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*
Departments of Pathology, University of Heidelberg, Heidelberg,
Germany.
Departments of Pathology, University of Erlangen, Erlangen,
Germany.
Departments of Pathology, University of Darmstadt, Darmstadt,
Germany.
§
Department of Internal Medicine, Heidelberg, Germany.
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Department of Internal Medicine, Knoll AG, Ludwigshafen,
Germany.
Correspondence to Prof. Dr. Kerstin Amann, Department of Pathology, University of Erlangen, Krankenhausstrasse 8-10, D-91054 Erlangen, Germany. Phone: +49-09131-8522291; Fax: +49-09131-8522291; E-mail: kerstin.amann{at}patho.imed.uni-erlangen.de
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In left ventricular hypertrophy (LVH), cardiomyocytes tend to outgrow their capillary supply (13,14,15,16), resulting in capillary-myocyte mismatch. This has been particularly well documented in chronic renal failure, both in animals (17,18) and in humans (19). In the renal failure model, the genesis of LVH is known to be in part independent of BP elevation (20). However, it has not been determined whether ET-receptor antagonists affect cardiac capillarization in relation to left ventricular mass (i.e., the capillary-myocyte ratio, which is an important determinant of cardiomyocyte oxygen supply).
Because there is evidence that the local ET system is activated in LVH (1,2,3,4,5), we reasoned that uremic LVH provided a convenient model to examine the hypothesis that a selective ETA-receptor antagonist prevents capillary-myocyte mismatch in the hearts of rats with chronic renal failure. To this end, we compared the effect of the specific ETA-receptor blocker LU 135252 (and of the angiotensin-converting enzyme [ACE] inhibitor trandolapril as a control) on cardiac capillary length density.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Experimental Design
Nine-wk-old male Sprague-Dawley rats (SD, 220 g; Janvier, Le Genest St.
Isle, France) were housed in single cages at constant temperature (22°C)
and humidity (50%) and were exposed to a 12-h dark/light cycle. The animals
had free access to a low nitrosamine diet (1% NaCl, Ssniff M/R powdered feed,
Sniff Spezialitäten GmbH, Soest, Germany) and
water. After 3 d of adaptation, the animals were randomly allocated to
subtotal nephrectomy (SNX) or sham operation (sham). First, the right kidney
was removed under ketamine/diazepam anesthesia (100 mg/kg or 2.5 µg/kg,
respectively), then the left kidney was subtotally resected by removing two
thirds (by weight) of the contralateral kidney, mainly by resection of
cortical tissue. The control animals' sham operation consisted of
decapsulating the kidney, taking special care that the adrenals were not
damaged. Twenty-four h after the operation, the animals were randomly
allocated to the different treatment groups. Two separate experiments were
performed.
Experiment I: Immunohistochemical and Molecular Biologic Study. The animals were randomly allocated to the two experimental groups (10 animals per group): (1) sham-operated controls and (2) untreated SNX. Body weight, food and water intake, and systolic BP were determined before the operation and in two weekly intervals during the study. BP measurements were performed in conscious animals using tail plethysmography. Before the experiment was terminated, animals were placed in individual metabolic cages and 24-h urine collections were performed for determination of urine volume, proteinuria, creatinine clearance, and immunoreactive ET-1 concentrations.
Tissue Preparation. At the end of the experiment, the abdominal aorta was catheterized under ketamine/diazepam anesthesia (100 mg/kg or 2.5 µg/kg, respectively) and blood samples for determination of serum parameters and plasma levels of the drugs used were taken. Then retrograde vascular perfusion was performed with ice cold NaCl at a controlled pressure as described in detail elsewhere (21). The hearts were divided into three horizontal slices and snapfrozen in liquid nitrogen for immunohistochemistry, PCR measurements, and in situ hybridization. Hematocrit, serum creatinine, urinary creatinine, and plasma renin were determined (22).
