Rolf-Hasso Bödeker

Pityriarubins, Novel Highly Selective Inhibitors of Respiratory Burst from Cultures of the Yeast Malassezia furfur: Comparison with the Bisindolylmaleimide Arcyriarubin A

Pityriasis versicolor is the most common skin mycosis in humans worldwide. Yeasts of the genus Malassezia, particularly M. furfur, a saprophyte occurring widely on human skin, are generally regarded as the causative agents. M. furfur is able to convert tryptophan into a variety of indole alkaloids, some of them showing biological properties that correlate well with certain clinical features of pityriasis versicolor. This suggests a possible role for these compounds in the pathophysiology of the disease. We here report that the novel pityriarubins A, B and C, isolated from cultures of the yeast, inhibit respiratory burst in human neutrophils, activated by various agents, in a highly selective, unexpected manner. The release of 5‐lipoxygenase products after challenge of neutrophils with the calcium ionophore A23187 is also inhibited in a dose‐dependent manner. These activities reflect the close structural relationship of pityriarubins to bisindolylmaleimides, which have recently gained great interest as protein kinase inhibitors.

Release of β-endorphin immunoreactive material under perioperative conditions into blood or cerebrospinal fluid: Significance for postoperative pain?

The function of beta-endorphin immunoreactive material (IRM) released under perioperative conditions remains to be clarified. In 17 patients undergoing orthopedic surgery, we determined beta-endorphin IRM in venous blood plasma and in cerebrospinal fluid (CSF) before surgery (t(A)); after termination of surgery and general anesthesia, but still under spinal anesthesia (t(B)); on occurrence of postoperative pain (t(C)); and 1 day after the operation (t(D)). Pain severity was rated by the patients by using a visual analog scale. Patients felt postoperative pain (t(C)), but they felt no pain at times t(A), t(B), and t(D). beta-Endorphin IRM plasma levels before surgery (t(A)) or with postoperative pain (t(C)) proved to be significantly higher than levels determined just after surgery, but still under spinal anesthesia (t(B)), or those determined 1 day after the operation (t(D)); beta-endorphin IRM plasma levels at times t(A) and t(C) correlated positively with postoperative pain severity (t(C)). beta-Endorphin IRM CSF levels after surgery, but still under spinal anesthesia (t(B)), were significantly higher than levels determined at times t(A), t(C), or t(D). No correlation was found between beta-endorphin IRM CSF levels and pain severity. In conclusion, postoperative pain severity appears to be related to beta-endorphin IRM levels in plasma before surgery as well as with postoperative pain; the analgesic significance of this material remains to be elucidated.

Assessing Cortisol Production in Preterm Infants: Do Not Dispose of the Nappies

The aim of this study was to develop a practical approach allowing a reliable and noninvasive assessment of cortisol production rates in premature infants. To measure daily urinary excretion rates of glucocorticoids, we developed a procedure using a hydraulic compression method to collect urine from cellulose nappies (diapers). Glucocorticoid metabolites were profiled by quantitative gas chromatography–mass spectrometry. Recovery of steroids after the process of hydraulic extraction from the nappy was approximately 100%. Consecutively, urinary excretion rates of glucocorticoids could be determined in nine healthy preterm infants. The median urinary excretion rate of glucocorticoids increased significantly during the first 5 d of life and remained between 566 μg/kg/d at d 5 and 302 μg/kg/d at 4 wk of age. However, this increase of urinary excretion rates of glucocorticoids in the first days of life was no longer significant when corrected for creatinine excretion. When calculated per square meter body surface area, the median urinary excretion rates of glucocorticoids were 5.1, 4.2, 4.1, and 3.7 mg/m2/d on d 5, and at wk, 2, 3, and 4, respectively. Urinary excretion rates of glucocorticoids constitute approximately 70% of the natural cortisol production rate as determined by stable isotope dilution technique in older children. Additionally, low cortisol production was detected in two of five preterm infants with arterial hypotension requiring treatment with catecholamines. In conclusion, 24-h urine collection using disposable nappies in combination with gas chromatography–mass spectrometry steroid profiling proved to be a reliable, noninvasive, nonstressful procedure to assess cortisol production and metabolism in premature infants.

