[Show abstract][Hide abstract] ABSTRACT: In adult and pediatric cardiology, n-terminal pro-B-type natriuretic peptide (nt-proBNP) serves as biomarker in the diagnosis and management of cardiovascular dysfunction. Elevated levels of circulating nt-proBNP are present in fetal conditions associated with myocardial pressure or volume load. Compared to fetal blood sampling, amniocentesis is technically easier and can be performed from early pregnancy onwards. We aimed to investigate amniotic fluid (AF) nt-proBNP concentrations in normal pregnancies between 10 and 34 weeks of gestation.
Nt-proBNP and total protein (TP) was measured in AF by chemiluminescence assay (photometry, respectively). To adjust for a potential dilutional effect, the AF-nt-proBNP/AF-TP ratio was analyzed. Reference intervals were constructed by regression modeling across gestational age.
132 samples were analyzed. A negative correlation between AF-nt-proBNP/AF-TP ratio and gestational age was observed. Curves for the mean and the 5% and 95% reference interval between 10 and 34 weeks of gestation were established.
In normal pregnancy, nt-proBNP is present in AF and decreases during gestation. Our data provide the basis for research on AF-nt-proBNP as biomarker in fetal medicine.
PLoS ONE 12/2014; 9(12):e114416. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Abstract Vascular endothelial cadherin and β-catenin play a key role in establishment and maintenance of the endothelial monolayer integrity, regulation of vascular barrier function, and initiation of angiogenesis. The cadherin-catenin complex has been shown to be reduced in Type 1 diabetic placenta, but the exact relationship between histopathologic findings and clinical data is not known. Immunohistochemistryof placental tissue from Type 1, Type 2 and gestational diabetes showed, that diabetes per se might be compatible with normal levels of vascular endothelial cadherin and β-catenin in fetoplacental vessels as long as the patient has not been treated with insulin. Immunoreactivity of VE-cadherin did correlate poorly with maternal glycaemic control as was investigated in this study by birthweight, body-mass-index, and HbA1c. There was no correlation found between the immunoreactivity of β-catenin and birthweight, body-mass-index, and HbA1c. However our data did show a storng correlation immunoreactivity and whether or not the patient had been treated with insulin or not. Therefore patients diagnosed with gestational diabetes, who had not been treated with insulin, had similar levels of VE-cadherin and β-catenin as the control group, thus indicating that diabetes per se must not necessarily lead to a reduction. Our study suggests that therapeutic intervention using insulin in pregnancies complicated by diabetes might have potentially harmful effects on placental morphology. Future studies should further investigate these findings.
Pediatric and Developmental Pathology 10/2014; · 0.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Inflammation, collagen deposition and tissue remodelling are involved in the pathogenesis and complications of cirrhosis with portal hypertension. CXCL9 and other chemokines play an important role in these processes and have been associated with liver injury and complications of liver disease in humans. However, their predictive value in patients with cirrhosis and portal hypertension remains to be established.
103 patients with liver cirrhosis who had received TIPS (transjugular intrahepatic portosystemic shunt) were included into this study. The TIPS indication was either refractory ascites or recurrent bleeding. Before and after TIPS procedure portal and hepatic venous blood samples were obtained in 78 patients. In 25 patients blood samples were obtained from portal vein, hepatic vein, right atrium and cubital vein at TIPS insertion. Serum levels of CXCL9 were measured by cytometric bead array and correlated with clinical parameters and overall outcome.
Portal venous levels of CXCL9 decreased after TIPS. Child-score, refractory ascites, renal dysfunction and alcoholic etiology of cirrhosis were associated with increased CXCL9 levels. Importantly, low levels of CXCL9 in portal and hepatic vein were prognostic factors for survival of patients receiving TIPS during long-time follow up.
The CXCR3 ligand CXCL9 affects the liver and/or is released by the liver and thereby might contribute to hepatic and extrahepatic organ dysfunction. Elevated levels of CXCL9 are associated with shorter survival in cirrhotic patients with severe portal hypertension receiving TIPS. This chemokine should be further evaluated as a novel biomarker for the outcome in patients with cirrhosis and portal hypertension and its modulation as a new therapeutic strategy.