Immunohistochemistry. Frozen sections (5 µm) were fixed in acetone at 4°C. Immunohistologic staining was performed using an unconjugated ET-1 polyclonal antibody (Bio Trend GmbH, Köln, Germany). To reduce nonspecific background staining, the sections were incubated for 20 min at 37°C in tissue unmasking factor. The samples were then rinsed in Tris-buffered saline (TBS, pH 7.6) and submitted to the avidin-biotin system. In brief, the slides were incubated with the primary antibody at a dilution of 1:25 for 60 min at room temperature. The secondary antibody (goat anti-rabbit immunoglobulin biotin; Biogenex, San Ramon, CA) was applied for 30 min. Then the sections were incubated for 30 min at room temperature with super-sensitive lable alkaline-phosphatase-conjugated streptavidin (Biogenex). Each incubation step was followed by a thorough double rinsing in TBS. Fast red substrate (Dako GmbH, Hamburg, Germany) served as a chromogen. Subsequently, sections were counterstained with hematoxylin and examined by light microscopy. The antibody used had been tested for specificity in the rat. Negative controls were performed by omitting the primary antibody. Staining of control and SNX sections was performed in the same run to reduce run-to-run variations in staining intensity.
Oligonucleotides. We amplified ETA receptor (ET-AR) and ETB receptor (ET-BR) using the oligonucleotides given by Liefeldt et al. (23). For ET-AR, we used as sense primer 5'-TGGGAATGGTGGGGAATG CAACTCT-3' and as antisense primer 5'-GAGCGCAGAGGTTGAGGACGGTGA-3', resulting in a PCR product of 258 bp length. For ET-BR, the sense primer was 5'-TTGGAGCTGAGATGT GTAAGC-3' and the antisense primer was 5'-CAGTGAAGCCATGTTGATACC-3', resulting in an amplification product of 625 bp. For ET-1, the sense primer was 5'-TGGCTTTCCAAGGAGC TCC-3' and the antisense primer was 5'-GCTTGGCAGAAATTCCAGC-3', resulting in a PCR fragment of 339 bp.
RT and PCR. RT was performed according Wagner et al. (24). Total RNA (1 µg) was dissolved in 40 µl of a reaction mixture containing 1 mM dATP, dCTP, dTTP, and dGTP; 10 U RNAsin (Life Technologies BLR, Grand Island, NY); 100 pmol random hexamers (Boehringer Mannheim GmbH, Mannheim, Germany); PCR buffer (final concentrations: 50 mM KCl, 20 mM Tris-HCl [pH 8.4], 2.5 mM MgCl2, and 10 µg/ml nuclease-free bovine serum albumin); and 200 U Superscript reverse transcriptase (Life Technologies BLR). After incubation at 42°C for 45 min, the enzyme was denatured for 5 min at 95°C. For each animal, RT was repeated four times. The resulting cDNA was pooled and realiquoted for PCR, each containing 0.25 µg of reverse-transcribed RNA. The cDNA was amplified in 100 µl of a solution containing PCR buffer (same final concentrations as above), 8 pmol/L each primer, and 2.5 U Taq polymerase (Life Technologies BLR). The reaction was run on a Perkin Elmer/Cetus thermal cycler (Norwalk, CT) under the following conditions: initial denaturation at 94°C for 3 min and 94°C for 1 min, annealing at 55°C for 1 min, and extension at 72°C for 1 min for 28 cycles. After PCR, 10 µl of loading buffer (50% glycerol, 10 mmol/L Tris-HCL [pH 8.0], and 0.25% bromphenol blue and xylene cyanol) was added to each sample. Gel electrophoresis was used to verify amplification products for the predicted size.
Competitive PCR. Quantification of ET-1, ET-AR, and ET-BR mRNA was carried out using deletion mutants of the ET-1, ET-AR, and ET-BR cDNA as internal standard. The cloned deletion mutants were a gift from Dr. L. Liefeldt (23). The amplification of the mutants resulted in PCR products of 295 bp for ET-1, 227 bp for ET-AR, and 557 bp for ET-BR. The mutant cDNAs were added to the PCR mixture after RT to compete with the endogenous ET-AR and ET-BR, respectively. For quantification of ET-AR, 0.5 pg of the plasmid was added to the PCR mixture per sample, for ET-BR 2 pg, and for ET-1 2.5 pg. For each animal, four competitive PCR were run for ET-AR and ET-BR, respectively.
