Rate dependence of acute PTH release and association between basal plasma calcium and set point of calcium–PTH curve in dialysis patients

Vincenzo De Cristofaro1,, Carla Colturi1, Alessandra Masa1, Mario Comelli2 and Luciano A. Pedrini1

1 Departments of Nephrology and Dialysis, Hospital of Sondrio, Sondrio, 2 Medical Statistics, University of Pavia, Pavia, Italy



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. In vivo, the control of calcium-mediated acute PTH release during induced hypo- or hypercalcaemia is linked not only to plasma calcium concentration per se but also to the rate and direction of calcium change. In fact, during induced hypocalcaemia, the predominant mechanism that causes PTH to be released is the reduction of plasma Ca2+ irrespective of the absolute starting concentration of ionized calcium. This mechanism, which is rate-dependent and even activated in conditions of hypercalcaemia, may be involved in the association, reported in several papers, between the basal Ca2+ and the set point of the calcium–PTH curve.

Methods. The calcium–PTH relationship was studied in 12 dialysis patients under conditions of induced low and high predialysis plasma Ca2+. At each level of basal Ca2+, dynamic tests were conducted using two methodological approaches. In method A patients underwent low (0.5 mmol/l) calcium dialysis in the stimulation test and high (2 mmol/l) calcium dialysis in the inhibition test, while the dialysate calcium (CaD) was kept constant during each test. In this way a higher but variable rate of change in plasma Ca2+ was achieved. In method B, CaD was progressively decreased (stimulation test) and increased (inhibition test) during the tests in order to obtain a lower but more constant rate of change in plasma Ca2+. Consequently, for each patient, four calcium–PTH curves were produced: low basal Ca2+ with methods A and B, and high basal Ca2+ with methods A and B.

Results. Basal plasma Ca2+ was similar in A and B at low (1.16±0.02 vs 1.15±0.02 mmol/l) and high (1.25±0.02 vs 1.26±0.02 mmol/l) basal plasma Ca2+. The set point was higher in A than in B both at low (1.12±0.02 vs 1.10±0.02 mmol/l, P=0.01) and high (1.20±0.02 vs 1.16±0.02 mmol/l, P=0.03) basal Ca2+ as was the slope (542±41 vs 426±44%/mmol, P=0.02; 615±73 vs 389±25%/mmol, P=0.01). No significant difference was found between A and B as regards minimal PTH and plasma Ca2+ at minimal PTH (Camin) in both calcaemic states. Maximal PTH was slightly higher in B at low (510±97 vs 548±107 pg/ml, P=NS) and high basal plasma Ca2+ (410±97 vs 464±108 pg/ml, P=0.02). Plasma calcium at maximal PTH (Camax) was significantly higher in A (1.1±0.03 vs 0.99±0.02 mmol/l, P=0.001) at high basal plasma Ca2+. The set point was strictly related to basal plasma Ca2+ in both methods, but the slope of the linear regression was significantly steeper with method A. The set point was predicted to increase by 0.881 (CI 0.772–0.990) mmol/l for each mmol/l of increase in basal plasma Ca2+ with method A and by 0.641 (CI 0.546–0.737) mmol/l for each mmol/l of increase in basal plasma Ca2+ with method B.

Conclusions. (i) Higher and variable rates of change in plasma Ca2+ produce a higher set point value and a steeper slope of the calcium–PTH curve when compared to lower and more constant rates of calcium change. (ii) The different slope of the linear correlations between basal plasma Ca2+ and set point in the two methods suggests that the rate-dependent mechanism of acute PTH release plays a significant role in the association between set point and basal plasma Ca2+. (iii) The significance of the set point is questionable when the calcium–PTH curve is carried out in vivo.