Journal of Hepatology 10/2014; · 10.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: There is evidence of a probable key role of the activator protein-2 γ (AP-2γ) in placental development. It is still an open question whether AP-2γ expression may be influenced by preeclampsia, which is a serious pregnancy complication, or by smoking, which has deleterious effects on trophoblastic development.
Archives of Gynecology and Obstetrics 10/2014; · 1.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Early diagnosis is the key for the successful treatment of breast cancer. A serum marker for the early detection of breast cancer could significantly reduce breast cancer morbidity and mortality by bringing the time of diagnosis at an earlier and therefore still curable stage. So far, no biomarker for the early detection is available for the clinical routine. The aim of the present study was to evaluate the use of calponin-h2 as a blood-based biomarker for the early diagnosis of this disease. Using two monoclonal antibodies against calponin-h2, we developed a sandwich ELISA to analyze the serum levels of calponin-h2. In order to evaluate the diagnostic potential of this biomarker, patients with breast cancer (n = 76), benign diseases of the breast (n = 51) and healthy females (n = 24) were analyzed. Serum levels above 10 ng/ml were only observed in patients with breast cancer (n = 8; 10.5 %). Further large-scale studies and preanalytic evaluations are necessary to clarify the definite role of calponin-h2 as a biomarker in breast cancer management.
[Show abstract][Hide abstract] ABSTRACT: Introduction
The estrogen antagonist tamoxifen (TAM) increases the thrombotic risk similar to estrogen containing oral contraceptives (OC). In OC users this risk is attributed to alterations of hemostasis resulting in acquired resistance to activated protein C (APC). TAM-induced APC resistance has not been reported yet.
Materials and Methods
Blood samples were collected prospectively from women with breast cancer before (n = 25) and monthly after start of adjuvant TAM treatment (n = 75). APC resistance was evaluated on basis of the effect of APC on the endogenous thrombin generation potential. To detect increased in vivo APC generation APC plasma levels were measured using a highly sensitive oligonucleotide-based enzyme capture assay. Routine hemostasis parameters were measured additionally.
APC sensitivity decreased by 41% (p = 0.001) compared to baseline after one month of TAM application and remained significantly decreased during the study period. Free protein S increased (p = 0.008) while other analyzed procoagulant factors, inhibitors, and activation markers of coagulation decreased or did not change significantly. In five patients the APC concentration increased to non-physiological levels but an overall significant increase of APC was not observed.
This is the first study showing acquired APC resistance under TAM therapy. Acquired APC resistance might explain the increased thrombotic risk during TAM treatment. Observed changes of hemostasis parameters suggest different determinants of TAM-induced APC resistance than in OC-induced APC resistance. The presence of acquired APC resistance in TAM patients warrants further evaluation if these patients may benefit from antithrombotic prophylaxis in the presence of additional thrombotic risk factors.
[Show abstract][Hide abstract] ABSTRACT: To investigate the impact of Bruch Membrane pathology on the choroid in Pseudoxanthoma elacticum (PXE) DESIGN: Monocenter cross sectional prospective case series.
The study included 61 eyes of 51 patients with PXE and 54 eyes of 54 normal subjects. The diagnosis of PXE was based on skin biopsy and/or genetic analysis. Eyes with PXE were subdivided into 3 groups: Eyes without choroidal neovascularization (CNV) or chorioretinal atrophy (group 1), eyes with active or fibrotic CNV (group 2) and eyes with chorioretinal atrophy only (group 3). Choroidal thickness was measured using enhanced depth imaging optical coherence tomography (EDI-OCT).
Compared to controls (331μm±24; mean±95%CI), mean subfoveal choroidal thickness in eyes of PXE patients was significantly reduced within all three groups (group 1: 243μm±29; group 2: 184μm±28; group 3: 104μm±28; p<0.001). Associated structural changes included apparent loss of small choroidal vessels. The difference of PXE compared to control eyes was most obvious close to the optic disc and approximated the level of controls towards the periphery. Within the PXE subgroups eyes without CNV or chorioretinal atrophy (group 1) showed the least reduction of choroidal thickness, while it was most pronounced within group 3.
The results indicate that changes of Bruch Membrane can be associated with choroidal alterations, which are most pronounced in presence of advanced disease. A role of Bruch Membrane for choroidal homeostasis may reflect a possible contribution of Bruch Membrane alterations to CNV and geographic atrophy development in age-related macular degeneration.