Analysis of PCR fragments. Relative amounts of ET-1, ET-AR, and ET-BR mRNA in each sample were quantified according to a modification of the method described by Wagner et al. (24). Twenty microliters of the amplification products were electrophoretically separated on 3% agarose gels (Life Technologies BLR). Images of the ethidium bromide—stained bands for ET-1, ET-AR, and ET-BR and their respective mutant cDNAs were digitized with a gel documentation system (Intas Co., Göttingen, Germany), and the intensities of the bands were densitometrically measured with the National Institutes of Health IMAGE 1.44 program. For each reaction, the relation of the intensity of the endogenous cDNA band to its respective mutant cDNA band was calculated. For each animal, the mean of four reactions was calculated.
In Situ Hybridization. Tissue preparation: For in situ hybridization, cryostat sections (10 µm) were thaw-mounted on silanized slides and fixed for 5 min at 4°C in 3% paraformaldehyde/phosphate buffered saline (pH 7.0). Deproteination was performed in 0.2 M HCl for 15 min. To reduce nonspecific background staining, the sections were acetylated for 20 min in 0.25% acetic anhydride (vol/vol) in 0.1 M triethanolamine (pH 8.0). Subsequently, the sections were dehydrated in graded alcohols, air-dried, and stored at -20°C until use.
Probe preparation and labeling: A 340-bp cDNA fragment of the ET-1 cDNA was obtained from a PCR product using rat ET-1 specific primers after RT of rat kidney total RNA. The segment encoding positions 222 to 561 of the rat ET-1 gene (25) was inserted into the pGEM-T vector system (Promega Biotech, Madison, WI). For preparation of the antisense RNA probe, the plasmid was linearized with SpeI and transcribed using T7 bacteriophage RNA polymerase. Linearization of the plasmid with NcoI and transcription with SP6 RNA polymerase generated the sense RNA probe. Digoxigenin-labeled RNA probes were synthesized using a DIG RNA labeling mix (Boehringer Mannheim GmbH). Briefly, labeled transcripts were generated in 20 µl of transcription buffer (40 mM Tris-HCl [pH 8.0], 6 mM MgCl2, 10 mM dithiothreitol, 2 mM spermidine) containing 1 µg of linearized plasmid, NTP-labeling mix (1 mM each of ATP, CTP, and GTP; 0.65 mM UTP; 0.35 mM DIG-UTP), 20 U of ribonuclease inhibitor, and 40 U of T7 and SP6 RNA polymerase, respectively. Digestion of the DNA template with RNase-free DNAse halted the reaction. Subsequently, the labeled transcripts were ethanol precipitated and resuspended in diethylpyrocarbonate-treated water. Integrity and size of the probes were checked by running aliquots on a denaturing formaldehyde gel beside RNA standards and blotting them onto a nylon membrane. The transcripts dilution series of the labeling reactions and of a labeled control RNA (Boehringer Mannheim) were spotted on nylon membranes that were processed in a colorimetric detection procedure.
In situ hybridization: The sections were hybridized with 4 ng of labeled probe in buffer containing 50% deionized formamide, 20 mM Tris-Hcl (pH 7.6), 0.33 M NaCl, 0.1 M dithiothreitol, 1 mM EDTA, 10% dextran sulfate, 0.5 mg/ml tRNA, 0.1 mg/ml poly-A-RNA, 1 x Denhardt's solution (0.02% Ficoll 400, 0.02% bovine serum albumin, 0.02% polyvinylpyrrolidone) in a moist chamber. Hybridization of the probe with native mRNA was allowed for 18 h at 50°C. Posthybridization steps included removal of unbound probe in 1 x standard saline citrate (SSC) at 50°C, two subsequent washes in 2 x SSC/50% formamide for 1 h at 50°C, RNase A treatment (20 µg/ml) in 0.5 M NaCl, 10 mM Tris-HCl (pH 8.0), 1 mM EDTA, for 30 min at 37°C, and washes for 10 min in 1 x SSC at 37°C and room temperature, respectively.