Keywords: acute PTH secretion; basal plasma calcium; four-parameter model; hysteresis; rate of change in plasma calcium; set point



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
The sigmoidal inverse relationship between plasma calcium concentration and PTH release, as first described by Mayer and Hurst [1], is frequently used in dialysis patients to study parathyroid function. Recent papers [26] have reported a strict association between the set point for calcium-related PTH secretion and the basal plasma Ca2+, irrespective of the functional secretory status of the parathyroid glands. The set point moves towards the existing plasma Ca2+ as though parathyroid cells were capable of adapting their own specific property to the ambient plasma calcium [3]. Nevertheless, in vivo, the control of calcium-mediated PTH release from the parathyroid glands is complex. Indeed, the response of the parathyroid glands is affected not only by the calcium concentration per se but also by the rate and direction of calcium change [712]. During acute induced hypocalcaemia, the predominant mechanism which causes PTH to be released is the reduction of ionized calcium and not the absolute concentration of Ca2+ [10]. This mechanism, which is rate dependent and even activated in conditions of hypercalcaemia, is the primary response of the parathyroid glands to acute change in the steady state plasma calcium. For these reasons, the shift of the set point towards the basal plasma Ca2+ may be bound to conventional parathyroid dynamic testing per se, which is typically carried out by creating acute change in existing plasma calcium. Since the rate-dependent mechanism of PTH release cannot be suppressed during dynamic tests, this study was planned to evaluate how different rate-dependent PTH profiles influenced the association between set point and basal plasma Ca2+ in the same patients.

We evaluated the calcium–PTH curve in 12 dialysis patients in conditions of induced low and high basal plasma Ca2+, using two methodological approaches to attain different rates of change in plasma Ca2+. In method A, inhibition and stimulation tests were conducted respectively with high- and low-calcium dialysis while dialysate calcium concentration (CaD) was kept constant over the tests. In method B, CaD was modulated during the tests in order to obtain a slower and more constant rate of change in plasma calcium. For each patient four curves were drawn up: curves 1 and 2, conditions of low basal plasma Ca2+, using methods A and B; curves 3 and 4, conditions of high basal plasma Ca2+, using methods A and B.

Each method yielded a typical pattern of PTH secretion as a consequence of the different rates of change in plasma Ca2+. The set point followed the basal Ca2+ in all patients whether the calcium–PTH curve was produced with method A or B. However, the slope of the linear regression between set point and basal Ca2+ was significantly steeper when the curve was produced with method A.



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Study design
Twelve maintenance haemodialysis patients (aged 59.5±5 years, five females and seven males, duration of haemodialysis of 45±19 months), with a basal PTH level of 167± 30 pg/ml (range 56–380), were included in the study. All but two were on vitamin D supplements (1.35±0.1 µg/week) and took calcium carbonate as a phosphate-binder (4.8±0.6 g/day). All patients had a plasma aluminium level lower than 30 µg/l (6.83±0.7 µg/l). The protocol was approved by the appropriate Committee for Human Studies and all patients gave their informed consent. Treatment with vitamin D was discontinued at least 4 weeks before the study. The patients were placed randomly in two different treatment sequences in order to change the basal plasma Ca2+. In the first, the patients were treated for at least 2 weeks with high CaD dialysis (1.94±0.03 mmol/l) and a larger amount of oral calcium carbonate (6±0.8 g/day) to increase basal Ca2+, followed by low CaD dialysis (1.33±0.03 mmol/l) and low doses of calcium carbonate (2.2±0.6 g/day) to decrease basal plasma Ca2+. In the second, the treatment sequence was reversed. Dynamic parathyroid tests were performed at the end of hypo and hypercalcic treatments with methods A and B. In method A, CaD was constant over the tests at 0.49±0.01 (stimulation test) and 1.99±0.01 mmol/l (inhibition test). In method B, changes in CaD were obtained using the technique we described in a previous paper [13]. Fresenius 2008E equipment was fitted with a peristaltic pump capable of modulating CaD, by adding a required amount of calcium chloride to calcium-free acid concentrate. During the stimulation test, CaD was linearly decreased to zero from an initial value equal to basal plasma Ca2+ minus 0.2 mmol/l (slope of linear regression: -0.012 mmol/l/min, r2 0.91). During the inhibition test, CaD was linearly increased up to 2.3–2.4 mmol/l from an initial value of the basal plasma Ca2+ plus 0.3 mmol/l (slope of linear regression: +0.007 mmol/l/min, r2 0.90). The stimulation tests lasted 90 min and the inhibition tests 120 min. A cuprophane membrane was used in all dialysis. Dialysate ionic and glucose concentration was the same in all studies and so too were the dialysate flow (500 ml/min), blood flow (300 ml/min) and UFR (0.55±0.06 l/h).

