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1.  Individual risk assessment of adverse pregnancy outcome by multivariate regression analysis may serve as basis for drug intervention studies: retrospective analysis of 426 high-risk patients including ethical aspects 
To identify patients at very high risk for adverse pregnancy outcome (APO) at the 20- to 23-week scan and to assess the effectiveness of Aspirin (ASS) and low molecular weight heparin (LMWH) starting after this examination.
Patients and methods
By applying an algorithm based on multivariate logistic regression analysis using the parameters maternal age, parity, body mass index (BMI), mean pulsatility index of both uterine arteries (meanPI), presence of uni- or bilateral notch, and depth of notch (mean notch index (meanNI), we retrospectively calculated the individual risk for APO of 21,302 singleton pregnancies. We isolated a subgroup of 426 patients with the highest calculated probability for APO (cpAPO > 27.8 %). 147 had been treated with ASS; 73 with LMWH, 15 patients with a combination of ASS and LMWH, and 191 patients had not received anticoagulants.
Administration of ASS starting after 20 gestational weeks in comparison to non-treated patients significantly reduced the frequency of intrauterine/neonatal death (IUD/NND), preeclampsia <33 weeks (PE < 33), and preterm delivery <33 weeks (PD < 33), while the frequency of IUGR showed a tendency to be elevated (P = 0.061). The subgroup of high-risk patients treated with LMWH was characterised by a higher a priori risk for APO and showed no significant reduction of any form of APO but an increased frequency of PE.
Individual assessment of risk for APO by applying a simple algorithm based on biometrical/biographical as well as sonographic parameters may serve as basis for drug intervention studies. The administration of ASS in high-risk patients starting after 20 gestational weeks reduced the frequency of most of the severe forms of adverse pregnancy outcome in high-risk patients. A complication-reducing effect of LMWH starting after 20 weeks of gestation in patients could not be proven. From an ethical point of view, it may not be justified any more to preclude high-risk patients from administration of ASS or to perform studies of ASS against placebo.
PMCID: PMC3682099  PMID: 23389246
Low molecular weight heparin; ASS; Adverse pregnancy outcome; Preeclampsia
2.  Evaluation of vardenafil for the treatment of subjective tinnitus: a controlled pilot study 
Vardenafil (Levitra®) represents a potent and highly selective phosphodiesterase type 5 (PDE5) inhibitor, which is established for treatment of various diseases. There are several unpublished reports from patients stating that vardenafil has a considerable therapeutic effect on their concomitant tinnitus. This pilot study was conducted to specifically assess the effect of vardenafil in patients with chronic tinnitus.
This trial was based on a prospective, randomized, double-blind, placebo-controlled, parallel group design. Fourty-two consecutive subjects with mon- or binaural chronic tinnitus received 10 mg vardenafil (N = 21) or matching placebo tablets (N = 21) administered orally twice a day over a period of 12 weeks. Clinical examination and data acquisition took place at each visit: at baseline, after 4 weeks, after 12 weeks (end of treatment with study medication), and at non-medicated follow-up after 16 weeks. Assessment of clinical effectiveness was based on a standardized tinnitus questionnaire (TQ), the Short Form 36 health survey (SF-36), audiometric measurements (mode, pitch and loudness of tinnitus; auditory thresholds) and biomarkers of oxidative stress in patients' blood (malondialdehyde, protein carbonyl, homocysteine and total antioxidative status). Therapeutic efficacy was evaluated by comparison of subjective and objective parameters with baseline data between both treatment groups (ANCOVA).
Vardenafil had no superior efficacy over placebo in the treatment of chronic tinnitus during this study. The primary efficacy criterion 'TQ total score' failed to demonstrate significant improvement compared to placebo. Subjective reports of TQ subscales and general quality of life areas (SF-36), objective audiometric examinations as well as investigated biomarkers for oxidative stress did not reveal any significant treatment effects. The safety profile was favorable and consistent with that in other vardenafil studies.
