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Biomedical subjects

M L Larsen

Publications and source records attributed to M L Larsen.

At least 19 recordsLinked to original sources

[Leadership and professionalism].

In 1990 a new organizational structure based on decentralization and team leadership, where the leader (usually a doctor) is responsible for the final decision, was introduced at the regional and university hospital of Tromsø. This structure replaces the traditional dual structure of leadership where the leaders (a doctor and a nurse) did not share responsibility for the whole department. In order to analyze organizational practices after the reform we constructed three different organization models of the hospital: the hierarchical model, the professional model and the workshop model. Of five teams, one functioned hierarchically, three resembled the professional model, and the fifth came close to the workshop model. The leader of the hierarchical team behaves autocratically and the employees are dissatisfied. In the three remaining teams conditions have changed very little compared with the situation before the reorganization. In the workshop team decisions are reached jointly. This team functions in an innovative way. Even though the new organizational structure has quite divergent consequences and some leaders have problems, the majority of the hospital employees support the new structure.

Clinical Competence

Analytical goal-setting for monitoring patients when two analytical methods are used.

Serial results from an individual are often obtained using more than one method. Results should be transferable over time and locale. Every method has inherent analytical error, and goals are required to delineate the maximum allowable random (imprecision) and systematic (inaccuracy, bias) errors to facilitate optimal patient care. Based on Harris's proposal [Am J Clin Pathol 1979;72:374-82] that desirable imprecision should be less than or equal to one-half the within-subject biological variation, if the methods have negligible imprecision, then the maximum allowable bias between two methods used for monitoring is one-third of the within-subject biological variation. A more general model has been developed that relates the analytical imprecisions of two methods, and the bias between them, to biological variation. Applying the general formula derived in specific clinical monitoring situations in which a known change in serial results (occurring at a stated probability) stimulates clinical action allows goals for the imprecisions of the two methods and allows the difference in bias between them to be determined quantitatively.

Bias

Extrinsic pathway inhibitor (EPI) released to the blood by heparin is a more powerful coagulation inhibitor than is recombinant EPI.

EPI released to the blood after injection of heparin, as well as recombinant EPI (r-EPI) added to normal plasma prolonged both the dilute Tissue Thromboplastin (TTP) time and the Activated Partial Thromboplastin Time (APTT). It is known that EPI inhibits both factor Xa and the factor VIIa-TTP complex. The prolongation of the APTT by EPI reflects only its inhibition of factor Xa. Addition of anti-EPI immunoglobulins (IgG) to normal plasma shortened the dilute TTP time 7.3 seconds (p less than 0.001) and the APTT by 0.7 seconds (p less than 0.001). In postheparin plasma, with polybrene added to neutralize the direct effect of heparin, the TTP was about 26 seconds longer and the APTT about 9 seconds longer than baseline values. These effects were completely abolished by anti-EPI IgG, as were the effects of r-EPI. The EPI activity (chromogenic substrate-assay) of this postheparin plasma was 1.7 U/ml. The EPI activity of the plasma spiked with r-EPI to obtain comparable effects on clotting were much higher; about 22 U/ml for the TTP effect and about 5 U/ml for the APTT effect. The findings indicate that r-EPI is considerably less potent than postheparin EPI as inhibitor of plasma coagulation. This is most striking when coagulation is initiated through the extrinsic pathway. Possibly, the anticoagulant effect of r-EPI mainly depends on its Xa inhibitory effect.

Blood Coagulation Tests

Involvement of the extrinsic pathway in the activities of low molecular weight heparins.