Blood samples for measurement of ionized calcium, acid–base status and PTH were obtained from the arterial line at 0, 15, 30, 45, 60 and 90 min in the stimulation and inhibition tests with the addition of another sample at 120 min in the inhibition test. The initial and final samples were processed to determine phosphate, magnesium, glucose, and alkaline phosphatase.

Laboratory methods
Phosphate, magnesium, glucose and alkaline phosphatase were measured by standard laboratory techniques. Ionized calcium and acid–basic state were determined at bedside in triplicate by the Selective Electrodes System (ABL 505 Radiometer, Copenhagen, Denmark). The mean intra-assay and inter-assay coefficients of variation for plasma Ca2+ were below 1.5%. Intact PTH was measured with an immunoradiometric assay (Diagnostic Products Corporation. Los Angeles, CA, USA; normal value 10–55 pg/ml). The intra-assay and interassay variation coefficients were 2.5 and 6.9% respectively. Blood samples were kept on ice, separated by cold centrifugation, and stored at -20°C until assay. All samples of a given patient were run in the same assay.

Statistics
The data were expressed as mean values with SEM as an index of dispersion. The comparisons were made with the Wilcoxon matched-pairs test and analysis of covariance, using the statistic software Graph Pad PRISM and SPSS program.

From the data obtained during the inhibition and stimulation tests four individual calcium–PTH curves were drawn up for each patient, using the four-parameter model described by Brown [14]. PTH values were expressed as a percentage, the top was considered constant (100%), the set point was the ionized Ca2+ corresponding to the midpoint between the maximal and minimal PTH, the slope was calculated at the midpoint. Moreover, for each curve the following parameters were defined: maximal PTH (PTHmax) as the highest PTH level observed in response to hypocalcaemia; minimal PTH (PTHmin) as the lowest PTH level during suppression by hypercalcaemia; Camax and Camin as the plasma Ca2+ at which maximal and minimal PTH were respectively registered. As in method B, PTH continued to increase even at the lowest Ca2+, PTHmax and Camax were calculated where the slope of the curve changed significantly. Cumulative calcium–PTH curves were constructed from the individual curves, using the mean of the PTH values obtained in each individual curve at fixed intervals of calcium concentration (0.05 mmol/l). Data were grouped as follows: low plasma Ca2+—curve produced from method A (LA); low plasma Ca2+—curve produced from method B (LB); high plasma Ca2+— curve produced from method A (HA); high plasma Ca2+—curve produced from method B (HB).



   Results
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
All selected patients completed the study. Blood pH, HCO3-, glucose, magnesium and alkaline phosphatase were similar in all groups at the beginning and at the end of the dynamic tests (Table 1Go). Serum phosphate was slightly lower at high basal plasma Ca2+, most probably due to the administration of a larger amount of chelating agents. Under hypercalcic treatment the mean value of basal PTH decreased in response to the increase of the predialysis plasma Ca2+.


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Table 1. Biochemical determinations at the beginning and at the end of the dynamic tests

 
The rate of change in plasma Ca2+ was constant with method B, whereas with method A it dropped significantly after the first 15 min and decreased progressively over time (Table 2Go). In the initial phase of the tests, the rate was always higher in method A than in method B.


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Table 2. Changes in plasma Ca2+ during dynamic tests with methods A and B, at low and high basal plasma Ca2+

 
Comparing PTH dynamics at low and high basal Ca2+ (Figure 1Go), it was found that with method A, in the stimulation test, PTH levels for a similar Ca2+ were significantly different. In contrast, with method B, PTH values for comparable plasma Ca2+ were close and, at the lowest Ca2+, were almost identical. As regards the inhibition test, no difference was observed between low and high basal Ca2+ in either method. Comparing PTH dynamics with methods A and B (Figure 2Go), it was found in the stimulation test that PTH level for similar Ca2+ were different, with the difference becoming significant at high basal Ca2+. In the inhibition test there was no difference between the two methods in both calcaemic states.



