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M Rohac

Publications and source records attributed to M Rohac.

16 recordsLinked to original sources

Direct adsorption of lipoproteins (DALI) from whole blood: first long-term clinical experience with a new LDL-apheresis system for the treatment of familial hypercholesterolaemia.

BACKGROUND: The DALI (direct adsorption of lipoproteins) LDL-apheresis system is a novel device for the removal of lipoproteins from whole blood. METHODS: We report the first long-term treatment experience (16.7 +/- 12.6 months; 57 +/- 43 treatments/patient) using different DALI adsorber sizes (DALI-500, DALI-750, DALI-1000) in seven patients with homozygous (n = 1) and severe heterozygous familial hypercholesterolaemia. For each treatment, 1.6 fold of the calculated blood volume was processed. Treatments were scheduled at weekly or two-weekly intervals. RESULTS: The smallest DALI-500 configuration was unable to achieve sufficient removal of LDL cholesterol, with the adsorber being exhausted already at desorption of 65% of the calculated blood volume. In contrast, both larger adsorber systems effectively removed lipoproteins until the end of treatment. Therefore, the DALI-750 device was used for long-term treatment. LDL cholesterol (mean pretreatment value: 179 +/- 44 mg/dl) was reduced by 73.4 +/- 7.7% and Lp(a) levels (mean pretreatment value: 43 +/- 33 mg/dl) by 69.5 +/- 8.3%. HDL cholesterol (mean pretreatment value: 47 +/- 15 mg/dl) was reduced by 16.3 +/- 8.0% during the treatment. In the long term, LDL cholesterol was reduced by 54.0 +/- 10.5%--from 259 +/- 101 mg/dl to 119 +/- 19 mg/dl. No serious side effects occurred during the treatment. Long-term evaluation of other laboratory parameters showed a reduction in haemoglobin due to treatment-associated blood loss despite frequent iron supplementation. CONCLUSION: Sufficient reductions in LDL cholesterol and Lp(a) were achieved using the DALI-750 system and the treatment was well tolerated. The easy use and short period of 153 +/- 22 minutes required for each treatment are the major advantages of the DALI system as compared to other available LDL-apheresis devices. Potential particle release from the adsorber into the circulation must be ruled out before the system can be introduced in clinical routine.

Adult↗

Therapeutic efficiency of lipoprotein(a) reduction by low-density lipoprotein immunoapheresis.

This study was performed to investigate the effect of low-density lipoprotein (LDL) immunoapheresis on lipoprotein(a) [Lp(a)] reduction in patients with heterozygous and homozygous familial hyperlipidemia (N=16) and insufficient response to lipid-lowering agents. By desorption of approximately 5,700+/-500 mL of plasma, a mean reduction in total cholesterol of 62% (P < .001) and in LDL-cholesterol of 70% (P < .001) was achieved. Lp(a), which was elevated at study entry in seven of these patients (82.1+/-34.3 mg/dL; range, 48 to 148 mg/dL), was reduced during the initial LDL-apheresis procedure by 74.8%+/-14.1% (P < .001). Long-term apheresis treatment performed at weekly intervals resulted in an mean reduction in Lp(a) pretreatment values to 39.1+/-28.5 mg/dL (-54%; P < .001). Desorbed Lp(a) was measured at the waste of the columns for 31 apheresis treatments. Lp(a) concentration of the column waste was higher in patients with elevated serum Lp(a) pretreatment values as compared with those with Lp(a) serum values within the normal range (elevated Lp(a), 1,420+/-380 mg; without elevated Lp(a), 235+/-190 mg; P < .001). The rate of return of Lp(a) following apheresis treatment scheduled at weekly intervals was comparable to that of LDL-cholesterol.

Adolescent↗

[Secondary prevention of diabetic retinopathy in type I diabetes mellitus. Dependence on retinopathy status before the intervention].