American Journal of Ophthalmology 04/2014; · 4.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose: To further characterize a subgroup of patients exhibiting the fundus autofluorescence (FAF) "diffuse-trickling" phenotype associated with geographic atrophy (GA). Methods: In the context of the Fundus Autofluorescence in Age related Macular Degeneration (FAM) Study, patients with "diffuse-trickling" GA were examined and characterized by FAF and spectral-domain optical coherence tomography imaging (HRA, Spectralis HRA+OCT, Heidelberg Engineering). Age, gender distribution, and medical history were compared to FAM study patients (n=288, 60.1% female) with other GA phenotypes ("non-diffuse-trickling"). In a subset of patients, subfoveal choroidal thickness (SCT) was analyzed. Results: Patients with "diffuse-trickling" (n=61) - compared to patients with "non-diffuse-trickling" GA - had a significantly younger age at first presentation (68.2±11.6 vs.75.4±8.1 years, p<0.001), a shift in the proportion of men from 55% in the age group <65 to 19% in the age group ≥65, and a significantly higher rate of myocardial infarction (MI) in the age group <65 (24% vs. 0%,p=0.011); all but one patient with MI were male. Further evaluation revealed that in the age group <65, 54% of patients with "diffuse-trickling" had been hospitalized due to cardiovascular diseases including hypertensive crisis, angina, and MI. Analysis of choroidal thickness revealed a significantly thinner SCT in "diffuse-trickling" compared to "non-diffuse-trickling" GA (135.2±56.4 vs. 191.4±77.8µm,p<0.001). Conclusions: The results indicate an association of "diffuse-trickling" GA with systemic cardiovascular disorders in the younger study population. Together with the ocular morphological characteristics including a lobular appearance and a thin choroid, a vascular insufficiency at the level of the choroid may play a pathogenetic role in this distinct GA phenotype.
[Show abstract][Hide abstract] ABSTRACT: The German Version of the Manchester Triage System (MTS) has found widespread use in EDs across German-speaking Europe. Studies about the quality criteria validity and reliability of the MTS currently only exist for the English-language version. Most importantly, the content of the German version differs from the English version with respect to presentation diagrams and change indicators, which have a significant impact on the category assigned. This investigation offers a preliminary assessment in terms of validity and inter-rater reliability of the German MTS.
Construct validity of assigned MTS level was assessed based on comparisons to hospitalization (general / intensive care), mortality, ED and hospital length of stay, level of prehospital care and number of invasive diagnostics. A sample of 45,469 patients was used. Inter-rater agreement between an expert and triage nurses (reliability) was calculated separately for a subset group of 167 emergency patients.
For general hospital admission the area under the curve (AUC) of the receiver operating characteristic was 0.749; for admission to ICU it was 0.871. An examination of MTS-level and number of deceased patients showed that the higher the priority derived from MTS, the higher the number of deaths (p<0.0001 / χ(2) Test). There was a substantial difference in the 30-day survival among the 5 MTS categories (p<0.0001 / log-rank test).The AUC for the predict 30-day mortality was 0.613. Categories orange and red had the highest numbers of heart catheter and endoscopy. Category red and orange were mostly accompanied by an emergency physician, whereas categories blue and green were walk-in patients. Inter-rater agreement between expert triage nurses was almost perfect (κ = 0.954).
The German version of the MTS is a reliable and valid instrument for a first assessment of emergency patients in the emergency department.
