Measuring antimicrobial use on dairy farms: A method comparison cohort study.

Antimicrobial use on UK dairy farms is measured for surveillance purposes, with veterinary sales data as a proxy for use. Two other methods of recording use have been used commonly on-farm: medicine waste bins and farm medicine records. However, none of these methods has been validated to measure antimicrobial use. The objective of this research was to assess agreement between the 3 most common methods for measuring on-farm antimicrobial use with a predetermined reference method on UK dairy farms. Antimicrobial use was measured prospectively on 26 UK dairy farms using medicine waste bins into which participants placed all discarded medicine packaging for a 12-mo period. At the end of 12 mo, farm medicine records and veterinary sales data were obtained retrospectively for participating farms. The reference method used was based on pre- and poststudy inventories combined with veterinary sales data. We investigated the systematic difference between the mean on-farm antimicrobial use measured by each of the 3 methods and a reference method, using one-way repeated-measures ANOVA models. Reliability and clinical relevance of the agreement between each pair of methods was quantified using the concordance correlation coefficient (CCC) and the Bland-Altman method, respectively. When compared with the reference method, veterinary sales data had excellent reliability for injectable antimicrobials and intramammary antimicrobials [95% confidence interval (CI) of CCC > 0.90] and moderate to excellent reliability for other antimicrobials (95% CI of CCC: 0.68-0.97). Medicine waste bins had good to excellent reliability for injectable (95% CI of CCC: 0.84-0.99), and intramammary products (95% CI of CCC: 0.78-0.94) and no agreement for other forms of antimicrobial. Farm medicine records did not agree for any form of antimicrobial when compared with the reference method. The use of veterinary sales data as a proxy for on-farm antimicrobial use in the UK represented excellent statistical reliability and offered clinically good agreement with the reference method when used to measure injectable antimicrobials. This study applies to the UK context and included a relatively small number of farms. However, these results have research and policy implications, both nationally and internationally, and are essential in accurately quantifying agricultural antimicrobial use to inform both animal and human health.

Endothelin-1 is induced by cytokines in human vascular smooth muscle cells: evidence for intracellular endothelin-converting enzyme.

Endothelin-1 (ET-1) is the predominant endothelin isopeptide generated by the vascular wall and therefore appears to be the most important peptide involved in regulation of cardiovascular events. Many pathologic conditions are associated with elevations of ET-1 in the blood vessel wall. Because these conditions are often cytokine driven, we examined the effects of a mixture of cytokines on ET-1 production in human vascular smooth muscle cells (VSMCs) derived from internal mammary artery and saphenous vein (SV). Incubation of IMA and SV VSMCs with tumor necrosis factor-alpha (10 ng/ml) and interferon-gamma (1000 U/ml) in combination for up to 48 h markedly elevated the expression of mRNA for prepro-ET-1 and the release of ET-1 into the culture medium. This cytokine-stimulated release of ET-1 was inhibited by a series of dual endothelin-converting enzyme (ECE)/neutral endopeptidase inhibitors, phosphoramidon, CGS 26303, and CGS 26393, with an accompanying increase in big ET-1 release but with no effect on expression of mRNA for prepro-ET-1. These same compounds were 10 times more potent at inhibiting the conversion of exogenously applied big ET-1 to ET-1. ECE-1b/c mRNA is present in SV VSMCs, however no ECE-1a is present in these cells. Thus VSMCs most probably contain, like endothelial cells, an intracellular ECE responsible for the endogenous synthesis of ET-1. Under the influence of pro-inflammatory mediators the vascular smooth muscle can therefore become an important site of ET-1 production, as has already been established for the dilator mediators nitric oxide, prostaglandin I2, and prostaglandin E2.

Coronary artery surgery is associated with different forms of atherogenic lipoprotein modifications.