OBJECTIVE: To assess prospectively the effect of improving the metabolic state on the course of diabetic retinopathy in relation to the extent of retinal changes before intervention. PATIENTS AND METHODS: 140 patients with type I (insulin-dependent) diabetes mellitus (IDDM) (55 men, 85 women; mean age 30 +/- 11 years; mean duration of illness 11 +/- 8 years), underwent intensified insulin treatment and were then followed for 4 years. At the beginning of the trial fundoscopy was unremarkable in 68 patients (stage 0), a few microaneurysms and (or) punctate bleeding (stage 1) in 21, nonproliferative retinopathy (stage 2) in 27, preproliferative retinopathy (stage 3) in six, proliferative retinopathy (stage 4) in 14, and proliferative retinopathy with complications (stage 5) in four. The average retinopathy stage was 1.2 +/- 1.0, mean HbA1c value 7.0 +/- 1.3%). RESULTS: The retinopathy remained unchanged in 94 patients (group A), it improved in 16 (group B), and deteriorated in 30 (group C). There was no significant change in mean HbA1c value in any of the groups (A: 6.2 +/- 0.9%; B: 6.4 +/- 1.0%; C: 6.3 +/- 6.0%). There were also no differences with respect to blood glucose, M-value according to Schlichtkrull, frequency of hypoglycaemia, serum lipids, blood pressure and renal biopsy parameters. However, significant differences (P < 0.001 C vs. A and B) were found in relation to duration of diabetes (A: 9.3 +/- 7.2 years; B: 8.8 +/- 8.6 years; C: 16.9 +/- 7.8 years) and mean retinopathy stage at beginning of the study (A: 0.8 +/- 0.8; B: 1.2 +/- 0.7; C: 2.4 +/- 1.6). CONCLUSION: Decisive for the course of retinopathy in patients with IDDM of long duration and secondarily optimised metabolic state is the duration of illness and especially the degree of fundal changes when intensified insulin treatment is undertaken.

Adult↗

Fish oil supplementation versus gemfibrozil treatment in hyperlipidemic NIDDM. A randomized crossover study.

To compare the impact of dietary fish oil supplementation (FO, 22 ml daily, containing 4.6 g of n-3 (omega-3) fatty acids, equalling 14.4 mmol) on carbohydrate and lipid metabolism with that of conventional lipostatic therapy (Gemfibrozil (G), 900 mg daily, equalling 3.6 mmol) on hyperlipidemic non-insulin dependent diabetes mellitus (NIDDM), 10 patients were selected for a randomized, short-time, cross-over study. Each patient was treated for a duration of 2 weeks, with an individual washout period of 8 weeks. Metabolic variables and intravenous glucose tolerances (1.2 mmol/kg body weight, t = 30 min) were determined on days 1 and 15 of each treatment period. Plasma lipid concentrations were identical at baseline, but were reduced more markedly following G as against FO exposure (% change vs. baseline: total cholesterol (chol), - 13**/-6* (G vs FO: p = 0.05); total triglycerides (TG), -39**/-18** (p < 0.05); APO B, -17**/- 10* (N.S.); LDL-chol, -15**/0 (p < 0.02); VLDL-chol, -50***/- 34*** (N.S.); VLDL-TG, -44***/-27** (N.S.); (p vs. baseline: * < 0.05, ** < 0.01, *** < 0.001). Total-HDL, HDL2, HDL3 and APO A were not influenced by either FO or G. Neither FO nor G induced a change in intravenous glucose tolerances or associated basal and incremental concentrations of insulin and C-peptide. We concluded, based on short-time applications, that (a) neither treatment affected the carbohydrate metabolism in patients with NIDDM, and (b) a greater hypolipidemic efficacy had to be assigned to Gemfibrozil than to fish oil. It would therefore appear that Gemfibrozil acts as a useful lipostatic pharmacologic compound, whilst fish oil could serve as a potential ingredient of a prudent cardio-protective diet which favours the low plasma triglyceride concentrations found in NIDDM patients.

Aged↗

No effect of short-term dietary supplementation of saturated and poly- and monounsaturated fatty acids on insulin secretion and sensitivity in healthy men.