Anticoagulant effects of the three LMW heparins (LMWHs) Enoxaparine, Fragmin, Logiparin and of unfractionated heparin (UFH) were compared. The heparins were added to plasma to nominal concentration of 0.2 and 0.5 anti XaU/ml plasma. Dilute tissue thromboplastin (TTP) and CaCl2 were added to platelet poor plasma (PPP), platelet rich plasma (PRP) and citrated blood. Thrombin activity was recorded with chromogenic substrate. In PPP, UFH was definitely more inhibitory than LMWH. In PRP, 0.2 U/ml of LMWHs were about as effective as UFH. At 0.5 U/ml PRP, UFH and Logiparin were more effective than Enoxaparine and Fragmin. Factor XII deficient plasma was very sensitive to heparin, and UFH and Logiparin were again more inhibitory. In whole blood, fibrinopeptide A determinations showed that UFH was more inhibitory than LMWH. We conclude that the net anticoagulant effects of these heparins result from interactions with platelets in addition to accelerated inactivation of clotting factors. The in vivo anticoagulant effect of these drugs can therefore not be predicted from their nominal anti Xa and anti IIa effects alone.

Blood Coagulation

Extrinsic pathway inhibitor (EPI) and the post-heparin anticoagulant effect in tissue thromboplastin induced coagulation.

It is known that the anticoagulant effect of blood or plasma is greater when heparin is given in vivo than when added in similar heparin concentrations in vitro. In this study, we neutralized heparin in citrated blood with polybrene, and then triggered coagulation with dilute tissue thromboplastin (TTP) and CaCl2. The clotting time was longer and the release of fibrinopeptide A (FPA) was retarded in the post injection samples compared to samples spiked with heparin in vitro. We have earlier reported that the extrinsic pathway inhibitor (EPI) is released to the blood after heparin injection. This was demonstrated here also for LMW heparin Enoxaparine both after intravenous and subcutaneous administration. Polyclonal blocking antibodies to EPI were added to blood or plasma heparinized in vivo or in vitro, and the direct heparin effect was neutralized with polybrene. When TTP and CaCl2 now were added and clotting time and the release of FPA recorded, the postheparin effect was greatly reduced by the antibodies. Addition of EPI antibodies to post-heparin plasma samples from cancer patients caused a marked reduction in the thromboplastin clotting times. We conclude that the release of EPI to the blood contributes significantly to the anticoagulant effect of heparin ex vivo.

Antibodies

A comparison of analytical goals for haemoglobin A1c assays derived using different strategies.

Analytical goals for the performance characteristics of assays of haemoglobin A1c (HbA1c) have been investigated using different assumptions for generation of estimates, these being based on strategies using data on biological variation and on the clinical use of results. The derived goals are highly dependent on the assumptions made. In general, in monitoring of patients (using results from the same laboratory), the analytical imprecision is the most demanding, whereas bias (inaccuracy) is the most important characteristic when strategies for several centres (laboratories) to achieve similar results are invoked. Goals for analytical quality should be given in a form in which both analytical imprecision and bias (or systematic error) are specified. When several goals are to be considered (for different relevant assumptions), the most demanding should be used.

Diabetes Mellitus, Type 1

Chromogenic substrate assay of extrinsic pathway inhibitor (EPI): levels in the normal population and relation to cholesterol.

A two-stage chromogenic substrate assay was standardized to measure extrinsic pathway inhibitor (EPI) activity in plasma and serum samples. In the first stage, diluted plasma or serum (0-0.8%) was incubated with factor VIIa (25 pM), tissue thromboplastin (tissue factor, TF, 1% v/v) with excess binding sites for factor VIIa, and factor Xa (0.8 nM). In the second stage, excess factor X and chromogenic substrate were added as substrate for residual TF/factor VIIa catalytic activity. Heating the samples at 56 degrees C for 15 min before assay removed greater than 95% of the factor VII amidolytic activity of the samples, defibrinated the plasma, and produced only slight reduction of EPI activity. The coefficient of variation for the same sample assayed on different days was 8.7-10.6% and the intra-assay coefficient of variation was 5.0%. Addition of anti-EPI immunoglobulin to normal plasma completely abolished the EPI activity of the sample. EPI activity was stable in plasma samples stored at -20 degrees C, but in serum, some samples lost greater than 50% activity after 3 months at -70 degrees C. Median EPI activity of umbilical cord blood was 45% (range 33-93%). In a cohort of healthy blood donors (n = 176) EPI activity was significantly correlated with age; the regression line was y = 68% + 0.60x (r = 0.39). The approximated standard deviation for the regression line was 17.9% and the age-adjusted reference limits were determined. Equal levels were seen in males and females.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult

Effect of long-term monitoring of glycosylated hemoglobin levels in insulin-dependent diabetes mellitus.