Immunohistologic detection of hybridized probes: After posthybridization washes, the sections were equilibrated in buffer I (0.1 M Tris-HCl, 0.15 M NaCl [pH 7.5]). Nonspecific background staining was blocked by incubation for 1 h with 0.5% blocking reagent/buffer I (Boehringer Mannheim). The hybridization products were visualized by enzyme-linked immunoassay using alkaline phosphatase-conjugated sheep antidigoxigenin-Fab fragments (Boehringer Mannheim, 750 U/ml) at a dilution of 1:300 in blocking solution. After incubation overnight at 4°C, unbound conjugate was removed by two washes in buffer I followed by equilibration of the sections in buffer II (0.1 M Tris-HCl, 0.1 M NaCl, 50 mM MgCl2 [pH 9.5]). Nitro-blue tetrazolium and 5-bromo-4-chloro-3-indolyl phosphate served as chromogens. Negative controls included hybridization with the sense RNA probe, incubation without probe for detection of unspecific binding of the primary antibody, and omission of both probe and primary antibody.
Experiment 2: Stereologic Study. The animals received either the specific orally active ETA-receptor antagonist LU 135252 (26) or the ACE inhibitor (ACE-i) trandolapril (Knoll AG, Ludwigshafe/Rhein, Germany). The drugs were administered in the diet. Daily food consumption was measured and the doses of drugs were determined by actual amount of food consumed. In addition, plasma levels of both drugs were measured by high-power liquid chromatography in four animals that underwent sham operation and four animals that underwent SNX (27).
The protocol of this arm of the study comprised the following groups (10 animals per group): (1) sham-operated controls (sham), (2) sham + ETA-receptor antagonist (LU 135252 20 mg/kg per d orally, sham + ET-RA), (3) untreated SNX (SNX), (4) SNX + ETA-receptor antagonist (LU 135252 20 mg/kg per d orally, SNX + ET-RA), and (5) SNX + ACE-i (trandolapril 0.3 mg/kg per d orally, SNX + ACE-i).
At the end of the 15-wk observation period, animals were placed in metabolic cages. Collections of 24-h urine were performed as in experiment 1.
Telemetric BP Measurements. Mean arterial pressure (MAP), systolic arterial pressure (SAP), diastolic arterial pressure (DAP), heart rate (HR, derived from the peak systolic BP signal, min-1), and motor activity of animals (U/10 min) were measured using a telemetry system (Data Sciences Inc., St. Paul, MN) in four animals per group according to Brockway et al. (28). Transmitters (TL 10-M2-C50-PE, TL11-M2-C50-PXT) were implanted in the abdominal aorta, and two electrodes were implanted subcutaneously (28). Receivers (RLA 1000, RA 1000) were placed underneath the cage. The maximum transmitter range was 40 cm.
Tissue Preparation. At the end of the experiment, retrograde perfusion fixation was performed as described above. Instead of ice cold NaCl, 3% glutaraldehyde was used (29). After the perfusion, the heart of each animal was taken out for determination of weight and volume, and tissue sampling and section staining were performed according to the orientator method (29,30). Uniformly random sampling was achieved by preparing a set of equidistant slices of the left ventricle and the interventricular septum with a random start. Two slices were selected by area weighted sampling and processed using the orientator method. Semithin sections (1 µm) were prepared and stained with methylene blue and basic fuchsin.
Quantitative Stereology. All investigations were performed in a blinded manner (i.e., the observer was unaware of the protocol). Length density (Lv) of capillaries (i.e., the length of capillaries per unit tissue volume) was measured on eight differentially oriented semithin sections per animal as described in detail elsewhere (29,30). Total capillary length per left ventricle was derived from Lv times left ventricular volume (LVvolume) (i.e., left ventricular weight [LVW] divided by specific weight). Intercapillary distance (i.e., the distance between the centers of two adjacent intramyocardial capillaries) was calculated according to a modification of the formula of Henquell and Honig (29,31). Morphologic techniques such as counting of capillary transects per area myocardial tissue and point counting are highly reproducible methods for tissue analysis. Intraobserver error of means of stereologic parameters (i.e., capillary Lv) is 1%, whereas interobserver error is approximately 3%.
Statistics
Data are given as mean ± SD. After testing for normality, ANOVA or
Kruskal-Wallis test, respectively, was chosen for analysis of variance. The
P value in Tables
1,2,3
refers to group heterogeneity by ANOVA. Whether the differences between groups
were significant was assessed using Duncan's multiple range test. The results
were considered significant when P was less than 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Quantitative PCR. ET-1 mRNA was significantly increased in the heart of untreated SNX compared with sham-operated rats. Cardiac ETA- and ETB-receptor mRNA was not significantly different between the groups (see Figure 1).