To evaluate the short-term influence of fatty acids with different grades of saturation on insulin secretion and sensitivity, 8 healthy males (age 26 +/- 3.5 years, body mass index 22.4 +/- 1.8 kg/m2) were provided with 800 kcal daily of either carbohydrates (CH; 200 g), or fat (90 g) enriched either with saturated fatty acids (SAFA; 72%) or (omega-6) polyunsaturated fatty acids (PUFA; 60%) or cis-monounsaturated fatty acids (MUFA; 40%; n = 5) in addition to a standard diet (2,000 kcal/ day; 50% CH, 15% protein, and 35% fat; 33% SAFA, MUFA, and PUFA each) for 1 week in a randomized order (washout period 2 weeks). The stimulated insulin secretion was quantified by the frequently sampled intravenous glucose tolerance test (FSIGT; 0.3 g glucose/kg body weight), while the insulin sensitivity was determined by an euglycemic-hyperinsulinemic 5-mU clamp. In parallel, basal and stimulated carbohydrate and fat oxidation rates were estimated by indirect calorimetry. One week of defined fat exposure failed to significantly affect the glucose-induced insulin secretion during FSIGT and insulin-dependent glucose disposal during an euglycemic clamp (M values: CH 9.6 +/- 1.6 mg/kg.min, SAFA 9.7 +/- 2.2, PUFA 9.8 +/- 2.5, and MUFA 11.5 +/- 3.2 mg/kg.min; NS). In addition, oxidation rates for fat and glucose in the postabsorptive state and during hyperinsulinemia did not differ between the different diets. We conclude that short-term (1-week) isocaloric supplementation of a standard diet with fatty acids of varying degree of saturation does not affect either insulin secretion or insulin sensitivity in healthy men, due to the compensatory metabolic capacity of healthy subjects.

Adult↗

Elevated concentrations of circulating adhesion molecules and their association with microvascular complications in insulin-dependent diabetes mellitus.

To better understand potential associations of circulating adhesion molecules (cAMs) with diabetic microangiopathy, circulating serum concentrations of intercellular adhesion molecule-1 (cICAM-1), vascular cell adhesion molecule-1 (cVCAM-1), and endothelial leukocyte adhesion molecule-1 (cELAM-1) were determined in patients with insulin-dependent diabetes mellitus (IDDM) (n = 70) presenting with varying degree of metabolic control and status of diabetic late complications, and were compared with age-matched healthy subjects (n = 70) in a cross-sectional study. Concentrations of cICAM-1 and cVCAM-1 were elevated in IDDM vs. age-matched controls (cICAM-1: 276 +/- 71 vs. 212 +/- 57 ng/mL; P < 0.0001; cVCAM-1: 781 +/- 245 vs. 615 +/- 151 ng/mL; P < 0.0001), whereas cELAM-1 did not differ between the groups (cELAM-1: 50 +/- 25 vs. 46 +/- 23 ng/mL, P = 0.31). The levels of cVCAM-1 were more markedly elevated in IDDM patients with diabetic retinopathy (n = 32) than in those without (n = 38) (cVCAM-1: 848 +/- 281 vs. 724 +/- 197 ng/mL, P < 0.05), as well as in patients with micro- or macroalbuminuria (n = 10) vs. those without (n = 60) (cVCAM-1: 947 +/- 256 ng/mL vs. 753 +/- 234 ng/mL, P < 0.05), whereas no difference in cICAM-1 and cELAM-1 was apparent regarding the clinical status of diabetic microangiopathy. No correlations were found between hemoglobin A1e and cAMs in the individual subgroups of patients and healthy subjects. Interestingly, however, low density lipoprotein cholesterol correlated with cVCAM-1 (r = 0.38, P = 0.03) in IDDM patients with diabetic microangiopathy (n = 33), but not in healthy controls or patients without microangiopathy (n = 37). Analyzing the pooled data of diabetic patients and healthy subjects (n = 140), concentrations of cICAM-1 were markedly related to cVCAM-1 (r = 0.45, P < 0.0001) and cELAM-1 (r = 0.31, P < 0.0002), whereas cVCAM-1 was related less to cELAM-1 (r = 0.19, P = 0.03), respectively. We conclude that, irrespective of actual metabolic control, serum concentrations of cICAM-1 and cVCAM-1 but not cELAM-1 are elevated in patients with IDDM, reflecting ongoing endothelial cell stimulation and leukocyte activation. More specifically, more marked elevation of cVCAM-1 may even hint at clinically manifest diabetic microangiopathy.

Adolescent↗

Islet amyloid polypeptide inhibits insulin secretion in conscious rats.

