[Pharmacokinetic parameters as criteria for clinical use of hydroxyethyl starch preparations]. / Pharmakokinetische Merkmale als Kriterien für den klinischen Einsatz von Hydroxyethylstärke.

Pharmacokinetic Parameters as Criteria for Clinical Use of Hydroxyethyl Starch Preparations In a study with volunteers (n = 2 x 6) pharmacokinetic data of two only marginally differing starch preparations were investigated. We were able to demonstrate that there exist significant differences in raw materials used which determined the pharmacokinetic data in humans. Newly implemented analyzing methods (LALLS) were used. In addition to the degree of substitution, further differences concerning the position of hydroxyethylization at the anhydroglucose molecule could be documented. The C2/C6 positions of hydroxyethylization at the molecule seem to be most essential. To classify and to differentiate starch preparations we propose to include these data in general informations for clinicians because these differences might determine clinical usage and efficacy.

Circannual oscillations of function compared with morphometric changes in the thyroid gland of the Wistar-rat.

To investigate biological rhythms of the thyroid gland circannual oscillations of thyroxine (T4), triiodothyronine (T3), and thyrotropin (TSH) were compared in serum samples of untreated young male Wistar-rats with the circannual changes of thyroid weights and with the relative proportion of colloid, epithelium, and interstitium of the thyroids. Animals were kept under standard environmental conditions, however, lighting conditions simulated the natural day-night changes. Thyroid weights, T4, T3, and TSH showed a statistically significant circannual rhythm with maxima in winter and spring and minima in summer and autumn. The same circannual patterns were observed in the proportion of epithelium and interstitium of the thyroids, while the colloid exhibited an inverse circannual pattern. These data were verified by biomathematical methods, like locally adjusted functional approximation, analysis of variance, and Spearman rank correlation. Our results represent an example for the concordance between functional and morphometrical changes in the course of circannual oscillations. Furthermore, these data confirm our earlier results describing higher T4-levels in the winter time (short-day) and lower serum titers in the summer time (long-day).

[The effect of ganglionectomy and cold exposure on the ventromedial hypothalamic nucleus, blood glucose and liver glycogen in regard to circadian rhythms]. / Zum Einfluss von Gangliektomie und Kälteexposition auf den Nucleus ventromedialis hypothalami sowie Blutglukose und Leberglykogen unter Berücksichtigung circadianer Rhythmen.

To analyse the importance of the ventromedial hypothalamic nucleus (VMH) for the circadian regulation of the carbohydrate metabolism rats were investigated after bilateral cervical sympathetic ganglionectomy (SCGx) 30 d earlier and exposure to cold (10 degrees C) 72 h earlier. In order to assess the circadian rhythms of nuclear volume oscillations of the VMH, blood glucose, and liver glycogen 4 times a day (light-dark cycle: 14L:10D, light on 05.00 h) rats were sacrificed at midlight and middark as well as 1 h after the onset of the light and dark periods. The circadian curves were calculated in a model-free way by the procedures of locally adjusted polynomial approximation. Ganglion removal and exposure to cold resulted in an increase of blood sugar and of nuclear volume of the VMH, but only of its lateral part. The liver glycogen decreased. Additionally, both the coordination between the circadian curves of the nuclear volume and of the blood glucose as well as of the inverse curves of the liver glycogen was destroyed after SCGx. These results are in agreement with the conviction that the enhanced blood glucose activates the VMH. The augmentation of blood glucose was discussed in connection with influences of the likewise increased thyrotropin-releasing hormone and thyrotropin on the increased plasma levels of catecholamines, with secondary increased plasma levels of glucagon as well as decreased insulin levels after SCGx and exposure to cold. The sympathetic denervation of the pineal gland (SCGx) produced the mentioned desynchronization of the curves. At the present we are not able to explain the approximate restitution of the circadian rhythms after additional exposure to cold.

[Biomathematical aspects of numerical evaluation and mathematical modelling of non-monotonous exponential measuring processes]. / Biomathematische Aspekte der numerischen Auswertung und mathematischen Modellierung nichtmonoton exponentieller Messwertverläufe.