PLoS ONE 02/2014; 9(2):e88995. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study investigated the efficacy of 131iodine-labeled lipiodol (131I-lipiodol) as a palliative therapy, evaluated overall survival (OS) across Barcelona Clinic Liver Cancer (BCLC) stages, and determined the main prognostic factors influencing OS in patients with hepatocellular carcinoma (HCC). Patients, methods: We retrospectively analyzed 57 (44 men; mean age, 65.7 years; mean activity per session, 1.6 GBq; mean cumulative activity in patients with >1 sessions, 3.9 GBq) HCC patients who underwent 131I-lipiodol therapy. A majority of patients exhibited Child-Pugh class B (53.6%) disease and a good Eastern Cooperative Oncology Group performance status (0-1; 72%). Multinodular disease was observed in 87.7% patients, bilobar disease in 73%, and portal vein occlusion (PVO) in 54%. Furthermore, 21.1% patients were staged as BCLC B and 59.6 % as BCLC C. All patients were followed until death. Results: The median OS was 6.4 months, which varied significantly with disease stage (median OS for BCLC A, B, C, and D was 29.4, 12.0, 4.6, and 2.7 months, respectively; p = 0.009); Child-Pugh score and class; presence of ascites, PVO, or extrahepatic disease; largest lesion size; favourable treatment response; international normalized ratio, baseline albumin and alpha-fetoprotein levels. Patients with a Child-Pugh A liver disease had a longer OS. Conclusion: Currently, different treatment modalities for HCC include radioembolization, transarterial chemoembolization, and systemic therapy with sorafenib; however, 131I-lipiodol therapy remains a feasible alternative for patients without a favourable response to other therapies, particularly for patients with Child-Pugh A liver cirrhosis.
[Show abstract][Hide abstract] ABSTRACT: The objective of this study was to investigate the efficacy of the fixed-dose combination olmesartan/amlodipine 40/10 mg in patients with moderate essential hypertension not controlled on candesartan 32 mg. This was a prospective, single-arm, phase IV study. The primary endpoint was the change in mean daytime systolic blood pressure (BP). A total of 77 of 89 screened patients started candesartan 32 mg, 62 olmesartan 40 mg, and 57 olmesartan 40 mg/amlodipine 10 mg. Mean daytime systolic BP was reduced by 9.8±15.2 mm Hg (P<.001) vs candesartan monotherapy. Office BP reduction was 9.2±18.8/5.0±8.9 mm Hg (P<0.001). Treatment goals (<140/90 mm Hg for office and <135/85 mm Hg for ambulatory BP) were achieved in 58.2% and 78.4% of patients, respectively. There was one drug-related adverse event (edema) and no serious adverse events. Patients of Caucasian ethnicity with moderate essential hypertension uncontrolled on candesartan experienced a further drop in BP using olmesartan and amlodipine.
Journal of Clinical Hypertension 01/2014; 16(1):41-6. · 2.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The actual number of resin microspheres is approximately 30-60 times higher than glass microspheres per 3 GBq vial. Thus, radioembolization (RE) with resin microspheres exerts an embolization effect besides the radiation effect. This embolization effect can occasionally cause early back flow of the microspheres before application of the entire calculated dose. To avoid these adverse side effects, RE has to be terminated at an earlier time point. Measurement of the residual activity in the delivery box, which includes the v-vial, tube and catheter, to calculate the achieved target dose is often challenging. The aim of the current study was to establish a post-RE measurement method comparable to the glass microspheres method without unnecessary radiation exposure to the staff and risk of contamination. Methods: Two different measurements were performed. First, total radioactivity in the shipping vial was measured in an ion chamber and then it was put in the delivery box and the radiation was measured from a 30 cm distance from the centre of the box with a dosimeter. The required radioactivity was then transferred to the v-vial, and the shipping vial was measured again. After that, the v-vial was measured from the same distance from the centre of the box with dosimeter. Results: Altogether 62 times the shipping vial with different activities were measured with a significant positive correlation between the amount of the activity measured in the iron chamber and the radiation dose, measured with dosimeter (r² = 0.98; p< 0.001). There was also a strong positive correlation between these measurements of the v-vial (r² = 0.98; p< 0.001). Conclusion:With measurement of the residual activity in the delivery box using a dosimeter the percentage of the whole injected activity can be easily calculated. This facilitates the calculation of the actual, achieved target and non-target dose in those cases, where therapy had to be stopped because of eminent flow reversal or obstruction.
