Considerable differences between methods for plasma D-dimer in the diagnosis of venous thrombosis: increased positive prediction using elevated discriminatory limits.

Four analytical methods for plasma D-dimer have been compared in a group of 82 consecutive patients with suspected venous thrombosis, 22 of whom subsequently received a positive clinical diagnosis. Differences in diagnostic power between methods were observed. In three of the four methods tested, the use of elevated discriminatory limits (rather than conventional 95-percentile upper reference limits) resulted in stronger positive predictive values for thromboembolism. We suggest that this approach may result in better diagnostic performance of the D-dimer method.

Validation of albumin determined in urine with the HemoCue point-of-care analyser.

Albumin concentrations persistently between 20 and 200 mg/L in first morning spot urine or urine collected overnight, referred to as microalbuminuria, indicate incipient nephropathy in diabetes mellitus. This study validates a new point-of-care device, the HemoCue Urine Albumin analyser, for handling, accuracy precision and predictive values (PV+/-) at 20 mg/L. Over a period of 2 months, 200 microalbuminuria samples were selected at the Department of Clinical Chemistry according to the results from the Integra 700 instrument (Roche, R) and analysed on the same day using the HemoCue analyser (HemoCue, H) and the Immage instrument (Beckman, B), in all cases closely following the manufacturers' instructions. Only 137 results were within the measuring range of H, 10-150 mg/L. Comparisons yielded regression lines H=1.06R-7.2 (r2=0.94), H=1.08B-3.1 (r2=0.94) and R=1.00B+4.3 (r2=0.99). Inter-assay (n=24) CV% at 12 mg/L was H=18.2, R=4.2 and B=2.9 and at 65 mg/L: H=6.1, R=1.8 and B=2.6. Intra-assay duplicate CV% for H at 21-40 mg/L was 13.2, at 41-80 mg/L 10.8 and at 81-150 mg/L 9.2. Intra-assay repeatability (n=8) CV% at 28 mg/L was 7.2-13.8, at 57 mg/L 6.4-8.4 and at 105 mg/L 4.3-7.1. External quality assurance urine albumin (B) was +5.7% cf. nephelometry and (R) +1.0% cf. turbidimetry (n=6) method-group means. PV+/- values were (H versus R) 0.98/0.37 and (H versus B) 0.95/0.65. HemoCue is easy to handle. Results below 20 mg/L need to be confirmed at the central laboratory to exclude microalbuminuria. Values above 20 mg/L can be used to follow microalbuminuria, as precision allows discerning steps of 10 mg/L.

Alkaline phosphatase activity: new assay for the Reflotron system. Results of the evaluation in eight clinical laboratories.

A new reagent carrier, Reflotron ALP, has been developed for the Reflotron system, allowing easy and rapid measurement (in less than 3 minutes) of alkaline phosphatase (ALP) activity in capillary blood, venous blood, heparinized plasma or serum. The evaluation of the analytical performance of the assay was carried out at eight clinical laboratories. The study of the imprecision using the measurements in human samples resulted in coefficients of variation ranging from 1.3% to 4.6% (within-run) and from 3.2% to 4.0% (day-to-day). The analytical specificity of the Reflotron ALP assay agrees well with ALP methods using a N-methyl-D-glucamine buffer solution. The calibration of the Reflotron ALP assay, however, is related to the reference intervals for ALP methods using a diethanolamine buffer solution. Method comparisons were performed with the ALP method on Hitachi instruments using diethanolamine buffer. Reflotron ALP measurements in blood and plasma in 157 randomly selected split samples showed excellent agreement (slope: 0.99; intercept: 0.7 U/l; median bias: 2.3%; median difference from the comparison method: -0.3%). Specimens from pregnant women and adolescents were excluded from this study. Differing values were obtained in a method comparison using 48 samples containing predominantly the ALP bone isoform (slope: 0.81; intercept: 31.5 U/l; median bias: 5.7%; median difference from the comparison method: -12.2%). Regression analysis of the results from 21 sera with prevailing placental ALP gave a slope of 1.51, and an intercept of -41.1 U/l (median bias: 8.6%; median difference from the comparison method: 35.6%). Reflotron ALP was compared with three different wet chemistry procedures using different buffer compounds: N-methyl-D-glucamine or diethanolamine or 2-amino-2-methyl-1-propanol. In samples containing predominantly ALP isoforms not of liver origin, the measurements with N-methyl-D-glucamine buffer gave the best fit with respect to Reflotron. In an interference study with 18 drugs, no effect on the test results could be detected. Total bilirubin up to 750 micromol/l and hemolysis up to 1.7 g/l free hemoglobin did not influence the test. Reflotron ALP proved to be an easy and rapid method with excellent precision. The accuracy related to an ALP method using diethanolamine buffer was good. The systematic differences for ALP in samples from pregnant women and adolescents have to be taken into account. The assay is well suited for differential diagnosis of hepatic diseases in decentralized testing.