BACKGROUND: Increasing evidence shows that thrombogenicity and atherogenicity of lipoproteins are related to modifications involving oxidative, enzymatic, or physical alterations of these molecules. Findings on lipid peroxidation associated with cardiopulmonary bypass are conflicting, and the possible other forms of atherogenic lipid modification are unknown. The various forms of lipoprotein modifications including lipid peroxidation, desialylation, and leukocytic elastase activity after coronary artery bypass graft operations are examined. METHODS: In patients undergoing coronary artery bypass graft operations, plasma total lipid hydroperoxides (n = 102), plasma leukocytic elastase activity (n = 125), free radical formation (n = 30), low-density lipoprotein oxidation, and sialic acid content before operation and at 2, 24, 48, and 72 hours after cardiopulmonary bypass and 3 months after operation were measured. RESULTS: Preoperative plasma lipid peroxide concentration (2.2 micromol/L) increased after cardiopulmonary bypass (peak, 7.5 micromol/L; p<0.001) and remained significantly elevated at 3 months after surgery (4.2 micromol/L; p<0.01). There was a significant correlation between increased free radical generation and lipid peroxide levels in blood at all postoperative intervals. Low-density lipoprotein separated from plasma samples showed increased oxidation 48 hours after bypass. Sialic acid content of low-density lipoprotein was significantly reduced 48 hours after bypass. Plasma elastase activity increased significantly at all postoperative intervals. CONCLUSIONS: Coronary artery bypass graft operation is associated with generation of sustained blood levels of modified lipoproteins. These thrombogenic and atherogenic particles may play an important role in hemostatic and arteriosclerotic complications of coronary artery bypass graft operations.

Elevated plasma lipid hydroperoxides in patients with coronary artery disease.

Sustained presence of lipid peroxides in the circulation and their plasma carrier is a controversial issue. Particularly, there is no firm evidence for an increased plasma lipid peroxide level in patients with atherosclerosis. In this study, a strong correlation was found between plasma total lipid hydroperoxide and lipid hydroperoxide content of LDL cholesterol (r = 0.882; p < 0.001; n = 16). Lipid hydroperoxides in plasma were carried almost exclusively (89%) in LDL. In 70 patients tested 3 months after coronary artery bypass graft surgery with a specific assay, plasma lipid hydroperoxide levels were significantly increased when compared with matched healthy controls (4.31 +/- 0.23 nmol/ml and 2.34 +/- 0.13 nmol/ml, p < 0.0001, patients vs controls, respectively). These concentrations are 10 times lower than those detected by the nonspecific thiobarbituric acid assay. However, considering the in vitro concentration range in which oxidized LDL exerts important atherogenic effects, the elevated plasma lipid hydroperoxide levels measured in atherosclerotic patients have pathologic significance.

A surgical approach to coexistent coronary and carotid artery disease.

OBJECTIVE: To assess the early results of combined coronary artery bypass graft surgery and carotid endarterectomy. DESIGN: Retrospective and ongoing analysis of patients who underwent combined coronary artery bypass graft surgery and carotid endarterectomy. SETTING: Cardiothoracic unit in a London teaching hospital. PATIENTS: From June 1987 to March 1995, 64 patients were identified. They were patients who were scheduled to have coronary artery bypass graft surgery or required urgent coronary revascularisation and who were found to have significant coexistent carotid disease. (Unilateral carotid stenosis > 70%, bilateral carotid stenosis > 50%, or unilateral carotid stenosis > 50% with contralateral occlusion.) INTERVENTIONS: Both procedures were performed during one anaesthesia: the carotid endarterectomy was performed first without cardiopulmonary bypass. After completion of carotid endarterectomy, coronary artery bypass graft surgery was performed. MAIN OUTCOME MEASURES: The incidence of stroke, transient ischaemic attack, and myocardial infarction in the early postoperative period was analysed. RESULTS: Myocardial revascularisation was successful in all 64 patients. There were no perioperative infarcts. In three patients (4.7%) a new neurological deficit developed postoperatively: two recovered fully before hospital discharge. CONCLUSIONS: Combined coronary artery bypass graft surgery and carotid endarterectomy were performed safely and with good results.

Myocardial revascularisation in elderly patients with refractory or unstable angina and advanced coronary disease.

