow continued to increase significantly with up to 10 min ischaemia and mean peak response was positively correlated with duration of ischaemia (r = 0.997, p less than 0.0002). This is in contrast to whole limb plethysmographic studies which have reported maximal peak flow responses after 3-5 min arterial occlusion. Resting blood flow was found to increase rapidly at skin temperatures above 33 degrees C. In ten subjects, local conductive heating from a median (range) skin temperature of 29.8(26.5-31.0) to 32.5(32.2-33.1) degrees C increased peak flow response after 4 min ischaemia from a mean (95% confidence interval) of 0.778(0.630-0.926) to 0.965(0.788-1.142) arbitrary units, p less than 0.001. The time course of the hyperaemic response was not altered. Local skin warming reduced the within subject coefficient of variation for peak response, calculated from 10 paired recordings, in two out of three subjects. These results show that the duration of ischaemia required to produce a maximal post-ischaemic peak flow response is longer for foot skin than for the whole limb and are consistent with temperature differences being the cause of this. A standard skin temperature (32-33 degrees C) may be useful for studying cutaneous blood flow responses.

Therapeutic defibrinogenation by ancrod: effect on limb blood flow in peripheral vascular disease.

Reduction of blood viscosity by venesection may improve peripheral blood flow but similar haemorheological changes have not been conclusively demonstrated following reduction of plasma viscosity by defibrinogenation. Ancrod is a defibrinogenating enzyme from the venom of the Malayan pit viper. We studied six male patients with severe intermittent claudication before, during and after treatment with ancrod for 48 h. Ancrod was given by initial infusion of 2 U/kg over 6 h and four subsequent bolus i.v. injections of 2 U/kg. Skin blood flow in feet and toes were measured repeatedly by laser Doppler velocimetry and calf blood flow by electronic plethysmography both before and after 2 min arterial occlusion. Plasma fibrinogen [median (range)] fell from 2.3(1.4-3.9) to 0.1(0.1-0.3) g/l and plasma viscosity from 1.81(1.61-1.90) to 1.49(1.45-1.72) cp. Dorsal foot and toe skin blood (resting or post-ischaemic) flows were not changed significantly by ancrod. Resting calf blood flow fell significantly after 49 h treatment with ancrod (P less than 0.04). Brachial and ankle blood pressures remained unchanged and haematocrit was not changed. Thus, treatment with ancrod for 48 h did not improve peripheral blood flow in patients with peripheral vascular disease. The fall observed in calf blood flow could be related to increased circulating fibrin/fibrinogen high-molecular-weight complexes and degradation products.