BACKGROUND: The value of routine measurements of glycosylated hemoglobin (hemoglobin A1c) in the care of patients with diabetes mellitus is uncertain. We undertook this study to determine whether knowledge of hemoglobin A1c values would result in improved metabolic control in a group of patients with insulin-dependent diabetes mellitus (IDDM). METHODS: We randomly assigned 240 patients with IDDM to one of two groups that were comparable in age, sex, duration of diabetes, and initial hemoglobin A1c levels. The patients were followed for a year, and the hemoglobin A1c concentration was measured at three-month intervals. The hemoglobin A1c values were used in assessing glycemic control and modifying therapy in one of the two groups. In the other, care givers were not aware of the hemoglobin A1c levels and relied on blood or urine glucose measurements to monitor treatment. RESULTS: Among the 222 patients still being followed after one year, the mean hemoglobin A1c value decreased significantly--from 10.1 to 9.5 percent (P less than 0.005)--in the group whose hemoglobin A1c level was monitored (n = 115), whereas the initial and one-year values in the control group (n = 107) were 10.0 and 10.1 percent, respectively. The proportion of patients with poor control, defined as those having a hemoglobin A1c value above 10.0 percent, decreased from 46 to 30 percent (P less than 0.01) in the group whose hemoglobin A1c level was monitored but did not change significantly (45 to 50 percent) in the control group. The patients in the group whose hemoglobin A1c level was monitored were seen and their insulin regimens changed more often, but they were hospitalized for acute care of their diabetes less often than those in the control group. A similar decrease in hemoglobin A1c values occurred in the control group in the following year, when their care givers knew their hemoglobin A1c values. CONCLUSIONS: Regular measurements of hemoglobin A1c lead to changes in diabetes treatment and improvement of metabolic control, indicated by a lowering of hemoglobin A1c values.

Diabetes Mellitus, Type 1

The influence of induced hyperglycaemia on gastric emptying rate in healthy humans.

The effect on gastric emptying rate (GER) of elevated plasma glucose was investigated in eight healthy non-diabetics. They received intravenous infusions of 1000 ml 10% glucose (555 mmol, 1720 kJ) in 2 h: one-half before and the rest during the measure of GER. A control group was established with infusion of hypertonic sodium chloride and in a third group the GER was measured twice without infusion. GER was measured after 6 h of fasting, and following ingestion of a 100 g omelette (1400 kJ) tagged with 40 MBq 99mTc-sulphur colloid and 150 ml water with 8 MBq 111In-DPTA. Anterior and posterior recordings were made on gamma camera every 10th min during 1 h. Time-activity curves from the gastric area were generated for solid and liquid phases, respectively, using geometric means. The GER of solids was delayed, at least partly, by prolongation of the lag phase, and the GER of liquids was delayed following the intravenous infusion of glucose. The GER of solids was delayed following hypertonic saline infusion but not to the same extent as followed glucose in spite of the double osmotic load of saline. The percentage delay of GER of solids following glucose infusion was related to the increase in plasma glucose.

Adult

Discrepancies in assessment of metabolic regulation in insulin-dependent diabetes mellitus--can we do without measurements of glycated haemoglobin?

