Activation of the complement cascade enhances motility of leukemic cells by downregulating expression of HO-1.

As a crucial arm of innate immunity, the complement cascade (ComC) is involved both in mobilization of normal hematopoietic stem/progenitor cells (HSPCs) from bone marrow (BM) into peripheral blood and in their homing to BM. Despite the fact that ComC cleavage fragments alone do not chemoattract normal HSPCs, we found that leukemia cell lines as well as clonogenic blasts from chronic myeloid leukemia and acute myeloid leukemia patients respond robustly to C3 and C5 cleavage fragments by chemotaxis and increased adhesion. This finding was supported by the detection of C3a and C5a receptors in cells from human malignant hematopoietic cell lines and patient blasts at the mRNA (reverse transcriptase-polymerase chain reaction) and protein level (fluorescence-activated cell sorting), and by the demonstration that these receptors respond to stimulation by C3a and C5a by phosphorylation of p42/44 and p38 mitogen-activated protein kinases (MAPK), and protein kinase B (PKB/AKT). We also found that inducible heme oxygenase 1 (HO-1) is a negative regulator of ComC-mediated trafficking of leukemic cells, and that stimulation of leukemic cells by C3 or C5 cleavage fragments activates p38 MAPK, which downregulates HO-1 expression, rendering cells more mobile. We conclude that activation of the ComC in leukemia/lymphoma patients (for example, as a result of accompanying infections) enhances the motility of malignant cells and contributes to their spread in a p38 MAPK-HO-1-dependent manner. Therefore, inhibition of p38 MAPK or upregulation of HO-1 by small-molecule modulators would have a beneficial effect on ameliorating cell migration-mediated expansion of leukemia/lymphoma cells when the ComC becomes activated.

[Are American physicians more satisfied?--results from an International Study of Physicians in University Hospitals]. / Sind amerikanische Arzte zufriedener?--Ergebnisse einer internationalen Studie unter Arzten an Universitätskliniken.

Understanding the factors that affect physicians' job satisfaction is important not only to physicians themselves, but also to patients, health system managers, and policy makers. Physicians represent the crucial resource in health-care delivery. In order to enhance efficiency and quality in health care, it is indispensable to analyse and consider the motivators of physicians. Physician job satisfaction has significant effects on productivity, the quality of care, and the supply of physicians. The purpose of our study was to assess the associations between work-related monetary and non-monetary factors and physicians' work satisfaction as perceived by similar groups of physicians practicing at academic medical centres in Germany and the U.S.A., two countries that, in spite of differing health-care systems, simultaneously experience problems in maintaining their physician workforce. We used descriptive statistics, factor and correlation analyses to evaluate physicians' responses to a self-administered questionnaire. Our study revealed that overall German physicians were less satisfied than U.S. physicians. With respect to particular work-related predictors of job satisfaction we found that similar factors contributed to job satisfaction in both countries. To improve physicians' satisfaction with working conditions, our results call for the implementation of policies that reduce the time burden on physicians to allow more time for interaction with patients and colleagues, increase monetary incentives, and enhance physicians' participation in the development of care management processes and in managerial decisions that affect patient care.

[Concepts for a demand-oriented structuring of palliative care in the German Health Care System: the example of Lower Saxony]. / Konzepte zur bedarfsgerechten Strukturierung der Palliativversorgung im deutschen Gesundheitswesen: Das Beispiel des Bundeslandes Niedersachsen.

Palliative care can be considered a holistic care approach for patients faced with incurable and progressive diseases in their last period of life. In this context, structural, cultural and content-related deficits are increasingly taken into account in the German health care system, however, there is a lack of scientific data. Therefore, it was the objective of an expert team at Hannover Medical School to analyse the current situation of palliative care in Lower Saxony from the perspective of health system research and to give recommendations for its further development, based on empirical studies in Lower Saxony and on a systematic national and international literature review. The study revealed that the main shortcomings were an unclear structuring and an inadequate definition with respect to other areas of care, a fundamental lack of integration in regard of routine processes of care and a lack of thorough tools for needs assessments. Therefore, a concept for the integration of palliative care in the care processes of cancer patients was developed and the specific need for hospice beds in regional districts was calculated by using parameters representing provision-related and epidemiological/demographic conditions. In comparison to current structures, an assessment of over- and undersupply as well as specific recommendations how to optimize palliative care were provided for politicians, payers and providers in Lower Saxony.