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Immunohistochemistry and In Situ Hybridization. ET-1 protein expression in interstitial tissue and in endothelial cells was increased in the heart of SNX compared with sham-operated rats. Representative examples are shown in Figure 2.
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In addition, cardiac ET-mRNA expression as assessed by nonradioactive in situ hybridization was markedly increased after SNX compared with sham-operated animals. ET-mRNA was predominantly found in the perivascular tissue and in the interstitium. Representative examples are shown in Figure 3.
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Experiment 2: Stereologic Study
Animal Data. After 15 wk, body weight was significantly lower in
untreated SNX than in control animals despite similar food intake. Heart
specimens had been perfused with fixative, and the resulting LVW/body weight
ratio was significantly higher in untreated SNX than in control animals. The
increase in relative LVW after SNX was completely prevented only by
trandolapril treatment. Hematocrit was significantly lower in all SNX groups.
S-creatinine, S-urea, and daily urinary protein excretion were significantly
higher in all SNX groups with values being lowest in the trandolapril-treated
SNX animals. At 10.00 h, morning plasma levels of the ACE-i trandolapril (4.49
± 3.65 ng/ml in controls versus 4.57 ± 1.47 ng/ml in
SNX) and the ETA-receptor antagonist LU 135252 (28.1 ± 12.5
µmol/L in controls versus 33.2 ± 17.0 µmol/L in SNX)
were not significantly different between control and SNX animals.
Daytime and nighttime MAP and SAP at week 15 were higher in untreated SNX compared with treated SNX animals and compared with treated and untreated controls, respectively (Table 5). The HR was higher in all SNX groups than in treated and untreated controls. Body activity was comparable in all groups.
Quantitative Morphology of the Myocardium. Capillary Lv was significantly lower and mean intercapillary distance was significantly higher in untreated SNX animals (3307 ± 535 mm/mm3 and 18.8 ± 1.4 µm) than in controls (3995 ± 471 mm/mm3 and 17.5 ± 1.7 µm, respectively). Reduced capillary Lv in untreated and ACE-i treated SNX animals (3503 ± 533 mm/mm3) was not seen in animals that were treated with the ETA-receptor antagonist (3800 ± 303 mm/mm3). Because this finding is crucial to the argument of this article, the experiment was repeated and the effect of the ETA-receptor antagonist on relative LVW and capillary Lv was fully confirmed. Values in this repeat experiment (group size, eight animals) were as follows: LVW/body weight, 2.23 ± 0.12 mg/g and Lv, 2680 ± 518 mm/mm3 in SNX versus 2.10 ± 0.04 mg/g (NS) and 3165 ± 289 mm/mm3 (P < 0.05) in SNX + ETA-receptor antagonist. In controls, treatment with either the ETA-receptor antagonist LU 135252 or the ACE-i trandolapril (data not shown) did not change capillary Lv.
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As shown in Table 3, capillary Lv decreased in SNX animals and relative LVW/body weight increased so that the ratio decreased. After ETA-receptor antagonist treatment, the changes were in the same direction but the resulting ratio was higher and closer to that of sham-operated controls.
Volume density of the interstitial tissue (Table 2) was significantly higher in untreated SNX animals (3.11 ± 0.63%) than in controls (2.08 ± 0.57% and 1.62 ± 0.50%, respectively) or in treated SNX animals (1.95 ± 0.44 in SNX + ET-receptor blocker and 1.70 ± 0.81 in SNX + ACE-i).
Figure 5 shows representative examples of capillary supply and interstitial expansion in controls, untreated animals, and ETA-receptor antagonist—treated SNX animals.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The main information of this study is that the ratio of capillary length to LVW was abnormal in SNX animals and was less abnormal after treatment with the ET-receptor antagonist. This finding indicates that myocyte growth outstrips capillary growth and that this specific effect—which seems to be unique to uremia (18)—is favorably influenced by the ET-receptor antagonist.