Sperm function and assisted reproduction technology

The evaluation of different functional sperm parameters has become a tool in andrological diagnosis. These assays determine the sperm’s capability to fertilize an oocyte. It also appears that sperm functions and semen parameters are interrelated and interdependent. Therefore, the question arose whether a given laboratory test or a battery of tests can predict the outcome inin vitro fertilization (IVF).One-hundred and sixty-one patients who underwent an IVF treatment were selected from a database of 4178 patients who had been examined for male infertility 3 months before or after IVF. Sperm concentration, motility, acrosin activity, acrosome reaction, sperm morphology, maternal age, number of transferred embryos, embryo score, fertilization rate and pregnancy rate were determined. In addition, logistic regression models to describe fertilization rate and pregnancy were developed. All the parameters in the models were dichotomized and intra- and interindividual variability of the parameters were assessed. Although the sperm parameters showed good correlations with IVF when correlated separately, the only essential parameter in the multivariate model was morphology. The enormous intra- and interindividual variability of the values was striking. In conclusion, our data indicate that the andrological status at the end of the respective treatment does not necessarily represent the status at the time of IVF. Despite a relatively low correlation coefficient in the logistic regression model, it appears that among the parameters tested, the most reliable parameter to predict fertilization is normal sperm morphology.

IABP before cardiac surgery: clinical benefit compared to intraoperative implantation

Background: The aim of this study was to determine whether preoperative compared to intraoperative intra-aortic balloon counterpulsation (IABP) is advantageous regarding 30-day and 2-year survival in high-risk patients (acute myocardial infarction, severely impaired left ventricular ejection fraction (LVEF), low output syndrome) undergoing coronary surgery. Methods: In the years 2004 to 2008, 156 consecutive patients undergoing coronary surgery with IABP support (119 preoperative, 37 intraoperative IABP) were observed. Applying Fisher’s exact test, as well as Wilcoxon and median tests, possible group differences were evaluated. After univariate analysis, models of logistic regression and Cox-regression were built. Results: Preoperative hemodynamic state and risk profile of the two patient groups were comparable: patients with preoperative IABP showed a similar level of urgency (21.9% vs. 18.9% emergencies), cardiogenic shock (8.4% vs. 10.8%), inotropes (8.4% vs. 8.1%), impaired LVEF (30.3% vs. 29.7%) and ventilation (5.9% vs. 5.4%) compared to patients with intraoperative IABP. Nevertheless, patients with intraoperative IABP demonstrated a significantly higher 30-day mortality rate (37.8% vs. 5.9%) and 2-year mortality rate (54.0% vs. 18.1%) compared to patients with preoperative IABP. Logistic regression revealed that patients with intraoperative IABP have a 16-times higher 30-day mortality rate after coronary surgery (OR: 16.386, 95% CI: 4.858-55.266) than patients with preoperative IABP. Two-year mortality (OR: 9.317, 95% CI: 3.430 to 25.311) and survival time were significantly better in patients with preoperative IABP therapy. Conclusion: Considering the significant benefit for patients with preoperative compared to intraoperative IABP and the absence of vascular problems after IABP insertion, the results of this study indicate a more liberal indication for IABP in high-risk patients before coronary bypass surgery.