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Fig. 1. PTH vs ionized calcium. Comparison between PTH values at similar ionized calcium in conditions of low and high basal plasma Ca2+. PTH is the mean of the values obtained in each individual curve at fixed intervals of calcium concentration. Method A (a, c), method B (b, d). Stimulation test (a, b), inhibition test (c, d). Low basal plasma Ca2+ ({blacksquare}), high plasma Ca2+ ({blacktriangleup}). Wilcoxon paired test *P=0.02, **P=0.005.

 


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Fig. 2. PTH vs ionized calcium. Comparison between PTH values at similar ionized calcium in methods A and B. Stimulation test (a, b), inhibition test (c, d). Low basal plasma Ca2+ (a, c), high basal plasma Ca2+ (b, d). Method A ({blacksquare}), method B ({blacktriangleup}). Wilcoxon paired test *P=0.002.

 
As shown in Table 3Go, the set point was significantly higher in both methods at high basal plasma Ca2+. Moreover, it was higher with method A in both calcaemic states. The calcium–PTH curve was significantly less steep in method B than in A. No difference was found between A and B as regards PTHmin and Camin in both calcaemic states. At high basal Ca2+, PTHmax was higher and Camax significantly lower in B than in A. With both methods, going from low to high basal Ca2+, PTHmax decreased, PTHmin and Camin remained the same and Camax shifted to the right, although to a larger degree with A.


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Table 3. Parameters of calcium–PTH curve with methods A and B at low and high basal plasma Ca2+

 
The set point of the cumulative calcium–PTH curves increased in both methods at high basal plasma Ca2+ although the increase was more pronounced in method A. The slope of the curve was steeper with method A in both calcaemic states (Figure 3Go).



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Fig. 3. Cumulative calcium–PTH curves with methods A (•) and B ({circ}) in condition of low and high basal plasma Ca2+. The values of PTH, expressed as percentages, were the mean of PTH values at fixed intervals of ionized calcium in the individual curves. In condition of high basal plasma Ca2+ the curves were shifted to the right in both methods but clearly more in method A. The set point with method A was 1.157 and 1.212 mmol/l respectively at low and high basal plasma Ca2+, while with method B it changed from 1.139 to 1.174 mmol/l. The slopes of the curves were steeper in A than in B in both conditions of basal plasma Ca2+: 416.1 vs 313.5%/mmol and 492 vs 314.6%/mmol respectively at low and high basal plasma Ca2+.

 
To analyse the effect of the basal plasma Ca2+ and the method on the value of the set point, a first model of covariance analysis was fitted to the set point. It included the following variables: subject, method, and basal Ca2+; the interaction of basal Ca2+ and method was also accounted for. In this model, which fitted the data very well (R2=0.959), the set point was predicted to increase by 0.881 (CI 0.772–0.990) mmol/l for each mmol/l of increase in basal Ca2+ with method A and by 0.641 (CI 0.546–0.737) mmol/l for each mmol/l of increase in basal Ca2+ with method B (Figure 4aGo). To explain the way in which the method influenced the association between set point and basal Ca2+, the main parameters of the curve and interactions were introduced into the covariance model. Only a second model (R2=0.975), containing Camax and its interaction with the method in addition to the terms already listed, succeeded in explaining the interaction formerly seen between basal Ca2+ and method. Taking into account the different effects of Camax on the set point within each method (Figure 4bGo), the effect of basal Ca2+ on the set point was the same for both methods (see Figure 4cGo). The set point could increase by 0.564 (CI 0.480–0.649) mmol/l for each mmol/l of increase in basal Ca2+ in both methods, if Camax were kept constant.