Towards common reference intervals in clinical chemistry. An attempt at harmonization between three hospital laboratories in Skåne, Sweden.

The population sample of the Kristianstad survey, a reference intervals survey in the county of Kristianstad, was used to establish new reference intervals in clinical chemistry at the laboratories of the Central Hospital in Kristianstad, the University Hospital in Lund and the University Hospital in Mälmo. Three-hundred and fifty nine subjects, male and female, aged 20-80+ years, were invited to participate in the study, with a participation rate of 70%. Up to 70 analyses were performed on each subject, general clinical chemistry parameters in all three laboratories, specialized analyses where available. Separate a priori exclusion criteria were defined for each test. In addition, the test pattern of each individual was evaluated for signs of preclinical disease. Twelve cases of preclinical disease were discovered and clinically confirmed. Details on all test methods are presented along with information concerning instruments used, calibration procedures, methods of calculation and obtained reference intervals. Although the methods were in general calibrated against acknowledged reference materials, in some instances differences were found that made common reference intervals across all laboratories impossible. Problems relating to the practical use of international recommendations and the establishment of reliable reference intervals are discussed.

No impaired cognitive function in treated patients with mild-moderate hypertension compared to normotensive controls.

Hypertension is a predictor for impaired cognitive function and dementia in several prospective studies. It is currently under debate whether treatment of hypertension, and thus blood pressure lowering, is another risk factor for cognitive decline. We recruited a sample of 123 treated hypertensive patients and 76 normotensive controls, from a population-based study in primary health care, for screening of blood pressure, metabolic variables and cognitive function, as measured by the Mini-Mental State Examination (MMSE). Treated hypertensives had higher blood pressure but did not differ in cognitive function from the normotensives. Neither educational level nor metabolic variables confounded the findings. In conclusion, treated hypertensives did not differ in cognitive function from normotensive controls. This does not support the notion that pharmacological blood pressure reduction impairs cognitive function.

Omega-3 Ethyl Ester Concentrate Decreases Total Apolipoprotein CIII and Increases Antithrombin III in Postmyocardial Infarction Patients.

This study investigated whether an ethyl ester preparation of fish oil (w-3) could normalise raised plasma concentrations of triglycerides, apolipoprotein CIII on apolipoprotein B-containing particles (LP CIII:B) found in patients with recent acute myocardial infarction. We also studied the effect of fish oil on antithrombin III levels. Out of 75 patients with a plasma triglyceride value >/=2.0 mmol/L, 22 normalised their triglycerides during diet and were therefore not randomised. The remaining patients were randomly assigned to 12 weeks' treatment with a daily dose of 4g w-3 or placebo. Mean plasma triglyceride concentrations were reduced by 24% from 3.10 +/- 1.15 (SD) to 2.53 +/- 0.94 mmol/L (p < 0.001) on w-3 (p < 0.001 vs placebo). The reduction was due to decreases in very low density lipoprotein concentrations. Total apolipoprotein CIII decreased significantly. This was due to reductions in LP CIII:non B concentrations, but the ratio LP CIII:non B/LP CIII:B was unaffected because of a slight insignificant decrease in LP CIII:B. The plasma triglyceride decreasing effect of w-3 could therefore not be due to redistribution of CIII between lipoproteins. Low density lipoprotein (LDL) cholesterol increased significantly with w-3 by 7%, and antithrombin III increased significantly with fish oil. In conclusion, w-3 had a moderate plasma triglyceride lowering effect and increased LDL cholesterol slightly, while antithrombin III increased in patients with hypertriglyceridaemia who had recently experienced a myocardial infarction.

Reference intervals for the glomerular filtration rate and cell-proliferation markers: serum cystatin C and serum beta 2-microglobulin/cystatin C-ratio.