Although hypoxia and ischemia play a special role in the pathogenesis of tinnitus, the PDE5-inhibitor-induced increase of nitric oxide-mediated vasodilatation exerted no specific influence on tinnitus symptomatology. Considering the unclear risk of rarely associated hearing impairment, systemic application of vardenafil or other PDE5 inhibitors prove to be not appropriate for therapy of chronic tinnitus.
PMCID: PMC2649886  PMID: 19222841
3.  Hematopoietic progenitor cells and interleukin-stimulated endothelium: expansion and differentiation of myeloid precursors 
BMC Immunology  2008;9:56.
Cytokine-stimulated endothelial cells (EC) propagate hematopoietic progenitor cell (HPC) expansion. However, the effects on the functional capacities of cultured progenitors have not been evaluated. HPC were assessed by flow cytometry, colony and cobblestone assays and long-term cultures (LTC) after culturing in the supernatant of EC stimulated by IL-1β, IL-3 or IL-6.
EC incubation with IL-6 did not improve cell expansion in comparison to non-stimulated EC supernatant, while the HPCs' phenotype and functional capacities were retained. In contrast, IL-1β and IL-3 stimulation resulted in a 10- and 100-fold increase in cell numbers with more than 90% of these cells being CD33(+). Plating efficiencies and LTC initiating cells were greatest in IL-6 supernatants, whereas the highest numbers of burst-forming units were observed using IL-3. IL-1β supernatants diminished the number of 5-week cobblestone-areas, whereas the number of 2-week cobblestone areas remained equal to freshly isolated HPC. Fewer 2-week cobblestones and greater amounts of 5-week cobblestones were observed with IL-6 and IL-3. Expanded progenitors from all interleukin conditions were further matured into functional granulocytes.
IL-1β and IL-3 stimulated endothelium induces proliferation and differentiation of myeloid precursors, while IL-6 treatment induced a benefit of HPC survival.
PMCID: PMC2570655  PMID: 18826654
4.  Detailed analysis of the variability of peptidylarginine deiminase type 4 in German patients with rheumatoid arthritis: a case–control study 
Peptidylarginine deiminase type 4 (PADI4) genotypes were shown to influence susceptibility to rheumatoid arthritis (RA) in the Japanese population. Such an association could not previously be confirmed in different European populations. In the present study, we analysed exons 2–4 of PADI4 in 102 German RA patients and 102 healthy individuals to study the influence of PADI4 variability on RA susceptibility by means of haplotype-specific DNA sequencing. Analyses of the influence of PADI4 and HLA-DRB1 genotypes on disease activity and on levels of anti-cyclic citrullinated peptide antibodies were performed.
Comparing the frequencies of PADI4 haplotype 4 (padi4_89*G, padi4_90*T, padi4_92*G, padi4_94*T, padi4_104*C, padi4_95*G, padi4_96*T) (patients, 14.7%; controls, 7.8%; odds ratio = 2.0, 95% confidence interval = 1.1–3.8) and carriers of this haplotype (patients, 27.5%; controls, 13.7%; odds ratio = 2.4, 95% confidence interval = 1.2–4.8), a significant positive association of PADI4 haplotype 4 with RA could be demonstrated. Other PADI4 haplotypes did not differ significantly between patients and controls. Regarding the individual PADI4 variants, padi4_89 (A→G), padi4_90 (C→T), and padi4_94 (C→T) were significantly associated with RA (patients, 49.5%; controls, 38.7%; odds ratio = 1.6, 95% confidence interval = 1.1–2.3). Considering novel PADI4 variants located in or near to exons 2, 3, and 4, no quantitative or qualitative differences between RA patients (8.8%) and healthy controls (10.8%) could be demonstrated. While the PADI4 genotype did not influence disease activity and the anti-cyclic citrullinated peptide antibody level, the presence of the HLA-DRB1 shared epitope was significantly associated with higher anti-cyclic citrullinated peptide antibody levels (P = 0.033).
The results of this small case–control study support the hypothesis that variability of the PADI4 gene may influence susceptibility to RA in the German population. Quantitative or qualitative differences in previously undefined PADI4 variants between patients and controls could not be demonstrated.
PMCID: PMC1526594  PMID: 16469113

Results 1-4 (4)