To investigate the effect of islet amyloid polypeptide (IAPP, amylin) exposure on insulin secretion in vivo, the plasma glucose level of conscious rats was clamped at 11.1 mmol/l (hyperglycemic clamp) during the last 2 h of a 24-h infusion study. Group parameters were A, 24-h saline; B and C, 22-h saline followed by 2-h IAPP (B, 8.5 pmol/min; C, 85 pmol/min), and D, 24-h IAPP (85 pmol/min). Induced hyperglycemia increased plasma insulin concentration by 426 +/- 34 pmol/l in control rats (group A). This effect on plasma insulin was reduced by 31% and 53% during short-term IAPP infusion (group B, 8.5 pmol/min, 294 +/- 41 pmol/l; C, 85 pmol/min, 202 +/- 25 pmol/l; short-term effect, P < 0.0001), whereas insulin levels tended to increase after 24 h of continuous IAPP exposure (group D, 682 +/- 120 pmol/l; P < 0.05 vs. group A). Glucose infusion rate required to maintain constant hyperglycemia fell dose dependently during short-term but not during long-term IAPP infusion (mumol.kg-1.min-1: group A, 203 +/- 11; B, 154 +/- 7; C, 119 +/- 7; D, 212 +/- 9; short-term effect, P < 0.0001). In parallel, muscle glycogen content was dose dependently reduced by short-term IAPP exposure. We conclude that IAPP inhibits glucose-stimulated insulin secretion and decreases muscle glycogen storage in conscious rats in vivo.

Amyloid↗

Insulin resistance caused by amylin in conscious rats is independent of induced hypocalcemia and fades during long-term exposure.

To compare the effect of short- vs long-term amylin infusion on insulin sensitivity, glucose tolerance and serum calcemia, euglycemic-hyperinsulinemic clamp (26 pmol.kg-1 x min-1) and glucose tolerance tests (2.4 mmol/kg over 30 min) were performed in lean Zucker rats. Three infusion protocols were employed: control group: 24 h of i.v. saline; short-term amylin exposure: 22 h of i.v. saline followed by 2 h of i.v. amylin (20 micrograms/h); long-term amylin exposure: 24 h of iv amylin (20 micrograms/h). Insulin resistance was induced by short-term amylin infusion during euglycemic clamping, as shown by a 41% decrease in space-corrected glucose infusion rates (mumol.kg-1 x min-1; control group, 106.0 +/- 15.0; short-term i.v. amylin, 62.7 +/- 15.0; p < 0.005). After long-term amylin exposure, insulin sensitivity was identical to control values (109.9 +/- 6.7). This fading action of amylin was confirmed by data from the glucose tolerance test, demonstrating glucose intolerance after short- but not after long-term amylin exposure. Serum calcium concentration decreased during short-term (2 h) amylin infusion (from 2.52 +/- 0.15 to 2.09 +/- 0.12 mmol/l; p < 0.01) and hypocalcemia of a similar extent also was present after 22 h and 24 h of amylin exposure (2.10 +/- 0.09 and 2.04 +/- 0.14 mmol/l, respectively). The data demonstrate that short-term amylin infusion induces insulin resistance and glucose intolerance, both of which vanish during long-term (> 22 h) amylin exposure, being apparently independent of induced hypocalcemia.

Amyloid↗

Identification of common allergenic structures in hazel pollen and hazelnuts: a possible explanation for sensitivity to hazelnuts in patients allergic to tree pollen.

It is known that most patients with type I allergy to tree pollens also suffer from intolerance to nuts. To identify allergenic structures common to hazel pollen and hazelnuts, cross-reactivity of patients' IgE was investigated. With use of immunoblotting,.serum IgE from 25 patients displaying type I allergic reactions to tree pollens and intolerance to hazelnuts (group I) bound to the 17 kd major hazel pollen allergen Cor a I (100%) and to the 14 kd hazel pollen profilin (16%). IgE binding to proteins of comparable molecular weights in hazelnut extracts was found (18 kd and 14 kd), suggesting that proteins similar to Cor a I and hazel profilin might be also expressed in hazelnuts. In contrast, only four sera (22%) from 18 patients (group II) with tree pollen allergy but without any case history of nut hypersensitivity showed IgE binding to the 18 kd protein of hazelnut extract, and none of these sera exhibited IgE reactivity to the hazelnut profilin. To characterize the hazel pollen and hazelnut allergens, purified recombinant Bet v I (major birch pollen allergen) and purified recombinant Bet v II (birch profilin), respectively, were used for IgE-inhibition experiments. Binding of IgE from patients (with nut allergy) to the blotted hazelnut allergens could be blocked by preincubation of patients' sera with the recombinant proteins. Furthermore, the 18 kd protein of hazelnut extract was purified and induced specific release of histamine from basophils of a patient suffering nut hypersensitivity but not from a healthy control donor. A rabbit antibody raised against celery profilin identified the 14 kd proteins in hazel pollen and hazelnuts as profilin. Our experiments suggest a protein with IgE binding properties similar to the major allergens from pollens of hazel, Cor a I, and of birch, Bet v I, as predominant allergens in hazelnuts, and show that the plant pan-allergen profilin can be detected in both hazel pollen and hazelnut extracts.