Recent studies have indicated that serum and plasma cystatin C are better markers for glomerular filtration rate (GFR) than serum creatinine, ubiquitously used for this purpose. To fully exploit the value of serum and plasma cystatin C as GFR markers, reliable age and sex-correlated reference intervals are required. The present study comprised cystatin C determinations in plasma and sera from 259 individuals from a well-defined area in the southernmost part of Sweden. From demographic lists two men and two women were randomly selected from each one-year birth cohort above 20 years of age. No sex differences were found for plasma and serum cystatin C, whereas an increase in the cystatin C levels with age was noted, corresponding to the known age-related decrease in GFR. The following reference intervals are recommended for practical clinical use: S-Cystatin C (both sexes): 20-50 years, 0.70-1.21 mg l-1 and 50+ years, 0.84-1.55 mg l-1. The same samples were also used for determination of beta 2-microglobulin levels in order to calculate reference intervals for the beta 2-microglobulin/cystatin C-ratio, which is a more distinct marker for cell proliferation, particularly lymphoproliferation, than is the serum level of beta 2-microglobulin alone, since the ratio should be virtually uninfluenced by GFR. The beta 2-microglobulin/cystatin C-ratios were uninfluenced by sex and age and 1.45-2.43 is recommended as the serum reference interval for practical clinical use. Serum creatinine was determined in the same samples and the creatinine level was found to be strongly influenced by sex and weakly by age.

Islet hormone secretion in pancreatic cancer patients with diabetes.

The diabetes or impaired glucose tolerance that occurs in most patients with pancreatic cancer is characterized by profound insulin resistance. Recent evidence suggests that the diabetes may result from the presence of the tumor rather than being a predisposing factor to development of the malignancy. Some islet hormones have been shown to exhibit diabetogenic effects. To investigate the potential role of these hormones in the diabetic state associated with pancreatic cancer, we measured islet hormones during fasting in pancreatic cancer patients (n = 30), patients with other malignancies (n = 43), and healthy controls (n = 25). Preoperative pancreatic cancer patients were classified as normal glucose tolerance (NGTT), impaired glucose tolerance (IGTT), non-insulin-requiring diabetes (NIRD), and insulin-requiring diabetes (IRD). Nine pancreatic cancer patients were studied after tumor removal by subtotal pancreatectomy. Some preoperative pancreatic cancer patients (n = 19), postoperative patients (n = 9), and controls (n = 8) were also studied during hyperglycemia and following glucagon injection. Fasting plasma C-peptide was elevated in NIRD pancreatic cancer patients compared to controls. Fasting levels of islet amyloid polypeptide (IAPP), glucagon, and somatostatin were elevated in NIRD and IRD patients. IAPP and glucagon, but not somatostatin, normalized following subtotal pancreatectomy. During hyperglycemia, increases in C-peptide and IAPP were seen only in controls and in NGTT and postoperative pancreatic cancer patients. After glucagon infusion, IAPP levels increased in controls and nondiabetic cancer patients; C-peptide levels increased in controls, nondiabetic patients, and NIRD. Responses of C-peptide and IAPP to glucagon normalized after pancreatectomy. During hyperglycemia, glucagon levels fell in all groups except IGTT patients and a decrease in somatostatin concentrations was seen in controls.

Insulin resistance is not exhibited by advanced chronic obstructive pulmonary disease patients.

We have previously reported increased blood glucose concentrations and skeletal muscle glycogen depletion in severe COPD patients with chronic respiratory failure. In order to see if insulin resistance exists in severe COPD, we investigated nine patients with advanced COPD with chronic hypoxaemia and seven healthy control subjects of similar age, using the euglycaemic hyperinsulinaemic glucose clamp technique. We could not demonstrate a subnormal intravenous glucose requirement in response to insulin when maintaining euglycaemia in the COPD patients with chronic hypoxaemia. This indicates that the net metabolism of glucose in COPD patients with chronic hypoxaemia is not resistant to insulin.

Characterization of the insulin-antagonistic effect of growth hormone in insulin-dependent diabetes mellitus.