Measurements of endocrinological and pharmacological processes often yield courses of time series with exponentially saturated increasing first part followed by an exponentially decreasing part. Such measured courses may be mathematically modelled by the so-called BATEMAN function type, an expression consisting of 2 e-function terms. In this paper, the method of locally adjusted functional approximation for model-free quantitative evaluation of measured time series is sketched. By means of 2 real examples of measured data, it will be demonstrated how the results of the model-free evaluation may serve for internal regression to estimate starting parameter values for an iterative fitting of a BATEMAN function to measured data courses. Furthermore, it is shown that the model-free approach of data evaluation may give substantial hints for the mathematical model building process and for model verification.

[Estimation of median regression from measured values]. / Schätzung der Medianregression aus Messwerten.

The median regression function is defined and demonstrated by examples. A lemma with sufficient conditions for continuity and differentiation of the median regression function is proved. Its estimation from a random sample is deduced firstly based on the empirical distribution function and secondly based on a kernel estimation with Gaussian kernels. Both estimations are demonstrated by GALTONS historical example. A comparison between the empirical median regression function and the empirical regression of the first kind is made by an example. A hint for curve fitting with the median estimation equation is also given by an example.

Circannual serum creatine kinase patterns after ganglionectomy and pinealectomy of the Wistar rat.

Previous investigations have shown that an inverse correlation exists between serum thyroxine levels (T4) and serum creatine kinase activity (CK) both in hypothyroid and hyperthyroid states. In the present study, serum T4 levels and total serum CK activity were analysed after thyroidectomy (TX), ganglionectomy (extirpation of the superior cervical sympathetic ganglion) (GX), or pinealectomy (PX) four times a year (March, June, September, and December). Blood samples were taken four times daily (at midlight, middark, and at 1 hour after the onset of the light and dark periods). Animals were kept under an artificial light schedule that simulated natural light-dark periods. The annual main values of serum T4 levels were significantly decreased after the operations, whereas serum CK activities were increased. Our circannual investigations demonstrated an inverse correlation between serum T4 levels and total serum CK activity (under hypothyroid circumstances). In addition, the circannual pattern of the serum CK activity demonstrated maxima under short-day (winter) conditions and minima under long-day (summer) conditions. GX and PX provoke an unimportant shift (a little longer than 2 months) in maxima and minima of the annual rhythm. Circannual curves exhibited differences in the degree of the increase of serum CK activity of GX and PX groups. These results indirectly confirm the assumption that experimental sympathetic denervation or removal of the pineal gland will induce a hypothyroid state over the long term.

Local approximation and its applications in statistics.

For the discrete and for the continuous case, the problem of evaluating the derivatives of a function f(x) in a given interval of x is solved by local approximation method. Examples of application of the resulting numerical procedures are quoted relating the estimation of smooth function and its derivative for measured values (of a growth process), internal regression, trend elimination of time series, Bernstein polynomial, and kernel estimation of a density function.

[Periodic local approximation for the model free description of measurement courses of biorhythmic processes--demonstration example for the selection of smoothness parameters]. / Periodische lokale Approximation zur modellfreien Beschreibung von Messwertverläufen biorhythmischer Vorgänge--Demonstrationsbeispiel für die Wahl des Glättungsparameterwertes.

Measured time series with known basic periodicity may be modelfreely evaluated by procedures of local adjusted approximation. Examples of motility time series recorded in chronobiological experiments in the seasonal course of a year demonstrate aspects of choosing values of the smoothing parameter and the resulting effects for the quantitative description of the measured variations as well as for their interpretation.

Morphometric investigations of the pineal gland after ganglionectomy and thyroidectomy under the aspect of circadian and seasonal variations.

It is well established that the pineal gland is involved in the regulation of thyrotropin (TSH) secretion. Previous investigations in our laboratory showed that under hypothyroid conditions the nuclear size of pinealocytes was diminished while an increase in the size of nuclei was seen under hyperthyroid conditions. In the present study we confirmed these results while considering circadian and circannual oscillations. After ganglionectomy (GX, removal of the sympathetic superior cervical ganglia) the mean annual values of the nuclear size of pinealocytes, pineal weights and thyroxine (T4) levels were diminished, whereas the pituitary weights increased. Comparable, but more drastical reactions were found after thyroidectomy (TX). The diminution of the nuclear size of pinealocytes was more pronounced in the wintertime (December, L: D = 8: 16), the finding for the summertime (June, L: D = 16: 8) being similar. Under short-day conditions the nuclear size was larger than under long-day regimes. In the winter the enhancement of the nuclear size was accompanied by decreased pituitary weights and increased T4 levels while under long-day conditions lower size of pinealocytes and T4 levels were associated with higher weights of pituitary glands. The statistically significant circadian patterns of the nuclear size of pinealocytes showed that the largest nuclei occurred at the end of the light phase or at the onset of the dark phase. In June, the largest nuclei were found in the middle of dark (control) or in the early light phase (ganglionectomy). Considering the circadian patterns of pineal weights and T4 levels, these results underline the existence of a functional connection between the pineal gland and the thyroid axis.(ABSTRACT TRUNCATED AT 250 WORDS)

[Modelling and model-free mathematical description of biological relationships]. / Modellierende und modellfreie mathematische Beschreibung biologischer Zusammenhänge.