Allergens↗

Inhibition by etomoxir of carnitine palmitoyltransferase I reduces hepatic glucose production and plasma lipids in non-insulin-dependent diabetes mellitus.

To determine the therapeutic effect of the carinitine palmitoyltransferase I (CPT-I) inhibitor, etomoxir, eight hospitalized obese non-insulin-dependent diabetes mellitus (NIDDM) patients were studied (body mass index [BMI], 28.7 +/- 1.3 kg/m2; age, 54 +/- 8 years [means +/- SE]) at baseline (placebo = t1), and after oral etomoxir (50 mg/d = t2, 100 mg = 3, 150 mg = t4, 200 mg = t5, placebo = t6). Fasting blood glucose (mmol/L), triglycerides (mmol/L), cholesterol (mmol/L), free fatty acids (mumol/L), beta-hydroxybutyrate (mumol/L), and alanine aminotransferase (GPT, U/L) were determined (t1 to t6), as were glucose utilization (M value; indirect calorimetry) and hepatic glucose production during a 10 mU/kg.min euglycemic clamp (t1 and t4). A dose-dependent decrease was induced by etomoxir in fasting blood glucose (t1 to t5: 9.5 +/- 0.7, 8.7 +/- 1.0, 8.3 +/- 1.1 [P v t1 less than .05], 7.8 +/- 0.9, [P v t1 less than .01], 7.9 +/- 1.1 [P v t1 less than .05]), which was reversible in t6 (9.9 +/- 1.1). Mean plasma lipids were reduced (t1 v t5) for triglycerides (-54%, P v t1 less than .01), cholesterol (-24%, P v t1 less than .05), and beta-hydroxybutyrate (-44%, P v t2 less than .01), while free fatty acids increased by 52% (P v t1 less than .05), as did GPT (t1: 17 +/- 3; t5: 32 +/- 7 U/L [P v t1 less than .01]).(ABSTRACT TRUNCATED AT 250 WORDS)

3-Hydroxybutyric Acid↗

The immunological relationship of epitopes on major tree pollen allergens.

The major allergens of birch (Bet v I), alder (Aln g I), hazel (Cor a I) and hornbeam (Car b I) were investigated by means of high-resolution two-dimensional electrophoresis combined with immunoblotting. Eleven sera derived from patients allergic to birch pollen as well as mouse monoclonal antibodies BIP 1 and BIP 4, raised against Bet v I, were used as probes. Human IgE antibodies detected 10 spots in birch (Mr 17 kDa, pI 4.9-5.9); four spots in alder (Mr 18.5 kDa, pI 4.7-5.3); four spots in hazel (Mr 17 kDa, pI 5.0-5.8); and 12 + 7 spots in hornbeam (Mr 16.5 kDa, pI 4.9-6.6 and Mr 18 kDa, pI 5.2-6.7), respectively, representing major allergens. Each patient tested reacted in a similar fashion with the spot cluster(s) of a certain allergen. BIP 1 detected the same spot clusters as patients' IgE. BIP 4 reacted with the 17-, 18.5- and 18-kDa spots of birch, alder and hornbeam, but did not react with the 17-kDa spots of hazel and the 16.5-kDa spots of hornbeam. In inhibition experiments with birch pollen extract as inhibitor, IgE binding to Bet v I, as well as to Aln g I, Cor a I and Car b I was abolished, thus suggesting that IgE binding to major tree pollen allergens is confined to shared epitopes. These findings indicate that it might be sufficient to use only Bet v I for diagnostic procedures as well as for immunotherapy in patients with tree pollen allergy.