Randomised, Double-Blind, Placebo-Controlled Study on the Efficacy and Tolerance of Trospium Chloride in Patients with Motor Urge Incontinence

ObjectiveTrospium chloride is an antimuscarinic drug with a quaternary ammonium structure for the treatment of detrusor instability and hyper-reflexia. It is generally considered to be well tolerated, but exhibits poor gastrointestinal absorption after oral administration. This study was conducted to assess the efficacy and safety of trospium chloride 15mg three times daily for 28 days in patients with motor urge incontinence.DesignMulticentre, double-blind, randomised, placebo-controlled study.Patients and Participants46 patients with motor urge incontinence.MethodsPatients were treated either with trospium chloride-coated tablets 15mg or placebo, administered three times daily for 28 days. The main parameter was the change in maximum bladder capacity as determined by cystometry before and after treatment. The occurrence and frequency of adverse events during treatment were assessed as secondary parameters.ResultsPretreatment values for maximum bladder capacity were comparable in the two groups (trospium chloride: 174.7ml, placebo: 206.2ml; p = 0.21). In patients assessed by per-protocol analysis, the mean maximum bladder capacity increased by 82.3ml in patients receiving trospium chloride therapy, but decreased slightly (−4. 1ml; p ≤ 0.01) in the placebo group. Dry mouth was reported as an adverse event 11 times in the trospium chloride group and 7 times in the placebo group (p = 0.41). Other adverse events were rarely observed in the two treatment groups (0 to 3 times).ConclusionIn this controlled clinical study in patients with urodynamically verified motor urge incontinence, treatment with trospium chloride 15mg three times daily for 28 days led to a significant increase in maximum bladder capacity compared with placebo treatment. There were no differences in the frequency of adverse events in the treatment group compared with the placebo group.

Release of melanotroph- and corticotroph-type proopiomelanocortin derivatives into blood after administration of corticotropin-releasing hormone in patients with septic shock without adrenocortical insufficiency.

The aim of the study was to assess the adequacy of pituitary function by determining the plasma concentrations of corticotroph-type (corticotropin, &bgr;-endorphin immunoreactive material [&bgr;-END IRM], authentic &bgr;-END, and &bgr;-lipotropin IRM) as well as melanotroph-type (&agr;-melanocyte-stimulating hormone [&agr;-MSH] and N-acetyl-&bgr;-END [Nac-&bgr;-END] IRM) proopiomelanocortin (POMC) derivatives in patients under septic shock upon administration of corticotropin-releasing hormone (CRH). The objectives were to assess whether an insufficient release of corticotroph- or melanotroph-type POMC derivatives from the pituitary into the cardiovascular compartment correlates with the 28-day mortality rate. Seventeen patients with septic shock but without adrenocortical insufficiency and 16 healthy volunteers were enrolled in the study, and CRH stimulation tests were performed with an i.v. bolus injection of 100 &mgr;g human CRH. After treatment with CRH, plasma concentrations of corticotroph-type POMC derivatives increased in survivors and nonsurvivors, melanotroph-type POMC derivatives such as &agr;-MSH or Nac-&bgr;-END IRM increased only in survivors in contrast to nonsurvivors. The release of &agr;-MSH and Nac-&bgr;-END IRM was suppressed by dexamethasone in survivors but not in nonsurvivors. In patients with septic shock, the response of the pituitary to CRH stimulation in terms of &agr;-MSH or Nac-&bgr;-END IRM release was impaired in nonsurvivors compared with survivors or controls. Reduced responses of &agr;-MSH or Nac-&bgr;-END IRM to CRH and the invalid suppression by dexamethasone reflect a state of dysfunction of the melanotroph-type POMC system in nonsurvivors. Considering anticytokine and anti-inflammatory effects of &agr;-MSH, this dysfunction may increase the risk of death in patients with septic shock.