Kinetics of photochromic reactions in condensed phases.

A review of kinetic data reported for a few organic photochromic systems is given. The kinetics of processes taking place in solid matrices and in crystals was briefly discussed. The effect of solid matrices manifests itself in the kinetics being controlled by distributions rather than by discrete rate constants. The photochromic reactions often require a substantial free volume to occur, hence they seldom take place in crystals without a destruction of the crystal lattice. The activation energies of thermally driven reactions are in this case related rather to crystal parameters than to the reactions themselves.

[Integrated delivery systems in California--success and failure determining factors for the first 10 years and impetus for Germany]. / Integrierte Versorgungssysteme in Kalifornien - Erfolgs- und Misserfolgsfaktoren der ersten 10 Jahre und Impulse für Deutschland.

Since the coming into effect of the Health Care Modernization Act (Gesundheitsmodernisierungsgesetz) the conditions for integrated health care delivery are favourable in Germany. However, comprehensive approaches are a long time in coming. In contrast, integrated health care delivery as an integral part of the spreading of managed care entered a further stage of development, which enables health care decision makers to draw conclusions regarding the further development of integrated health care delivery in Germany. Based on case studies integrated delivery systems in the San Francisco Bay Area have been analyzed with the objective to evaluate pitfalls and successful strategies for integrated health care delivery. The major pitfalls refer to an insufficient local focus, a lack of actual integration and the application of per capita reimbursement (which is a key subject on the political agenda in Germany as well) within integrated delivery systems. On the contrary, successful strategies include achieving a dynamic tension between centralized and decentralized coordination, internal and external relationship management, well organised human resource management including a well-defined corporate policy and a comprehensive implementation of information technology. Based on US experiences with integrated delivery systems implications for the design of integrated health care delivery in Germany are discussed.

The effect of food or water deprivation on paracetamol pharmacokinetics in calves.

This study investigated the effect of food or water deprivation on the pharmacokinetics of paracetamol in 30 Holstein-Friesian preruminant calves (10 controls, 10 food withheld and 10 water-deprived) aged 24-25 days. Control calves were given paracetamol at 24-25 days and again at 28-29 days of age. In the food withheld and water-deprived calves paracetamol studies were performed before and after 4 days of food or water deprivation. In the control group there were no significant differences in pharmacokinetic parameters for paracetamol in 24-25 and 28-29-day-old calves. Witholding food for 4 days was associated with an increase in the mean residence time (MRT) of paracetamol (P < 0.01). When food was withheld total body clearance (ClB) of paracetamol was significantly decreased (P < 0.05). The volume of distribution (Vss) was not significantly altered. Similarly, water deprivation was associated with a significant increase in MRT and significant decrease in ClB of paracetamol (P < 0.01). The Vss was not significantly altered. Food or water deprivation also influenced the formation of major metabolites (glucuronide and sulphate) of paracetamol. It is concluded that food or water deprivation may impair the elimination drugs that undergo metabolism by UDP-glucuronyltransferase and sulphotransferase in cattle.

The effect of short-term starvation or water deprivation on caffeine pharmacokinetics in calves.

