Christel Weiß

Prognostic Value of Plasma N-Terminal Pro-Brain Natriuretic Peptide in Patients With Severe Sepsis

Background—Increased plasma levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) have been identified as predictors of cardiac dysfunction and prognosis in congestive heart failure and ischemic heart disease. In severe sepsis patients, however, no information is available yet about the prognostic value of natriuretic peptides. Therefore, the aim of the present study was to determine the role of the N-terminal prohormone forms of ANP (NT-proANP) and BNP (NT-proBNP) in the context of outcome of septic patients. Furthermore, the effect of treatment with recombinant human activated protein C [drotrecogin alfa (activated)] on plasma levels of natriuretic peptides in severe sepsis was evaluated. Methods and Results—Fifty-seven patients with severe sepsis were included. Levels of NT-proANP and NT-proBNP were measured on the second day of sepsis by ELISA. Septic patients with NT-proBNP levels >1400 pmol/L were 3.9 times more likely (relative risk [RR], 3.9; 95% CI, 1.6 to 9.7) to die from sepsis than patients with lower NT-proBNP values (P<0.01). NT-proANP levels, however, were not predictive of survival in our patient population. A highly significant correlation was found between troponin I levels and plasma concentrations of NT-proBNP in septic patients (r=0.68, P<0.0001). In addition, troponin I significantly accounted for the variation in NT-proBNP levels (P<0.0001), suggesting an important role for NT-proBNP in the context of cardiac injury and dysfunction in septic patients. Twenty-three septic patients who received treatment with drotrecogin alfa (activated) presented with significantly lower concentrations of NT-proANP, NT-proBNP, and troponin I compared with patients not receiving drotrecogin alfa (activated). Conclusions—NT-proBNP may serve as useful laboratory marker to predict survival in patients presenting with severe sepsis.

Transcutaneous measurement of glomerular filtration rate using FITC-sinistrin in rats

BACKGROUND Inulin/sinistrin (I/S) clearance is a gold standard for an accurate assessment of glomerular filtration rate (GFR). Here we describe and validate an approach for a transcutaneous determination of GFR by using fluorescein-isothiocyanate-labelled sinistrin (FITC-S) in rats. METHODS Using a small animal imager, fluorescence is measured over the depilated ear of a rat after the injection of FITC-S. The decay curve of fluorescence is used for the calculation of half-life and GFR. The thus obtained transcutaneous data were validated by simultaneously performed enzymatic and fluorometric measurements in plasma of both FITC-S and sinistrin. RESULTS The results of enzymatic sinistrin determination versus transcutaneous half-life of FITC-S or plasma fluorescence correlated well with each other (R(2) > 0.90). Furthermore, Bland-Altman analyses proved a good degree of agreement of the three methods used. The measurements performed in healthy animals as well as different models of renal failure demonstrate its appropriateness in a wide range of renal function. CONCLUSIONS The transcutaneous method described offers a precise assessment of GFR in small animals. As neither blood and/or urine sampling nor time-consuming lab work is required, GFR can be determined immediately after the clearance procedure is finished. This method, therefore, simplifies and fastens GFR determinations in small lab animals compared to conventional bolus clearance techniques based on blood sampling. A low-cost device for the measurement of transcutaneous fluorescence intensity over time is under construction.

Basiswissen Medizinische Statistik

Neben den rein statistischen Grosen zu Beginn, wird im zweiten Teil des Buches auf die Epidemiologie eingegangen und damit der alltagliche Bezug zur Medizin hergestellt. Auch in diesem Teil wird wieder ausfuhrlich und gut verstandlich erklart. Wunschen wurde man sich allerdings vielleicht die Einarbeitung aktueller groser, bekannter Studien, die in ihrer Wichtigkeit fur den klinischen Alltag von ungebrochener Bedeutung sind und damit sehr gut als „Learning by doing“ dienen konnten.

Combination therapy with extracorporeal photopheresis, interferon‐α, PUVA and topical corticosteroids in the management of Sézary syndrome

Background: Extracorporeal photopheresis (ECP) is recommended for the treatment of Sézary syndrome (SS), the leukemic variant of cutaneous T‐cell lymphoma (CTCL). Several combination therapies are used to increase response rates to ECP.

Simvastatin and atorvastatin attenuate VCAM-1 and uPAR expression on human endothelial cells and platelet surface expression of CD40 ligand.