To characterize its insulin-antagonistic effect, growth hormone (GH) was infused at variable rates (24, 12 or 6 mU kg-1 min-1) for 1 h in 7 IDDM patients. Saline infusion was used as control (C) and all patients participated in all studies. The effect of insulin was measured with the euglycaemic clamp technique for 6 h combined with d-(3-3H)-glucose to evaluate glucose turnover. The insulin levels during the clamps were similar in all studies (23 +/- 3 mU l-1). The infusions produced peak GH levels of (24 rate = 24) 157 +/- 11, (12 rate = 12) 76 +/- 7, and (6 rate = 6) 45 +/- 8 mU l-1 (mean +/- SEM). The insulin-antagonistic effect of GH on glucose uptake was seen after 2 h and was at a maximum 4 to 5 h after the start of the GH infusion (difference in glucose infusion rate between C and 24 was 1.7 +/- 0.4 mg kg-1 min-1, p < 0.01). The resistance was due to a less pronounced effect of insulin to both inhibit rate of appearance and to stimulate rate of disappearance. Infusion of GH at 12 mU kg-1 min-1 induced a less pronounced insulin resistance both with regards to maximal effect (glucose infusion rate C - GH 1.4 +/- 0.5 mg kg-1 min-1, p < 0.05) and duration (3 h). At 6 mU kg-1 min-1, a clear GH-induced insulin-antagonistic effect was only seen during the third hour of the clamp (glucose infusion rate C-GH 1.3 +/- 0.5 mg kg-1 min-1, p < 0.05). GH infusion impaired the effect of insulin to lower both the levels of free fatty acids (NEFA) and glycerol between 2 and 5 h after the start of the infusion (NEFA, C:110 +/- 29, 24:303 +/- 95, p < 0.05: glycerol, C:32 +/- 4, 24:50 +/- 7 mumol l-1, p < 0.05). The present study therefore demonstrates that the insulin-antagonistic effect of GH in IDDM is related to the plasma levels both with regard to duration and response. The results also indicate that GH impairs the effect of insulin on lipolysis in IDDM after physiological peaks.

Fat metabolism and its response to infusion of insulin and glucose in patients with advanced chronic obstructive pulmonary disease.

In order to investigate fat metabolism and the regulation of lipolysis and blood fuel metabolites by insulin, nine patients with chronic obstructive pulmonary disease (COPD) with chronic hypoxaemia and seven healthy control subjects of similar age were investigated by determination of the turnover rate of free fatty acids (TOR), using 1-14C-oleic acid as a tracer, and arterial concentrations of FFA, glycerol and 3-hydroxybutyrate. The measurements were performed in the basal state and during insulin and glucose infusion, aiming at euglycaemia at insulin levels of 50 and 100 mU l-1. The subjects' ages were 64 +/- 2.7 and 66 +/- 1.1 (mean +/- SEM) years in the COPD and control groups, respectively. TOR was 0.73 +/- 0.06 and 0.52 +/- 0.02 mmol min-1 (P < 0.05) in the basal state, 0.33 +/- 0.04 and 0.30 +/- 0.02 at an insulin level of 50 mU l-1 and 0.32 +/- 0.08 and 0.24 +/- 0.02 at an insulin level of 100 mU l-1, in the COPD and control groups, respectively. Arterial FFA concentration was 0.98 +/- 0.08 and 0.75 +/- 0.06 mmol l-1 (P < 0.05) in the basal state in the COPD and control groups, respectively. During the clamp, the decrease in FFA mirrored that in TOR. The results show that the state of lipolysis is increased in severe COPD patients with chronic hypoxaemia. Furthermore, the results suggest a reduced effect of insulin in lipolysis.

Regulation of insulin-like growth factor binding protein-1 (IGFBP-1) in insulin-dependent diabetes mellitus. Effects of hyperglycaemia and insulin.

The aim of the present study was to characterize the effect of 44 h of hyperglycaemia on diurnal levels of insulin-like growth factor binding protein-1 (IGFBP-1), insulin-like growth factor-1 (IGF-1), growth hormone (GH) and glucagon in 7 well-controlled subjects with insulin-dependent diabetes mellitus (IDDM). Hyperglycaemia (approximately 15 mmol/l) was induced by a glucose infusion, while the degree of insulinisation was similar to that of a corresponding period with near normoglycaemia (approximately 6.9 mmol/l). Hyperglycaemia for 44 h did not alter the normal diurnal IGFBP-1 levels when the degree of insulinisation was unchanged. The diurnal secretion pattern of IGFBP-1 was preserved in both genders and without any difference between the control and hyperglycaemic periods. However, the IGFBP-1 levels were increased in these IDDM subjects despite a peripheral hyperinsulinemia. An inverse correlation was found between IGFBP-1 and peripheral insulin levels both during periods of rapid changes in IGFBP-1 and insulin concentrations (i.e. morning hours) as well as during the total 24-h sampling period. Total IGF-1 levels were low, but no further decrease was seen after 24 h of hyperglycaemia in the presence of unchanged insulin levels. In conclusion, the present study clearly shows that the increased IGFBP-1 level seen during poor metabolic control in IDDM is not caused by hyperglycaemia. Glucose levels per se do not influence either total IGF-1 or IGFBP-1 concentrations in well-insulinised diabetic patients.