The aim of this study was to determine the effect of short-term starvation or water deprivation on the pharmacokinetics of caffeine in calves. The experiment was carried out on 30 Holstein-Friesian calves (10 calves in a control group, 10 calves in a 'starved' group and 10 calves in a 'water-deprived' group) aged 24-25 days. Control group calves were given caffeine at 24-25 and 28-29 days of age. In the experimental groups caffeine studies were performed before and after 4 days of starvation or water deprivation. In the control group no significant differences between the pharmacokinetic parameters of caffeine in 24-25 and 28-29 day-old calves were observed. Starvation for 4 days was associated with an increase in the mean residence time (MRT) of caffeine in each subject. The increase was statistically significant (P < 0.01). After starvation the total plasma clearance of caffeine decreased (about 20 per cent). The decrease was statistically significant (P < 0.05). The volume of caffeine distribution (V(ss)) was slightly but not significantly increased. Similarly, water deprivation was associated with significant increase in the mean residence time of caffeine in each subject. The total plasma clearance of caffeine decreased (about 30 per cent). This decrease was statistically significant (P < 0.01). The volume of caffeine distribution was slightly but not significantly decreased. Results obtained in this study indicate that short-term (for 4 days) starvation or water deprivation leads to a general inhibition of hepatic P450 enzymatic system and may impair the elimination of drugs that undergo metabolism by these enzymes.

The effect of sex and age on caffeine pharmacokinetics in cattle.

The aim of this study was to determine the effect of sex on the pharmacokinetics of caffeine in cattle at different ages. Ten female and 10 male Holstein cattle were subject to a caffeine test when they were aged 1, 2, 4, 6, 8, 12 and 18 months. Caffeine, 5 mg kg(-1)body weight, was given intravenously as a sterile isotonic solution. An automated, enzyme-multiplied, immunoassay technique (EMIT) was used to determine plasma caffeine concentration. The volume of distribution of caffeine (V(SS)) decreased significantly between 1 and 18 months of life. Mean V(SS)values observed in males and females were not statistically different. The experimental period was characterised by a steady decrease (statistically significant) in caffeine mean residence time (MRT). These values did not differ significantly between males and females under 8 months of age. In 8-, 12- and 18-month-old animals, the caffeine MRT in the females was significantly shorter than in the males. The total plasma clearance (Cl(tot)) of caffeine increased significantly between 1 and 18 months of age. No significant differences were observed between total plasma clearance of caffeine in males and females under 8 months of age. In 8-, 12- and 18-month-old animals, the Cl(tot)of caffeine was significantly higher in females than in males. In conclusion, we report a sex-linked difference in pharmacokinetics of caffeine in cattle over 8 months of age, the females being the more active metabolisers. The results of the present study support the hypothesis that the metabolism of xenobiotics is sexually different in ruminants.

The effect of sex on antipyrine metabolism in cattle at different ages.

The aim of this study was to determine the effect of sex on the metabolism of antipyrine by measuring the antipyrine plasma clearance as well as excretion of three major metabolites in urine in cattle of different ages. The experiment was carried out on 10 female and 10 male cattle of Black and White breed. The antipyrine test was carried out at 1, 2, 4, 6, 8, 12 and 18 months of age for each animal (single dose of 10 mg/kg antipyrine were given intravenously). The concentrations of antipyrine, 4-hydroxyantipyrine (4-OHA), 3-hydroxymethylantipyrine (HMA) and norantipyrine (NORA) were measured in plasma and urine by high performance liquid chromatography (HPLC). The apparent volume of distribution of antipyrine (aVd) decreased significantly between 1 and 18 months of age, but mean aVd values observed in males and females were not statistically different. The experimental period was characterised by a steady decrease (statistically significant) in antipyrine half-life (t1/2beta). These values did not differ significantly between males and females under 12 months. In 12 and 18 month-old animals the antipyrine half-life in the females was significantly shorter than in the males. The systemic clearance (Cls) of antipyrine increased significantly between 1 and 18 months of age. No significant differences were observed between systemic clearance of antipyrine in males and females under 12 months. In 12 and 18 month-old animals the Cls values were significantly higher in females than in males. Following intravenous administration, recovery of antipyrine and its three main metabolites increased significantly with age. These values did not differ significantly between males and females under 12 month of age. In 12 and 18 month-old females the excretion of 4-OHA and HMA in urine was significantly higher than in males at the same age. The excretion of NORA and unchanged antipyrine in males and females did not differ significantly. The partial clearances of antipyrine metabolites (Cl(m)) increased significantly between 1 and 18 months of age. No significant differences were observed between Cl(m) values in males and females under 12 months of age. In 12 and 18 month-old females the partial clearances of 4-OHA and HMA were significantly higher than in males. The clearance of NORA was significantly higher in 18 month-old females than in males. In conclusion, we report a sex-linked difference in plasma antipyrine clearance and urinary excretion of the main metabolites of antipyrine in cattle over 12 months of age, the females being the more active metabolizers.