BACKGROUND In addition to their cholesterol lowering ability, statins have proven pleiotropic effects in the cardiovascular system. Chronic inflammation with interactions between platelets and endothelial cells leads to an upregulation of activity markers of atherosclerosis. The purpose of this study was to investigate the effects of simvastatin and atorvastatin on platelets and endothelial cells in an in vitro endothelial cell model. METHODS AND RESULTS After a 24 h incubation period with either simvastatin or atorvastatin (1 μmol/L), human umbilical vein endothelial cells were stimulated for 1 h with lipopolysaccharide (LPS), and were then incubated in direct contact with activated platelets. Platelet surface expression of CD40L and CD62P and expression of ICAM-1, VCAM-1, uPAR and MT1-MMP on endothelial cells were measured by flow cytometry. Supernatants were analyzed by ELISA for soluble MMP-1. The increased expression of VCAM-1 and uPAR on endothelial cells by stimulation with LPS and by direct contact with activated platelets was significantly reduced to a similar extent through pre-incubation with both atorvastatin and simvastatin (p < 0.05). Platelets without endothelial cell contact, but in direct contact with either statin, showed similar significant reductions in surface expression of CD40L (p < 0.005). CONCLUSIONS These effects may explain the ability of statins to reduce the progression of atherosclerosis in addition to their cholesterol-lowering properties.

Efficacy and survival in patients with cardiac contractility modulation: Long-term single center experience in 81 patients

AIMS To analyze long-term efficacy and survival in patients with chronic heart failure treated with cardiac contractility modulation. METHODS 81 patients implanted with a CCM device between 2004 and 2012 were included in this retrospective analysis. Changes in NYHA class, ejection fraction (EF), Minnesota Living with Heart Failure Questionnaire, NT-proBNP and peak VO₂ were analyzed during a mean follow up of 34.2 ± 28 months (6-123 months). Observed mortality rate was compared with that predicted by the MAGGIC Score. RESULTS Patients were 61 ± 12 years old with EF 23 ± 7%. Heart failure was due to ischemic (n=48, 59.3%) or idiopathic dilated (n=33, 40.7%) cardiomyopathy. EF increased from 23.1 ± 7.9 to 29.4 ± 8.6% (p<0.05), mean NT-proBNP decreased from 4395 ± 3818 to 2762 ± 3490 ng/l (p<0.05) and mean peak VO2 increased from 13.9 ± 3.3 to 14.6 ± 3.5 ml/kg/min (p=0.1). The overall clinical responder rate (at least 1 class improvement of NYHA within 6 months or last follow-up) was 74.1%. 21 (25.9%) patients died during follow up, 11 (52.4%) due to cardiac conditions and 10 (47.6%) due to non-cardiac conditions. Mortality rates at 1 and 3 years were 5.2% and 29.5% compared to mortality rates estimated from the MAGGIC risk score of 18.4% (p<0.001) and 40% (p=ns), respectively. Log-Rank analysis of all events through 3 years of follow-up, however, was significantly less than predicted (p=0.022). CONCLUSIONS CCM therapy improved quality of life, exercise capacity, NYHA class, EF and NT-proBNP levels during long-term follow up. Mortality rates appeared to be lower than estimated from the MAGGIC score.

Interleukin 18 Promoter Variants (−137G>C and −607C>A) in Patients with Chronic Hepatitis C: Association with Treatment Response

BackgroundRecently, two functional IL18 promoter variants, −607C>A (rs1946518) and −137G>C (rs187238), were associated with viral clearance in patients with hepatitis C. The present study focused on their relevance for treatment response.MethodsSeven hundred fifty-seven chronically infected European patients and 791 controls were enrolled in the study. IL18 genotyping was performed by allele-specific PCR. Liver histology was available in 67.9%.ResultsGenotype and allele frequencies were equally distributed in patients and controls. No significant association with various disease characteristics was observed. However, when comparing patients with sustained virological response (SR) and non-SR, statistically significant associations were found for both variants (p = 0.0416 and p = 0.0274, respectively). In viral genotype 1, the −607A allele was positively associated with treatment response (p = 0.0190; OR 1.537; 95% CI, 1.072–2.205) and the −137G allele with a higher rate of nonresponse (p = 0.0302; OR 1.524; 95% CI, 1.040–2.233).ConclusionsThe association of IL18 variants with treatment response in genotype 1 hepatitis C patients implies a predictive and modifying role of these genetic variants.