Insulin treatment improves microalbuminuria and other cardiovascular risk factors in patients with type 2 diabetes mellitus.

OBJECTIVES: Insulin treatment of patients with type 2 diabetes causes hyperinsulinaemia and improves glycaemic control. We have studied how this affects risk factors for cardiovascular disease. DESIGN: Patients with secondary failure to oral hypoglycaemic agents were studied whilst still taking oral agents and after insulin treatment for 8 weeks in an open study. SETTING: Department of Internal Medicine, University Hospital, Linköping. SUBJECTS: Ten consecutive patients with type 2 diabetes and secondary failure to oral hypoglycaemic agents. INTERVENTIONS: Switching oral treatment to insulin treatment. MAIN OUTCOME MEASURES: Effect on several cardiovascular risk factors. RESULTS: Fasting and postprandial plasma insulin concentrations were increased by insulin treatment whereas C-peptide concentrations were lowered. HbA1c was reduced from 8.9 +/- 0.3% (mean +/- SEM) to 6.3 +/- 0.2% after 8 weeks. There was a weight gain of 2.8 +/- 0.7 kg. Plasma concentrations of total- and very-low-density-lipoprotein (VLDL) cholesterol, VLDL-, low density lipoprotein and high-density-lipoprotein triglycerides were all reduced. The plasma concentration of apolipoprotein B was also lowered. Tissue plasminogen activator antigen measured after venous occlusion showed a significant reduction whilst plasminogen activator inhibitor 1 activity was 26.0 +/- 9.8 IU ml-1 on oral treatment and 18.2 +/- 4.7 IU ml-1 on insulin treatment (NS). Albumin excretion in the urine was reduced and the percentage reduction correlated with the percentage lowering of the tissue plasminogen activator antigen concentration after venous occlusion but not with the percentage change of basal tissue plasminogen activator antigen concentration. CONCLUSIONS: Insulin treatment of patients with type 2 diabetes and secondary failure to oral hypoglycaemic agents causes hyperinsulinaemia and improves or has no unfavourable effect on several cardiovascular risk factors.

Feeding dependence and nutritional status after acute stroke.

BACKGROUND AND PURPOSE: We assessed the nutritional status of patients with acute stroke and evaluated it in relation to the patients' dependence on assistance with feeding. METHODS: Fifty patients aged 70 years or older, admitted from their homes, were included. Weight index, triceps skinfold thickness, arm muscle circumference, serum proteins, delayed hypersensitivity, body composition measured by bioelectric impedance, and functional condition were determined on admission and 2 and 9 weeks after admission. Food and fluid consumption were also recorded. RESULTS: On admission, four patients were regarded as protein-energy malnourished. Those who required assistance with feeding after admission (n = 18, 36%) had lower serum albumin (P < .05), lower body cell mass (P < .01), and were more anergic than the independent patients (P < .01) on admission. The mean food consumption was 72% of the food served without significant difference between dependent and independent patients. Nine weeks after the onset of stroke symptoms, the patients who were dependent on assisted feeding showed a decrease in body cell mass. The loss of body cell mass was related to their activity and feeding dependence. CONCLUSIONS: Low serum albumin and anergy commonly occur in elderly patients with acute stroke, and they occur more prevalently among those with a severely impaired functional condition. During the recovery period, the patients use body fat to compensate for energy needs, and immobility leads to loss of body cell mass.

Immunofixation superior to plasma agarose electrophoresis in detecting small M-components in patients with polyneuropathy.