Influence of short-term water deprivation on antipyrine disposition in calves.

The effect of four days water deprivation on the metabolism of antipyrine was studied in female Holstein-Friesian calves, aged 24 to 25 days, by measuring the antipyrine plasma clearance and the excretion of three major metabolites of antipyrine in urine. Water deprivation was associated with a statistically significant (P < 0.01) increase in the plasma antipyrine elimination half-life from 10.85(1.14) hours to 14.00(1.05) hours. In water deprived calves the systemic clearance of antipyrine was significantly (P < 0.05) decreased from 0.75(0.07) ml min-1 kg-1 to 0.56(0.05) ml min-1 kg-1. The excretion of three major metabolites of antipyrine: 4-hydroxyantipyrine, 3-hydroxymethylantipyrine and norantipyrine in urine was significantly (P < 0.01) decreased after water deprivation. In the control group no significant differences between the pharmacokinetic parameters of antipyrine in 24 to 25 and 28 to 29 day-old calves were observed. Also urinary profiles of antipyrine in calves from the control group did not differ significantly between 24 to 25 and 28 to 29 days of life. Our data indicate that water deprivation inhibits antipyrine elimination in calves.

Effect of spironolactone on antipyrine metabolism in calves.

Ten female calves of the Black and White breed aged seven to eight days were studied before and after seven days of treatment with spironolactone at a dose rate of 1 mg kg bodyweight-1 twice a day. The treatment was associated with a statistically significant decrease in the half-life of antipyrine in plasma and an increase in its rate of metabolic clearance. The excretion of 4-hydroxyantipyrine in urine was significantly increased after the treatment with spironolactone, but there were no changes in the rates of excretion of 3-hydroxymethylantipyrine or norantipyrine. These results indicate that spironolactone enhanced the activity of the microsomal drug-metabolising enzyme system and induced cytochrome P-450 in the calves.

Effect of age on the pharmacokinetics of antipyrine in calves.

Single doses of 15 mg kg-1 antipyrine were given intravenously to 10 female calves of the black and white breed at one, two, four, six, eight and 12 weeks of age, and the concentrations of antipyrine, 4-hydroxyantipyrine (4-OHA), 3-hydroxymethyl-antipyrine (HMA) and norantipyrine (NORA) were measured in plasma and urine by high performance liquid chromatography. The first three months of life were characterised by a steady decrease in the apparent volume of distribution (aVd) and half-life (t0.5) of antipyrine. The systemic clearance (CIs) of antipyrine per unit bodyweight increased significantly between one and 12 weeks of age. Age did not influence the excretion of HMA and NORA in urine, but the excretion of 4-OHA by 12-week-old calves was significantly greater than by one-week-old calves. There was an age-related change in the partial clearances of the antipyrine metabolites when expressed per unit bodyweight.

Pharmacokinetics of antipyrine in calves at neonatal period fed with casein supplemented food.

The purpose of the studies was to evaluate (on the basis of pharmacokinetics of antipyrine) hepatic biotransformation rate in calves in neonatal period, which received supplementary casein dose in their food. It was found that 25% increase in protein content in food ration of the examined animals significantly increased hepatic biotransformation rate (activity of monooxygenases dependent on cytochrome P-450). The results obtained also indicate that a protein-rich diet may significantly increase metabolism of other xenobiotics in MFO-P-450 enzymatic system, provided that they undergo the same biotransformation process as antipyrine.