BACKGROUND: Elderly patients with ischaemic heart disease are often treated more conservatively and for longer than younger patients, but this strategy may result in subsequent invasive intervention of more advanced and higher risk coronary disease. METHODS: We performed a retrospective analysis of 109 patients aged > or = 70 years (mean age 74 years, 66% men), who presented with angina refractory to maximal medical treatment or unstable angina over a 2-year period (1988-1990), to compare the relative risks and benefits of myocardial revascularisation [coronary artery bypass grafting (CABG) and percutaneous transluminal coronary angioplasty (PTCA)] in this higher-risk age group. RESULTS: Sixty patients underwent CABG and 49 patients PTCA. There were eight periprocedural deaths in total (six in the CABG group, and two in the PTCA group, P = 0.29). Six patients in the CABG group suffered a cerebrovascular accident (two fatal). Acute Q-wave myocardial infarction occurred in one patient in the CABG group and in two patients in the PTCA group. The length of hospital stay was longer for the CABG group (CABG group 11.4 +/- 5.4 days, range 7-30 days, PTCA group 7.4 +/- 7.6 days, range 1-39 days, P = 0.01). Outcome was assessed using the major cardiac event rate (MACE; i.e. the rate of death, myocardial infarction, repeat CABG or PTCA). The cumulative event-free survival in the CABG group in 1, 2 and 3 years was 87, 85 and 85%, respectively. In contrast, in the PTCA group it was 55, 48 and 48% (P = 0.0001). Age, sex, number of diseased vessels, degree of revascularisation and left ventricular function were not predictive of the recurrence of angina in both groups. Actuarial survival (total mortality, including perioperative mortality) was lower at 1 year in the CABG group due to the higher perioperative mortality, but similar in both groups after the second year (P = 0.62). CONCLUSIONS: Elderly patients with refractory or unstable angina who are revascularised surgically have a better long-term outcome (less frequent event rate of the composite end-point--myocardial infarction, revascularisation procedures and death) compared with those who are revascularised with PTCA. This benefit is been realised after the second year. Total mortality is similar in both groups after the second year. Therefore elderly patients who are fit for surgery should not be denied the benefits of CABG. PTCA may be regarded as a complementary and satisfactory treatment, especially for those whose life expectancy is limited to less than 2 years. The use of stents may improve outcome in the PTCA group and this needs to be evaluated.

Evidence against hypercoagulability in coronary artery disease.

The strong epidemiological association between elevated plasma clotting factors and coronary artery disease is generally interpreted as evidence that patients with coronary atherosclerosis are in a procoagulant (hypercoagulable) state. A dynamic global test was used to assess the overall coagulation status of 761 patients with coronary artery disease scheduled for coronary artery bypass grafting and compared to healthy matched controls (n = 100). Platelet reactivity to shear-stress was simultaneously measured from identical, non-anticoagulated blood samples. Contrary to expectation, the overall coagulation in cardiac patients did not differ significantly from that of controls. Furthermore, the coagulation status of patients bore no relationship to the severity of coronary atherosclerosis. The latter is in contrast with platelet reactivities, which were significantly increased in patients with > or = 2 vessel disease as compared with single vessel disease. The present results do not necessarily conflict with the finding of elevated plasma clotting factors in cardiac patients. However, they do not support the claim that these markers are a reflection of a hypercoagulable state. Indeed, this study confirms that such patients are in a prothrombotic state, which is related to enhanced platelet reactivities, and not to a prothrombotic imbalance of the coagulation mechanism.

Surgery for radiation-induced valvular disease.

The effects of radiation on the heart have been well described including acute and chronic pericarditis, myocardial fibrosis, accelerated arteriosclerosis of the coronary arteries. However, valvular dysfunction secondary to mediastinal irradiation has received less attention. We report two cases who developed valvular dysfunction associated with coronary artery disease possibly caused by mediastinal irradiation and a review of the literature regarding surgery for radiation induced valvular disease. Both patients underwent aortic valve replacement and coronary artery bypass graft surgery. With increasingly prolonged survival following mediastinal irradiation, we believe that long term follow up in patients who receive mediastinal irradiation is indicated.