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Fig. 4. (a) The two lines represent the association between set point and basal plasma Ca2+ in methods A and B, estimated by the first covariance model fitted. The intercepts are computed by averaging out the experimental subject contributions. The lines diverge because an interaction term between experimental method and basal plasma Ca2+ is contained in the model. (b) The two lines represent the association between set point and Camax in methods A and B, estimated by the second covariance model fitted. The intercepts are computed by averaging out the experimental subject contributions and by keeping the value of basal plasma Ca2+ constantly equal to its grand mean. The lines diverge because an interaction term between experimental method and Camax is contained in the model. (c) The two lines represent the association between set point and basal plasma Ca2+ in methods A and B, estimated by the second covariance model fitted. The intercepts are computed by averaging out the experimental subject contributions and by keeping the Camax value constantly equal to its grand mean. The lines are parallel because no interaction between experimental method and basal plasma Ca2+ is contained in the model.

 



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
In vivo, when an acute reduction in basal plasma Ca2+ is produced, the parathyroid glands respond first of all to the change (rate-dependent PTH release) and only subsequently adapt PTH secretion to the value of the plasma Ca2+ (steady-state PTH release). This happens irrespective of the absolute value of the basal Ca2+ because the rate-dependent control of PTH release is evident even in the presence of hypercalcaemia [10]. The superimposition of rate-dependent on concentration-dependent control of PTH during induction of hypocalcaemia either from normocalcaemic or hypercalcaemic levels could produce apparent hysteresis with PTH values higher at any given ionized calcium levels [15]. Moreover, parathyroid cells are able to sense not only the rate of change but also the variation of the rate (i.e. marked deceleration) as suggested by a recent work of Estepa et al. [16]. Apparent hysteresis, rather than exhaustion of the parathyroid glands, could explain the biphasic pattern of PTH achieved in the stimulation test with the citrate clamps technique [10,12]. The PTH level is high during the acute induction of hypocalcaemia but it decreases rapidly when stable hypocalcaemia is achieved with citrate clamps. In this phase the parathyroid glands sense the significant reduction of the rate of change in calcium and reduce PTH secretion in spite of hypocalcaemia. As additional variables, besides simply Ca2+ concentration per se, have an impact on the calcium–PTH relationship [9,15], the set point determined in vivo must be carefully interpreted.

Method A vs method B
Apparent hysteresis was present in method A, which produced a higher but variable rate of change in plasma Ca2+. In the stimulation test, after an initial rapid increase due to an exponential decrease in plasma Ca2+ in the first few minutes, PTH values did not significantly change and, on the contrary, at the lowest values of hypocalcaemia these values tended to decrease in response to the marked reduction in the rate of calcium change. On the other hand, in method B the more constant rate of change in plasma Ca2+ yielded a PTH profile that did assume a sigmoidal pattern, but with negative asymptotic slope, marked by a lower increase of PTH values. As a consequence of different PTH profiles, the set point and the slope of the calcium–PTH curve were significantly higher with method A in both calcaemic states. In method A the faster decrease in plasma Ca2+ in the initial phase of the test, followed by a reduced rate of change, produced a steeper curve, which shifted upward and to the right and so increasing the set point value. The pattern of PTH only changed significantly during the stimulation test, most probably due to the lower susceptibility of the parathyroid cells to the effects of the rate during the rise in Ca2+ [9].

Low vs high basal plasma Ca2+
The effect of the basal calcaemic status on the calcium–PTH curve was significant only with method A and during the stimulation test (Figure 1Go). With this method, at high basal plasma Ca2+, the higher blood–dialysate calcium gradient caused, in the first 15 min, a greater decrease in plasma Ca2+ (0.13±0.01 vs 0.10±0.01 mmol/l P=0.02). The responding increase in PTH release was much more elevated as a percentage of the basal value. In the following minutes PTH did not change further and at the lowest Ca2+ values, PTH was significantly less than in the hypocalcaemic state. In contrast, with method B, where the rate of change in plasma Ca2+ was similar in the two calcaemic states, the difference of the PTH values at given values of ionized calcium was not so apparent as with method A. At the lowest hypocalcaemic range the values were quite similar. It is likely that in method B the lower rate of change in plasma Ca2+ and the lack of apparent hysteresis allowed the parathyroid cells to adapt PTH secretion more closely to values of Ca2+. This difference in the behaviour of PTH secretion may explain why, at high basal plasma Ca2+, Camax and the set point shifted to the right to a lesser degree in method B than in A (Table 3Go).