Seasonal variations of antipyrine pharmacokinetics parameters in calves.

In the experiment the values of parameters of antipyrine kinetics were defined (Vd - volume of distribution, t0.5 - half-life, CA - metabolic clearance) in calves in January, April, July and October 1986 and in January and July 1987. Statistically significant increase of distribution volume and increase of hepatic antipyrine clearance were recorded, as well as significant shortening of half-life of this substance in the organism of tested animals in summer 1986 and 1987, compared with the remaining seasons of the year. Antipyrine pharmacokinetics in winter, spring, autumn 1986 and winter 1986/87 did not differ significantly.

Pharmacokinetics of antipyrine in calves during first 35 days of life.

The experiment was carried out on 10 bull-calves of black-white breed, aged 2-35 days. The following parameters of antipyrine pharmacokinetics were determined: Vd - volume of distribution, t0.5 - biological half-life, CA - metabolic clearance. It has been shown statistically that the volume of antipyrine distribution (expressed in 1/kg) was significantly decreasing with age of examined animals. The antipyrine half-life proved to be the longest on the 20th day of calves' life and the shortest on the 10th and 30th day. The maximum values of metabolic clearance of antipyrine were observed in calves aged 10 days and the minimum ones in animals aged 20 days. In the cases of t0.5 and CA a tendency to changes of values of these parameters of antipyrine pharmacokinetics in 10 days periods was observed.

Monthly variations in the pharmacokinetics of antipyrine in calves.

In the experiment (on the basis of values of antipyrine (phenazone) pharmacokinetics parameter), biotransformation activity of calves liver during a year was determined. The experiment was carried out on calves aged 28-30 days. Volume of distribution (Vd), half-life (t0.5) and metabolic clearance (CA) of antipyrine were from month to month determined. Not significant changes between values of Vd, t0.5 and CA in several months were observed. Results of experiment indicated that calves' liver is characterized by the relatively stabile biotransformational activity during the whole year.

Effect of short-term starvation and water deprivation on pharmacokinetics of antipyrine in calves.

The experiment was carried out on 15 calves of black and white breed at the age of 21-22 days. The effect of 72 hours simultaneous starvation and water deprivation on pharmacokinetics of antipyrine (phenazone) was studied. The following parameters were determined: Vd--volume of distribution, delta Vd--apparent volume of distribution, t0.5--half-life, ClA--metabolic clearance rate. There were shown statistically significant increase of half-life and decrease of metabolic clearance rate and volume of antipyrine distribution in fasted and water deprived calves. Apparent volume of antipyrine distribution in the control and experimental groups did not differ significantly. The obtained results indicate that starvation and water deprivation considerably inhibits liver biotransformation process (estimated on the basis of antipyrine test) in calves during neonatal period.

[The influence of ACTH and hydrocortisone on drug kinetics in calves in the example of the antipyrine test]. / Wplyw ACTH i hydrokortyzonu na kinetyke leku u cielat na przykladzie testu antypirynowego.

The aim of the experiment carried out on 2 groups (to comprise 8 specimens) bull calves, of ncb. breed, at the age of 60 to 65 days and of an average body weight 90 +/- 5 kg, was to define the effect of intramuscular ACTH (0.2 j.m./kg b.w.) and hydrocortisone (0.2 mg/kg b.w.) injections on the hepatic biotransformation of antipyrine. No changes were noticed in the quantity of antipyrine distribution space Vd under the influence of the hormonal preparations applied. Shorter time of antipyrine halflife from the body T/2 was observed, yet the differences stated have not confirmed statistically. ACTH and hydrocortisone injections caused the increase in constant elimination value of antipyrine from the organism k as well as the increase in the quantity of hepatic antipyrine clearance ClA. The differences observed have not turned out to be statistically significant.