The features of the modelling and the model free approaches for handling measured data of functional connections in respect to their advantages as well as to their troubles will be discussed theoretically and by means of morphometrical, histokinetical, and chronobiological examples.

[Complementarity of causality and finality in biology--a report reviewing two lectures given at the 1987 annual meeting of the Leopoldina]. / Komplementarität von Kausalität und Finalität in der Biologie--ein rezensorischer Bericht über 2 Vorträge zur Jahresversammlung 1987 der LEOPOLDINA.

Reviews of the opening lecture of H. Mohr "The Elementary in the Science--Possibilities and Limits of the Reductionism" and of the final lecture of N. Bischof "Order and Organization as Heuristic Principles of the Reductive Way of Thinking" at the meeting 1987 of the Deutsche Akademie der Naturforscher LEOPOLDINA are framed by remarks about the connections between Biology and Physics.

["Openess--Aspects of Time--Complexity"--Recensorial remarks on a book of the same name to the theory of open systems]. / "Offenheit--Zeitlichkeit--Komplexität"--rezensorische Bemerkungen über ein gleichnamiges Buch zur Theorie der Offenen Systeme.

The 9 papers collected in the book "Offenheit--Zeitlichkeit--Komplexität" (Campus, Frankfurt/M., New York 1984, 1987) are discussed in view of their possible contributions to a better understanding of the phenomena arising in complex biological, ecological, economical, and social systems which would be the basis also for solving the problems caused by the enlarging technologic-economical supersystems.

Changes in the daily rhythm of serum testosterone levels following superior cervical sympathetic ganglionectomy in the cold-exposed rat: the role of the pineal.

The effect superior cervical sympathetic ganglionectomy (Gx) exerted on the daily rhythm of serum testosterone levels was investigated in cold-exposed rats. Rhythmic changes in pineal and pituitary weights were also measured. 1. Exposure to cold (10 degrees C for 72 h) resulted in a significant decrease of serum testosterone level and in an increase of the pineal weight. 2. In neutral ambient temperature (24 degrees C) Gx, 30 d after operation, led to a moderate, statistically insignificant increase of serum testosterone levels and to decreased pineal weights (statistically significant). 3. The reactions provoked by cold exposure were counteracted by Gx. Testosterone levels, as well as the pineal weight, showed no remarkable change in the Gx, cold-exposed animals. 4. These results confirm our assumption that experimental manipulations of the pineal gland can provoke significant changes in the neuroendocrine system only under special loading circumstances, e.g., cold exposure. Sympathetic denervation of the pineal gland counteracts the cold-induced decrease of testosterone levels by counteracting the pineal antigonadotropic activity. 5. The empirical regression curves of the investigated parameters indicate that Gx or cold exposure provide a shift in the upper and lower limits of the daily rhythm. Partly inverted rhythms were also observed. 6. The presented results are discussed in relation to the parallel changes previously described in serum thyroxin, cholesterol, thyrotropin (TSH), and pituitary TSH levels. Thyroidal-gonadal interactions, as well as cold exposure as a stress-generating factor, have been considered in the possible explanation of the data herein reported.

Circannual oscillations of thyroxine and cholesterol levels after pinealectomy and ganglionectomy related to the weight changes of the pineal, pituitary, and thyroid glands.