Clonal Evolution and Blast Crisis Correlate with Enhanced Proteolytic Activity of Separase in BCR-ABL b3a2 Fusion Type CML under Imatinib Therapy.

Unbalanced (major route) additional cytogenetic aberrations (ACA) at diagnosis of chronic myeloid leukemia (CML) indicate an increased risk of progression and shorter survival. Moreover, newly arising ACA under imatinib treatment and clonal evolution are considered features of acceleration and define failure of therapy according to the European LeukemiaNet (ELN) recommendations. On the basis of 1151 Philadelphia chromosome positive chronic phase patients of the randomized CML-study IV, we examined the incidence of newly arising ACA under imatinib treatment with regard to the p210BCR-ABL breakpoint variants b2a2 and b3a2. We found a preferential acquisition of unbalanced ACA in patients with b3a2 vs. b2a2 fusion type (ratio: 6.3 vs. 1.6, p = 0.0246) concurring with a faster progress to blast crisis for b3a2 patients (p = 0.0124). ESPL1/Separase, a cysteine endopeptidase, is a key player in chromosomal segregation during mitosis. Separase overexpression and/or hyperactivity has been reported from a wide range of cancers and cause defective mitotic spindles, chromosome missegregation and aneuploidy. We investigated the influence of p210BCR-ABL breakpoint variants and imatinib treatment on expression and proteolytic activity of Separase as measured with a specific fluorogenic assay on CML cell lines (b2a2: KCL-22, BV-173; b3a2: K562, LAMA-84). Despite a drop in Separase protein levels an up to 5.4-fold increase of Separase activity under imatinib treatment was observed exclusively in b3a2 but not in b2a2 cell lines. Mimicking the influence of imatinib on BV-173 and LAMA-84 cells by ESPL1 silencing stimulated Separase proteolytic activity in both b3a2 and b2a2 cell lines. Our data suggest the existence of a fusion type-related feedback mechanism that posttranslationally stimulates Separase proteolytic activity after therapy-induced decreases in Separase protein levels. This could render b3a2 CML cells more prone to aneuploidy and clonal evolution than b2a2 progenitors and may therefore explain the cytogenetic results of CML patients.

Discriminatory potential of C-reactive protein, cytokines, and fecal markers in infectious gastroenteritis in adults.

This study evaluates potential markers in blood and stools for their ability to distinguish bacterial from viral gastroenteritis. A total of 108 patients were prospectively recruited, of which 27 showed bacterial, 30 viral, and 51 no detectable pathogen, respectively. Cytokines, C-reactive protein (CRP), and white blood cells as well as the 2 fecal markers lactoferrin and calprotectin were determined. Statistics comprised Kruskal-Wallis test and U test in addition to an assessment of receiver operating characteristic. Interferon γ (IFNγ) levels were significantly increased in the viral group compared to the bacterial and nonspecific group. For the bacterial group, both fecal markers lactoferrin and calprotectin as well as CRP were significantly higher in comparison to the other 2 groups. To differentiate between bacterial and viral gastroenteritis, CRP, serum IFNγ, and the fecal proteins lactoferrin and calprotectin may be useful. A corresponding algorithm should be evaluated prospectively.

8-bit or 11-bit monochrome displays—which image is preferred by the radiologist?

ObjectivesVendors of medical displays promise a better diagnostic performance using 10- or 11-bit instead of 8-bit monochrome displays. We measured the gain of “Just Noticeable Difference” (JND) steps using high grayscale resolutions and evaluated the preference of radiologists regarding different aspects of image quality.MethodsThe amount of JND steps was measured on a display using 8-, 10- and 11-bit Look Up Tables (LUT). Radiological images were presented simultaneously using an 8-bit and an 11-bit LUT, radiologists where asked to determine the better image presentation regarding quality parameters like sharpness, contrast and detectability of details.ResultsThe 10-bit technology realized more than twice the number of JND steps compared to an 8-bit LUT, an 11-bit LUT presented only few additional JND steps. The radiologists did not attest the higher grayscale resolution a better image quality, they regarded the 8-bit technology to show a better sharpness and contrast, although this had no impact on the detectability of details.ConclusionsOur measurements confirmed that the higher grayscale resolution results in a more complete visualization of image information. But radiologists partially judged this as a lack of sharpness and contrast and generally preferred the 8-bit display.