The association between basal Ca2+ and the set point
The set point was strictly related to the basal plasma Ca2+ in both methods, but the slope of the linear regression was significantly steeper with method A (Figure 4aGo). The additional effect of the method on the association between set point and basal calcium was shown to be mediated by Camax which, at high basal Ca2+, moved to the right much more in method A than in method B. As the parathyroid glands cannot sense Camax, the effect of Camax on the set point was only related to the way in which the parathyroid tests were carried out. When this effect within each method was taken into account, the effect of basal plasma Ca2+ on the set point was the same for both methods. We suppose that the shift of the set point towards the basal plasma Ca2+ may be linked to dynamic parathyroid tests per se, which are typically performed with acute changes of the steady-state plasma calcium. As the response of the parathyroid glands is immediate, irrespective of the value of the existing plasma Ca2+, the set point necessarily shifts in the direction of the calcium starting value. The rate of change in plasma Ca2+ defines the entity of the shift. This hypothesis is supported by the results of a study in normal humans on the behaviour of the PTH secretion during citrate clamp immediately following a 120-min calcium clamp [10]. In hypercalcaemia the parathyroid response was immediate, although smaller than in normocalcaemia, with a qualitatively similar pattern of PTH secretion. In contrast, in a study in dogs [17], parathyroid response in hypercalcaemia did not commence until the plasma Ca2+ decreased below a normal value. However, the experimental conditions of these two studies were significantly different.

In theory, if any deviation from the baseline plasma Ca2+ induces an immediate response of the parathyroid glands, it should be natural that the set point and the basal plasma Ca2+ coincide [18]. Indeed, the calcium-related PTH secretion curve should be steepest at the basal plasma Ca2+ value and the logistic curve should be steepest near to the inflection point (set point). In reality the set point in all experimental curves was approximately 0.05 mmol/l (range 0.03–0.09) lower than the basal Ca2+ with a larger difference with method B at high basal plasma Ca2+. However, this could be merely a mathematical artefact of the curve used to fit the experimental points. First of all, for a sigmoidal curve, the top of the logistic should be a defined parameter indicating the inability of the parathyroid glands to change PTH secretion in response to a further decrease in plasma Ca2+. Instead, in method A, PTHmax is greatly affected by the apparent hysteresis and in method B the change of PTH secretion per unit change in plasma Ca2+ at the upper asymptote settles to a low but not nil value. Secondly, the experimental starting point of the PTH is much lower than the midpoint between its maximum and minimum values. This could be due to: (i) the greater absolute increase of PTH in response to hypocalcaemic stimulus than the corresponding decrease with induced hypercalcaemia; (ii) the tonic level of PTH secretion that cannot be suppressed. The logistic curve forces the inflection point to climb up to half-way between the upper and lower asymptotes. Correspondingly, the abscissa of the inflection point is artificially moved to the left of the basal plasma Ca2+.

In conclusion, the results of this study, although confined to a selected population, suggest that the set point follows the basal plasma Ca2+ because of the rate-dependent mechanism of PTH release during dynamic parathyroid testing. In vivo, the set point for calcium-related PTH release corresponding to the mid-point between maximal and minimal PTH of the logistic curve could be an artificial parameter that might not be a real measure of the sensitivity of the parathyroid cells to calcium.



   Acknowledgments
 
The authors wish to thank Dr Giancarlo Orlandini and Dr Giuseppe Erba from Fresenius for their technical and organizational support and Mr Isidoro Azzalini and Mr Massimo Murada from the renal unit of Sondrio Hospital for their assistance in the execution of dialytic procedures.



   Notes
 
Correspondence and offprint requests to: Vincenzo De Cristofaro, Department of Nephrology and Dialysis, Hospital of Sondrio, Via Stelvio 25, I-23100 Sondrio, Italy. Back



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 19. 5.00
Revision received 8. 1.01.



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