Monoclonal immunoglobulins (M-components) in blood are found in some patients with polyneuropathy and are thought to be of pathogenetic importance, especially if the M-component is of IgM isotype. As the finding of an M-component may indicate a treatable polyneuropathy, the potential of the method to uncover an M-component is of importance. Cellulose acetate or agarose electrophoresis used in routine practice may miss small M-components covered by other proteins. We therefore applied the uncovering and specific method of immunofixation in comparison with agarose electrophoresis on patients investigated for polyneuropathy. Of 83 consecutive patients, 5 had M-components. Two of these 5 patients, one with an axonal polyneuropathy and the other with a lower motor neuron syndrome, had extra bands on agarose electrophoresis, verified as IgG M-components by immunofixation. In the 3 additional patients an M-component was uncovered only by immunofixation, not seen in the agarose electrophoresis of plasma; 2 of them were of IgM isotype and one was of IgG isotype. These 3 patients were diagnosed as having a demyelinating (i.e., possibly immune-mediated) polyneuropathy by means of neurophysiology and in one by means of nerve biopsy. A 6th patient had 2 small bands in the gamma region on the agarose electrophoresis, verified as oligoclonal bands of IgG isotype by immunofixation but was not judged as an M-component. Three out of the 83 patients, were judged as having motor neuron diseases. All remaining 80 were found to have polyneuropathy.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypoglycaemia caused by atypical insulin antibodies in a patient with benign monoclonal gammopathy.

We describe a 48-year-old woman with recurrent severe hypoglycaemia apparently caused by a paraprotein with insulin-binding capacity. Very high fasting values were found for serum insulin (170 and > 250 mU l-1) as well as for proinsulin 125 pmol l-1 and an insulinoma was suspected. Hypoglycaemia developed after an oral glucose tolerance (OGTT) test but not during fasting for 48 h. Free insulin and C-peptide were normal during OGTT whereas serum insulin was very high. 125I-insulin binding to serum, determined with a polyethylene glycol (PEG) precipitation method was high (40%), and equally high after addition of 1.7 x 10(-5) mol l-1 cold insulin to estimate non-specific binding. By adding very high concentrations of cold insulin, displacement of 125I-insulin bound to serum was found (50% displacement at 4 x 10(-5) mol l-1). No immunoglobulin G (IgG) insulin antibodies were detected by radioimmunoelectrophoresis. On agarose electrophoresis a small paraprotein (4 g l-1) in the gamma-globulin fraction was detected. 125I-insulin binding to this paraprotein was demonstrated. We conclude that if insulin autoantibodies are suspected as a cause of hypoglycaemia screening for insulin antibodies should always be done with a PEG-precipitation method.

Measurement by microdialysis of the insulin concentration in subcutaneous interstitial fluid. Importance of the endothelial barrier for insulin.

To evaluate the interstitial insulin and inulin concentrations, 20-min microdialysis samples from the abdominal subcutaneous tissue were obtained by using two 45-mm polypropylene dialyzing tubes (o.d. approximately 0.5 mm, pore size 0.2 micron) during a euglycemic hyperinsulinemic (120 mU.m-2 x min-1) clamp (n = 9) or during a constant inulin infusion (n = 5). After in situ calibration of the microdialysis catheters during steady-state conditions, interstitial and plasma insulin concentrations were estimated to 654 +/- 102 and 1176 +/- 66 pM, respectively, i.e., a 44% difference (P < 0.001). A doubling of the insulin infusion rate (240 mU.m-2 x m-1), leading to supraphysiological plasma insulin levels, raised the interstitial insulin concentrations markedly slower (approximately 20 min) than in plasma. Moreover, at steady state the concentration difference in the two compartments prevailed even during the high insulin infusion rate (55% difference, P < 0.01). In contrast, the interstitial inulin levels were similar to the plasma concentrations in subjects given a constant inulin infusion. Thus, the data suggest the presence of an endothelial barrier for insulin in the subcutaneous tissue. This barrier, in combination with tissue clearance of insulin, leads to lower insulin levels and altered kinetics with a slower rise in the interstitial fluid compared with plasma.

Improved formulae for the judgement of intrathecally produced IgA and IgM in the presence of blood CSF barrier damage.

In order to discriminate between transsudated and intrathecally produced IgA and IgM in patients with blood cerebrospinal fluid (CSF) barrier (BCB) damage, we developed extended indices (IgA-EI and IgM-EI) for these immunoglobulins according to the general formula for extended index of a component X in CSF: X-EI = (CSF-X/serum-X)/(CSF-albumin/serum-albumin)a where a is a parameter specific for X. For IgA parameter a was found to be 1.15 and for IgM 1.9. A preliminary evaluation of IgA-EI and IgM-EI indicated lower false positive rates as compared to CSF IgA and IgM concentrations as well as 'conventional' IgA and IgM indices in cases with BCB damage, and essentially the same rates as for the hyperbolic formulae of Reiber and Felgenhauer. The importance of reliable sampling and analytical technique for IgM in CSF is discussed.