Chronic ethanol administration impairs degradation of formaldehyde-treated albumin by the perfused rat liver.

Nonparenchymal cells of the liver appear to be important in the pathogenesis of various liver diseases, including that caused by ethanol. It is known that chronic ethanol administration impairs the process of receptor-mediated endocytosis in hepatocytes. Liver endothelial cells are also actively endocytic cells, playing a prominent role in the clearance from the circulation of a variety of macromolecules. In this study, we assessed the effect of ethanol administration on this "scavenger" function of liver endothelial cells by measuring the degradation of formaldehyde-treated albumin in isolated, perfused livers of ethanol-fed rats. Rats were pair-fed for 1 or 4 weeks with a liquid diet containing either ethanol as 36% of total calories or an isocaloric amount of carbohydrate. Chronic ethanol administration in this manner for 1 or 4 weeks significantly impaired the degradation of this endothelial cell ligand (by 60 +/- 9% and 37 +/- 9%, respectively). Liver perfusions were also performed on rats that had been administered ethanol acutely or in which ethanol was added to the perfusate. No acute effect of ethanol on the degradation of this ligand was seen. These results demonstrate that chronic ethanol ingestion impairs receptor-mediated endocytosis of formaldehyde-treated albumin by liver endothelial cells, indicating that the adverse effects of ethanol on protein trafficking within the liver are not limited to the hepatocytes.

Different anticoagulants and platelet reactivity in cardiac surgical patients.

A technique for assessing platelet reactivity to shear stress from nonanticoagulated blood samples was employed to compare the relative effects of an unfractionated heparin, a low-molecular-weight heparin, and hirudin. The in vitro platelet effect of unfractionated heparin (5 U/mL) was measured in 290, the effect of a low-molecular-weight heparin (1 anti-Xa unit/mL) in 74, and the effect of hirudin (8 micrograms/mL) in 50 cardiac surgical patients. The relative proportions of patients exhibiting an enhanced platelet reactivity, a mild to moderate inhibition, and a severe inhibition were, respectively: 8.6%, 58.6%, and 32.8% for unfractionated heparin; 22%, 66%, and 12% for the low-molecular-weight heparin; and 6%, 66%, and 28% for hirudin. At the concentrations examined, a significantly greater proportion (p < 0.01) of the patients exhibited enhanced platelet reactivity and a significantly smaller proportion (p < 0.01) showed severely inhibited platelet reactivity associated with the low-molecular-weight heparin versus the unfractionated heparin, whereas there was no significant difference between the patients treated with hirudin and unfractionated heparin. Although the relevance of this study is limited because the clinically appropriate concentration of the alternative anticoagulants and comparative doses are unknown, it can be inferred that low-molecular-weight heparin may reduce the blood loss associated with cardiopulmonary bypass.

Inhibition of platelet function by heparin. An etiologic factor in postbypass hemorrhage.

The effect of heparin (5 U/ml) on platelet function was examined by hemostatometry in vitro. A wide individual variation of this effect was found in 290 patients who underwent cardiac operations: 8.6% (25) experienced a proaggregatory effect, 58.6% (170) experienced a mild to moderate inhibition of platelet function, and 32.8% (95) experienced a severe inhibition. No significant difference was found among patient characteristics, including antiplatelet medication, in these three subgroups. In vitro measurements correlated significantly with ex vivo measurements, that is, from blood taken after heparinization (p < 0.0001; r = 0.97, n = 15). In 111 patients who underwent cardiac surgical intervention, a significant correlation (p < 0.0001; 0.4 < r < 0.52) was found between preoperative measurements of the degree of inhibition of platelet function by heparin and the total postoperative blood loss after 4, 12, and 18 hours. Similarly, there was a significant difference (p < 0.0001) in the total blood loss at 4, 12, and 18 hours between the subgroups that showed, in vitro, a mild to moderate inhibition of platelet function preoperatively compared with a severe inhibition (713 +/- 43 ml versus 1172 +/- 76 ml at 18 hours). It is concluded that platelet inhibition as a result of heparin varies among patients and appears to be a previously unrecognized etiologic factor in bleeding after cardiopulmonary bypass.