[Show abstract][Hide abstract] ABSTRACT: Systemic mast cell activation disease (MCAD) comprises disorders characterized by an enhanced release of mast cell mediators accompanied by accumulation of dysfunctional mast cells. Demonstration of familial clustering would be an important step towards defining the genetic contribution to the risk of systemic MCAD. The present study aimed to quantify familial aggregation for MCAD and to investigate the variability of clinical and molecular findings (e.g. somatic mutations in KIT) among affected family members in three selected pedigrees. Our data suggest that systemic MCAD pedigrees include more systemic MCAD cases than would be expected by chance, i.e., compared with the prevalence of MCAD in the general population. The prevalence of MCAD suspected by symptom self-report in first-degree relatives of patients with MCAD amounted to approximately 46%, compared to prevalence in the general German population of about 17% (p<0.0001). In three families with a high familial loading of MCAD, the subtype of MCAD and the severity of mediator-related symptoms varied between family members. In addition, genetic alterations detected in KIT were variable, and included mutations at position 816 of the amino acid sequence. In conclusion, our data provide evidence for common familial occurrence of MCAD. Our findings observed in the three pedigrees together with recent reports in the literature suggest that, in familial cases (i.e., in the majority of MCAD), mutated disease-related operator and/or regulator genes could be responsible for the development of somatic mutations in KIT and other proteins important for the regulation of mast cell activity. Accordingly, the immunohistochemically different subtypes of MCAD (i.e. mast cell activation syndrome and systemic mastocytosis) should be more accurately regarded as varying presentations of a common generic root process of mast cell dysfunction, than as distinct diseases.
PLoS ONE 09/2013; 8(9):e76241. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: PURPOSE:
To assess tight junction integrity in cultured human foetal retinal pigment epithelium (RPE) after exposure to clinically relevant indocyanine green (ICG) concentrations.
Human foetal RPE was cultured with the Hu & Bok method. The apical compartments of well-differentiated cultures were exposed to 0.125, 0.05 and 0.025 mg/ml ICG with or without 10-min illumination. Vehicle and trypsin/EDTA or EDTA alone served as controls. Three minutes was chosen to mimic surgical exposure time, while 3 h was used for toxicity assays, with subsequent wash out. Cell-cell junctions were studied before and after exposure by phase contrast microscopy and immunofluorescence (ZO-1). Blood-retinal barrier function was measured through transepithelial electrical resistance (TER).
At 6-8 weeks postconfluence, RPE had grown into pigmented hexagonal monolayers with stable TER (435-1227 Ω*cm2 ). After 3 min ICG exposure, cell morphology remained unchanged, with patchy cell-cell dissociation in positive controls. A continuous ZO-1 signal was detected in ICG groups, whereas trypsin controls showed patchy loss of the tight junction stain. TER had dropped at 1.5 h after 3 min exposure to 22.8 ± 3.1%, compared with 10.2 ± 3.9% in positive controls. Surgical light illumination did not affect TER. After 3 h exposure to 0.05 mg/ml ICG, TER decreased to 58.1 ± 8.3%, while vehicle controls maintained similar levels as prior to exposure (92.7 ± 2.4%). TER recovered in all ICG groups to prior levels within 3 days.
Indocyanine green (ICG) exposure induced a transient decrease in transepithelial electrical resistance, despite unaltered tight junction structure.
[Show abstract][Hide abstract] ABSTRACT: Mastocytosis is a rare heterogeneous disease characterized by increase of mast cells (MCs) in different organs. Neurotrophins have been shown to promote differentiation and survival of MCs, which in turn represent a major source of neurotrophins. Thus, a contribution of neurotrophins to mastocytosis seems highly conceivable, but has not yet been investigated. We could demonstrate expression of high-affinity neurotrophin receptors TrkA for nerve growth factor (NGF)-β, TrkB for brain-derived neurotrophic factor (BDNF) and NT-4 and TrkC for NT-3 on skin MCs and of TrkA and TrkC on intestinal MCs of patients with mastocytosis. Moreover increased expression of NGF-β, NT-3, TrkA, B, C and isoforms truncated TrkB-T1 and truncated TrkC were observed on skin mast cells. Patients with mastocytosis featured elevated serum levels of NGF, NT-3 and NT-4. Levels of NGF-β and NT-4 correlated with tryptase levels, suggesting a link between mast cell load and blood levels of NGF and NT-4. Migration of CD117(+) progenitor cells from the blood was enhanced towards NGF-β gradient in both mastocytosis and controls. Together with enhanced neurotrophin levels, the elevated expression of modified Trk receptors on skin and gut mast cells might contribute to the pathophysiology of mastocytosis in autocrine and paracrine loops.