Our purpose was to compare physicians' assessment of metabolic control in insulin-dependent diabetes mellitus (IDDM) with measurements of glycated haemoglobin HbA1c. One hundred and twenty diabetics were evaluated by physicians without access to HbA1c. Simultaneously HbA1c was measured by a highly precise isoelectric focusing method (interval of non-diabetics 5.2-6.8%). A comparison between physicians' classification into good, acceptable or poor control, and a biochemical classification by HbA1c showed a considerable discrepancy. Identity between classifications was seen in 52%, but 30% of the diabetics were considered in good or acceptable control despite HbA1c values above 10.0%. Mean HbA1c was significantly higher in women than in men (p less than 0.01). Among patients, overrated by the physicians, were relatively more women, whereas no other differences could be demonstrated. Home blood glucose monitoring did not lead to better agreement between classifications. We conclude that measurements of HbA1c is presently the most accurate single assay of metabolic control in insulin-dependent diabetics.

Adult

Influence of analytical quality and preanalytical variations on measurements of cholesterol in screening programmes.

In screening programmes one should distinguish between the traditional bimodal distributions of results and a unimodal distribution as the basis for interpretation. A model for evaluation of the effects of biological within-subject and preanalytical variation as well as analytical variation is described. It is concluded that bias from blood sampling and analytical performance influences the outcome of screening programs significantly. At least three blood specimens are needed for estimating the homeostatic set point of cholesterol in individuals.

Chemistry, Clinical

Setting analytical goals for random analytical error in specific clinical monitoring situations.

Strategies abound for the setting of analytical goals in clinical chemistry. Many, especially those more recently proposed for particular clinical situations, are concerned with tests used in diagnosis. We suggest a general theory for the setting of goals in situations that specifically involve the monitoring of individuals. Goals are calculated from the formula CVA less than [(delta c 2/2Z2)-CVB2]1/2, where CVA is the analytical imprecision (as coefficient of variation, CV); delta c is the percentage change in serial results that is considered clinically significant; Z is the Z-statistic, which depends only on the probability selected for statistical significance; and CVB is the average inherent within-subject biological variation (as CV). Examples given show applications in hematology and in monitoring diabetes mellitus, chronic renal failure, and hepatitis. The derived goals are for total random analytical error (imprecision and intermittent systematic variation), and provide objective criteria that should be achieved in practice. The effect of analytical variability on both variability in test results and the probability that a stated change can be considered significant should be calculated whether or not the goals are attained.

Chemistry, Clinical

Association of IDDM and attenuated response of 2',5'-oligoadenylate synthetase to yellow fever vaccine.

Basal and yellow fever vaccination-induced 2',5'-oligoadenylate synthetase (2',5'A) activity was determined in blood mononuclear cells (peripheral blood lymphocytes [PBLs]) from insulin-dependent diabetes mellitus (IDDM) and matched control subjects. The live attenuated yellow fever vaccine represented a primary stimulus in all subjects. First, basal 2',5'A activity increased severalfold in response to yellow fever vaccination. In IDDM subjects, this increase was significantly lower (P = .025). Second, the 2',5'A activity increased proportionately to the higher basal 2',5'A activity in IDDM subjects. In control subjects, the increase in 2',5'A activity was not dependent on the basal activity. There was no relationship between basal or stimulated 2',5'A activity and age, sex, duration of IDDM, age at onset of IDDM, metabolic control, or HLA-DQ beta-chain gene polymorphism. There is a direct relationship between 2',5'A activity and latent viral infections associated with the presence of double-stranded RNA and with cellular interferons (IFNs) formed in response to viral infections. The higher basal 2',5'A activity (P = .05) in relation to the stimulated activity may therefore signify a latent infection or the presence of double-stranded RNA in PBLs of IDDM subjects. In vitro stimulation of PBLs showed increased IFN sensitivity in IDDM subjects. Analysis of 2',5'A activity is proposed to be a sensitive measure of the activation of the IFN system and the level of latent infectivity.

2',5'-Oligoadenylate Synthetase