Circannual rhythms of thyroxine (T4) and cholesterol blood levels, as well as of pineal, pituitary and thyroid weights were compared in intact, pinealectomized (Px), and ganglionectomized (Gx) rats. Special emphasis was put on the similarities and differences between the effect of Px and of Gx exerted on the neuroendocrine regulation of thyroid function. Animals were kept under changing lighting schedules simulating the natural seasonal conditions (December, L:D 8:16; June, L:D 16:8; March and September, L:D 12:12). Animals were killed 90 d after surgical interventions in the above-mentioned 4 months. In each season, animals were killed at four time points of the daily rhythm, and the means of the four data of a single day were used for further analysis evaluating circannual changes. All the investigated five parameters showed a monophasic circannual rhythm. The lowest T4 blood level was measured in summer; in contrast, cholesterol level and organ weights had a maximum in the same season of the year. The annual mean value of T4 level was diminished, while cholesterol level and pituitary and thyroid weights were increased in Px and Gx animals. Pineal weight showed a decrease in the Gx animals. Both Px and Gx failed to influence the circannual rhythms of the measured parameters. However, a significant T4-decreasing effect of Px and Gx was observed in the second half of the year, whereas a cholesterol-level-increasing effect, as well as thyroid hypertrophy, was registered in the first half of the year. These results suggest a prothyroid function of the pineal gland.

[Effect of particle size and emulsifier on pharmacokinetic values of a parenterally administered fat emulsion]. / Uber den Einfluss von Teilchengrösse und Emulgator auf pharmakokinetische Kenndaten einer parenteral applizierten Fettemulsion.

To evaluate pharmacokinetic data during parenteral application of a fat emulsion a controlled study in healthy volunteers was performed. Another aim of the study was to investigate whether these kinetics could be changed by modification of the emulsion. For this purpose, 10 male medical students--free of any metabolic disorders--received modified batches of one fat emulsion (Lipovenös), differing with respect to particle size or emulsifier. The emulsions were applied using a pump-controlled continuous infusion technique. The dosage was calculated according to body weight: 0.1 g/kg B.W./h. There was a 7-10 day interval between one application and the following study period, again using the same volunteers. Thus every volunteer served as his own control. Routine laboratory parameters as well as parameters relating to fat metabolism were measured. While routine laboratory parameters were not statistically different between the groups, pharmacokinetic data showed differences according to the batches used. Highest triglyceride and free fatty acid levels i.s. were present after application of the emulsion with low medium particle size, while lowest levels were found after increasing the particle size to 380 nm. In addition, it could be documented that an increase in medium particle size resulted in higher elimination rate, transfer and pool size. The modified emulsifier led to an additional increase of these effects, thus inducing beneficial metabolic profiles. The results of the present investigation might perhaps enable us to adjust the profile of future fat emulsions, with the aim of optimizing or restoring metabolic hemostasis.

Information theoretical aspects of the aging process of organismic systems.

The aging process is understood as the temporally changing ability of the organism to maintain the degree of inner order and organisation which is necessary for viability. This inner order and organisation may be represented by a multidimensional state variable 'vitality'. The quantity 'vitality entropy' is defined in a manner similar to information theoretical or thermodynamical entropy. It is an aggregate measure of the age-dependent distribution of vitality in the state space. In these terms a mathematical description of the aging process may be given as temporal changes of the extension of this distribution. In an initial phase of differentiation of an organism the vitality entropy decreases to a minimum as the distribution becomes concentrated at the optimal states. With aging in the narrower sense, the distribution spreads in the state space with the decrease of order and organisation, and the consequent increase of vitality entropy.

[Acute normovolemic hemodilution in extensive surgical interventions]. / Die akute normovolämische Hämodilution bei grossen operativen Eingriffen.

In order to ascertain the effect of acute isovolaemic haemodilution on haemodynamics and various laboratory parameters as well as homologous blood consumption 44 patients undergoing major liver surgery were investigated in two groups: group I (n = 22) underwent acute normovolaemic haemodilution after induction of anaesthesia; group II (n = 22) had no blood withdrawn and served as control. Haemodilution led to typical haemodynamic effects such as increase in cardiac index and decrease in systemic as well as pulmonary vascular resistance; no detrimental effect of the procedure could be observed. Haemodilution led to a marked reduction in the consumption of banked blood which was on the average 1.8 units/patient against control intraoperatively and 3.1 units/patient postoperatively summing up to a total of 4.9 units/patient.

[Case studies of the use of the locally adjusted polynomial regression]. / Fallstudien zur Anwendung der lokal angepassten polynomialen Regression.

Firstly the operation mode of the procedures of local adjusted polynomial regression is explained by an artificial example of data. After that, the properties of these nonparametric estimation procedures of unknown continuous functions from measured data are demonstrated by some examples arising in experimental examinations. Especially the aspect is discussed how far the main task of separating the deterministic component from the random one in the course of measured values may be fulfilled by using different degrees of polynomials in connection with different values of the smoothing parameter.