Adolescent↗

Metabolic effects of fish-oil supplementation in patients with impaired glucose tolerance.

To determine the impact of fish-oil supplementation on glucose and lipid metabolism in patients with impaired glucose tolerance (IGT), 30 ml fish oil containing 3.8 g eicosapentaenoic acid (EPA; 20:5 omega 3) and 2.5 g docosahexaenoic acid (DHA; 22:5 omega 3) were given to eight obese subjects with IGT (mean +/- SD age 50.3 +/- 8.0 yr) in addition to their regular diet for 2 wk. Studies were performed in randomized order versus an isocaloric control period with a washout phase of 3 wk. Hyperinsulinemic clamp examinations (1 and 10 mU.kg-1.min-1) were performed. Glucose disposal rate (M value) rose from basal 14.3 +/- 5.1 to 17.9 +/- 4.4 mumol.kg-1.min-1 after fish oil (P less than 0.001) during the 1-mU clamp, whereas no change was seen during the 10-mU clamp (without fish oil, 42.2 +/- 8.9 mumol.kg-1.min-1; with fish oil, 45.1 +/- 9.8 mumol.kg-1.min-1;NS). Basal hepatic glucose output remained unaffected by fish oil, whereas fractional glucose clearance after intravenous glucose loading (2.4 mmol/kg body wt, t = 30 min) tended to increase (K value: without fish oil, 2.15 +/- 1.02%/min; with fish oil, 2.74 +/- 1.26%/min; NS). Neither the fasting concentrations of glucose and insulin nor induced glycemia and insulin response during intravenous glucose loading calculated as incremental area under the curve changed after fish-oil supplementation.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Glucose↗

Monoclonal antibodies against birch pollen allergens: characterization by immunoblotting and use for single-step affinity purification of the major allergen Bet v I.

Two monoclonal antibodies against birch pollen proteins were produced by immunizing BALB/c mice with birch pollen extract. In immunoblotting experiments, antibody BIP 1 reacted with a 17-kilodalton (kD) protein considered to represent the major birch pollen allergen Bet v I. A second monoclonal antibody, BIP 3, reacted with 3 different birch pollen proteins of molecular weights 32, 36 and 68 kD of which the 36- and 68-kD proteins corresponded to minor allergens of birch pollen. Two-dimensional electrophoresis/immunoblotting experiments revealed that BIP 1 reacted with all Bet v I isoallergens, also identified by human IgE antibodies. Using BIP 1 coupled to Sepharose 4B as reverse immunosorbent, Bet v I was obtained in a single-step procedure and characterized as single band by SDS-PAGE.

Allergens↗

Comparison of two solid phase chemistry systems: Reflotron and Ektachem DT 60.

Solid phase chemistry can be used for clinical analysis at the bedside, and it is even applicable to whole blood. We compared precision, accuracy, method linearity, and practicability of two solid phase chemistry analysers. Reflotron (Boehringer Mannheim, W. Germany) and Ektachem DT 60 (Eastman Kodak Co, USA). Eight analytes, glucose, cholesterol, triacylglycerols, urea, uric acid, alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyltransferase were investigated. The precision of both instruments was good. Coefficients of variation for within run and day to day precision were below 10% for all analytes. Methods were compared by analysing 88 to 105 patients sera for each investigated analyte on Reflotron, on Ektachem DT 60 and on a wet chemistry reference instrument. Linear regression analysis showed good agreement between wet chemistry and solid phase chemistry results. Coefficients of correlation (r) ranged from 0.957 to 0.999. Reflotron and Ektachem are desk top analysers. Reflotron is the smaller instrument. Currently, it offers 9 analytes and rapid single test performance. Whole blood can be used for all tests. Test strips can be stored at room temperature. Ektachem DT 60 has a modular design, and 22 analytes are available. Series of up to 100 tests per hour are possible. Whole blood can be used for the preparation of glucose and haemoglobin test slides. The slides must be deep frozen for prolonged storage. Reflotron may be suitable for the physician's office, Ektachem for small laboratories. The problem of quality control has not yet been satisfactorily solved for either instrument, as only analyser-specific control specimens can be used. Reagent costs of solid phase chemistry tests are high, especially when large test series are performed. Operation of both instruments requires well trained personnel.

Alanine Transaminase↗