Reduction of heparin binding to and inhibition of platelets by aprotinin.

The direct effect of aprotinin on in vitro platelet function was assessed by hemostatometry (n = 10). No significant enhancement was demonstrated. However, aprotinin reduced platelet inhibition secondary to heparin. Hemostatometry demonstrated a significant preservation of in vitro platelet function (n = 25) (p = 0.04), which was particularly marked (p = 0.003) in the subgroup (n = 7) demonstrating a severe inhibition of platelet function with heparin. Aprotinin significantly reduced the binding of tritium-labeled heparin to both nonactivated (n = 25) (p = 0.004) and activated platelets (n = 25) (p < 0.0001). We conclude that interference with heparin-induced inhibition of platelet function by aprotinin may be one of its hemostatic actions in cardiac surgery. This effect is probably secondary to aprotinin reducing binding of heparin to platelets.

Effect of warfarin on arterial thrombogenesis: problems of monitoring.

Platelet reactivity to shear stress and collagen and dynamic overall coagulation were measured in vitro from nonanticoagulated blood of 137 patients on warfarin. One hundred five matched, healthy subjects served as controls. Platelet reactivity to both stimuli and contribution of platelets to plasmatic coagulation were significantly inhibited in patients on warfarin. No correlation was found between platelet reactivity and the coagulation status assessed by the international normalized prothrombin time ratio (INR). Despite similar INR, platelet reactivity showed great individual variation. In 98 patients who were followed up for 3 months, measurement of platelet reactivity to shear stress could discriminate between those who had either bleeding or thromboembolic episodes. These findings suggest that monitored platelet function would help in individualizing oral anticoagulant regimens and hence would increase the benefit of therapy without the risk of bleeding complications.

Coronary artery anastomotic contour--a method for individual surgeons to assess their suture techniques.

A method is described whereby individual surgeons may monitor their coronary graft suturing techniques. The coronary artery anastomotic contour is measured quantitatively in corrosion resin cast models made of anastomoses between long saphenous vein and the left anterior descending coronary artery of a pig's heart. The relevant parameter assessing the contour is the mean anastomotic narrowing expressed as a percent (MAN%). To provide an example of the potential of the method, a single surgeon compared a continuous suture technique (n = 30) with an interrupted one (n = 30) using corrosion resin models. There was significantly less (P < 0.05) narrowing of the anastomotic contour with the interrupted technique (mean MAN% = 0.3 +/- 2.9) than with the continuous (mean MAN% = 10.5 +/- 3).

Effect of heparin on in vitro platelet reactivity in cardiac surgical patients--a comparative assessment by whole blood platelet aggregometry and haemostatometry.

The in vitro effect of heparin on platelet reactivity was assessed simultaneously by haemostatometry (response to shear stress) and whole blood platelet aggregometry response to collagen (WBPA). From each blood sample a ratio (HR for haemostatometry and MR and IR for WBPA) showing platelet reactivity in the presence or absence of heparin (5 U/ml) was calculated. A value less than 1 represented a proaggregatory effect and greater than 1 an inhibitory effect. Non-anticoagulated blood samples obtained from 290 cardiac surgical patients were tested by haemostatometry and citrated whole blood samples from 100 patients with aggregometry. Haemostatometry demonstrated a proaggregatory effect of heparin in 8.6% (25) and an inhibitory effect in 91.4% (265). Assessed by WBPA, heparin was proaggregatory in 41-46% and inhibitory in 54-59%. In the 100 patients tested by both methods there was a significant correlation between the findings with the two techniques (r = 0.46, p less than 0.0001). A wide individual variation in the platelet effect of heparin was demonstrated. This variation appeared greater and a higher proportion showed inhibition when blood was tested by haemostatometry.