Comparative Study of 2% Sertaconazole Solution and Cream Formulations in Patients with Tinea Corporis, Tinea Pedis Interdigitalis, or a Corresponding Candidosis

AbstractBackground: Based on the results of numerous preclinical and clinical studies, sertaconazole can be considered a safe and effective drug for the treatment of fungal skin infections. Objective: The objective of the study was to compare the efficacy of a solution containing 2% sertaconazole with the well established 2% sertaconazole cream formulation in patients with tinea corporis, tinea pedis interdigitalis, or a corresponding candidosis. Methods: This was a prospective, open-label, randomized, controlled, parallel-group, multicenter, noninferiority therapy study. Patients received either sertaconazole solution or cream twice daily for 28 days. The full analysis set comprised 160 patients in the solution group and 153 patients in the cream group. The primary efficacy parameter was a combination of culture test result and total clinical score. Efficacy was defined by eradication of the pathogen and reduction of the total clinical score between pretreatment and the final visit. Results: Efficacy was documented in 90.6% of patients using the solution and 88.9% of those using the cream (full analysis set). No adverse events occurred. Conclusion: Solution and cream formulations of 2% sertaconazole applied for 28 days were associated with comparable efficacy and safety in the treatment of fungal skin infections.

Persistent high activity of the fetal adrenal cortex in preterm infants: is there a clinical significance?

BACKGROUND In preterm infants, the activity of the fetal adrenal cortex continues until term. Dehydroepiandrosterone sulphate can block the synthesis of surfactant in vitro. The incidence of pulmonary disease is higher in male than in female preterm infants. OBJECTIVE To investigate the relationship between urinary excretion of fetal zone steroids (3beta-OH-5-ene-steroids) and the severity of lung disease in preterm infants with respect to gender. PATIENTS AND METHODS 3beta-OH-5-ene-steroids were profiled by gas chromatography-mass spectrometry in 24-h urinary samples in 61 preterm infants of less than 30 weeks gestational age. RESULTS The incidence of respiratory distress syndrome treated with surfactant in females (n = 30) was 47% and in males (n = 31) 71%, p = 0.07. Medians of total excretion rates of fetal zone steroids (microg/kg/d) in female (male) preterm infants were at day 1: 1,317 (895); day 2: 3,154 (7,723), p = 0.03; day 3: 5,502 (9,494), p = 0.08; day 5: 7,140 (10,407); week 2: 8,731 (9,720); week 3: 8,571 (10,079); week 4: 7,620 (7,825). Regression analysis did not reveal a significant influence of maximum excretion rates of fetal zone steroids or gender on the incidence of respiratory distress syndrome treated with surfactant. CONCLUSIONS Excretion rates of fetal zone steroids were 4-fold higher than previously reported indicating a persistent high activity of the fetal adrenal zone in preterm infants. Excretion rates of fetal zone steroids were significantly higher in male preterm infants compared to females at day 2 (trend at day 3) but did not have a significant influence on the incidence of respiratory distress syndrome.

Production of Interleukin-13 is Influenced by the Interleukin-4 −34TT and −590TT Genotype in Patients with Aggressive Periodontitis

Aggressive periodontitis (AgP) is a specific form of periodontal disease, with rapid destruction of the tissues supporting the teeth in otherwise young healthy individuals. We recently showed a higher frequency of the interleukin‐4 (IL‐4) −34TT and −590TT genotype in AgP patients compared to controls (P < 0.05). Herein, we demonstrated that this specific IL‐4 genotype exerts its function by increasing expression of IL‐4 and STAT6, and producing higher concentrations of IL‐4 in activated CD4+ cells of patients with AgP. In the present study, we investigated the effects of the IL‐4‐specific genotype on IL‐13, IL‐2 and IFN‐γ expression and production in activated CD4+ cells of patients with AgP and healthy controls. Results revealed higher IFN‐γ and IL‐2 expression and significantly increased IL‐13 production in the cells of the patients who were homozygous for the −34T and −590T alleles in comparison with the patients who were homozygous for the −34C and −590C alleles (P < 0.05). Results of controls with the −34C and −590C alleles were similar to those of AgP with the same genotype. To our knowledge, the present study is the first to show an effect of the −34TT and −590TT genotype on IL‐13 production. There is an increased production of IL‐13 by the T cells of aggressive periodontitis patients with the IL‐4 genotype.