Some methodical points deserve comment. The ETA-receptor antagonist and the ACE-i were given from the beginning of the experiment. The present experiment is therefore a prevention study, and the results cannot necessarily be extrapolated to indicate that ETA-receptor antagonists are similarly effective in causing regression. The effects of the ETA receptor antagonist (LU 135252) on the morphometric findings were not dose dependent; a higher dose of LU (50 mg/kg per d) did not yield additional benefit (data not given). A relatively small amount of renal tissue was removed so that the decrease in hemoglobin and the increase in S-urea were modest. Consequently, potential confounding effects of anemia or advanced uremia are unlikely. We investigated only the model of LVH in renal failure, but reports in the literature suggest that ET-1 plays a role in other models of LVH as well (e.g., in aortic banding and renovascular hypertension [33,34]). Consequently, the findings in the present model of LVH may have more general importance. We excluded pharmacokinetic artifacts as a result of impaired renal excretion by measuring plasma concentrations of LU 135252 and trandolapril. The concentrations were not significantly different between control and SNX animals.
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The potent vasoconstrictor ET-1 (35) causes hypertrophy and proliferation of cultured ventricular myocytes (1). Synthesis of all three ET isoforms has been shown in cardiomyocytes (36) and in endothelial cells of the heart (37). Using immunohistochemistry and in situ hybridization, we confirmed that in our model of LVH, ET-1 is expressed in interstitial and endothelial cells of the heart. Ito et al. (3) demonstrated that ET-1 mediates myocardial hypertrophy in the rat. In myocardial hypertrophy, ET-1 was shown to act via induction of immediate-early gene Egr-1 and c-fos in adult rat cardiomyocytes (38). Sakai and co-workers (4) reported a selective increase in myocardial ET-1 mRNA in LVH after abdominal aortic banding and aortic valve regurgitation, respectively. In addition, Brown et al. (39) found increased ET-1 and ETA receptor mRNA in the rat aortovenacaval fistula model of LVH. Cardiomyocyte hypertrophy in the norepinephrine-induced model of LVH is also mediated by ET-1, and this can be prevented by the ETA/ETB antagonist bosentan (40). Right ventricular hypertrophy as a result of pulmonary hypertension and the corresponding switch in myosin heavy chain gene expression was prevented with a selective ETA-receptor antagonist (41). In pressure overload, cardiac hypertrophy of rats' preproET-1 mRNA expression was documented in cardiomyocytes, and this was accompanied by increased ET-1 binding sites (33). In contrast, Fareh et al. (42) found no change in plasma and cardiac ET-1 concentrations and ET-1 receptor regulation in cardiomyocytes and fibroblasts in the volume overload model of LVH in the rat. According to Karam et al. (43), treatment of spontaneously hypertensive rats with the mixed ET-receptor antagonist bosentan resulted in a slight decrease of LVH and fibrosis.
Concerning the molecular mechanism(s) involved in the genesis of capillary-myocyte mismatch, it is attractive also to consider a potential role of vascular endothelial growth factor (VEGF), which may interact with ET-1. VEGF mediates proliferation of vascular endothelial cells in many situations of increased angiogenesis (e.g., hypoxia, platelet-derived growth factor excess, tumor growth). Indeed, immunohistochemical studies showed increased expression of VEGF in the heart of SNX animals (21). ET-1 and ET-3 stimulate VEGF gene and protein expression in cultured human vascular smooth muscle cells (44). The effect is similar in magnitude to that of hypoxia and is mediated via the ETA- and ETB-receptor. Whether the stimulatory effect of ET-1 is abrogated in SNX animals or whether increased VEGF expression is the consequence of the increase in ET-1 requires further studies.
An issue that remains unresolved is whether the tendency (NS) for increased capillary density with ACE-i is caused by reduced ET-1 secretion (45). The same applies to the expansion of the cardiac interstitium, which is significantly reduced both by the ET- receptor antagonist and by the ACE-i. These issues are complex because there are strong interactions between the renin-angiotensin and ET systems.
Although some caution is necessary when extrapolating from animal to human data, it is nevertheless of interest that increased ET-1 levels are found in patients with renal failure (46). Such increase is correlated to thickening of artery walls and LVH (47). These findings are consistent with (but not proof of) a pathogenetic role of ET-1 in cardiac and vascular remodeling of renal failure.
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Acknowledgments |
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Dr. Vitali Balajew received a training grant from the Department of Pathology, University of Heidelberg.
The skillful technical assistance of Zlata Antoni, Harald Derks, Gudrun Gorsberg, Diana Lutz, Petra Numrich, Peter Rieger, Dr. Johannes Törnig, and Monika Weckbach is gratefully acknowledged.
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