Fuchs S.I.,Marien Hospital Wesel GgmbH |
Schwerk N.,Leibniz University of Hanover |
Pittschieler K.,Marienklinik Bozen |
Ahrens F.,Childrens Hospital Altona |
And 11 more authors.
Respiratory Medicine | Year: 2016
Patients with alpha-1-antitrypsin deficiency (AATD) and a PI-ZZ genotype are at high risk to develop severe emphysema during adulthood. However, little is known about early stages of emphysema and disease manifestation in other PI-types. Spirometry is commonly used for monitoring although early manifestation of emphysema is suspected within the peripheral airways that are not accessible by forced expiratory manoeuvres. We hypothesized that the Lung Clearance Index (LCI) derived from multiple breath nitrogen-washout (N2-washout) is useful to bridge this diagnostic gap. Patients from age 4 years onward and different PI-types performed N2-washout and spirometry. Results were compared to controls. 193 patients (4-79 years, 75% PI-ZZ) and 33 controls (8-60 years) were included. Mean (SD) LCI in patients was 9.1 (3.1) and 6.3 (0.6) in controls (p ≤ 0.001). 47% of adult patients with other than PI-ZZ genotypes and 39% of all patients with normal spirometry had abnormal LCIs. The LCI measured by N2-washout discriminates between patients with AATD and controls, reflects AATD related lung disease in all stages and appears to identify early peripheral lung changes in younger age than spirometry. We conclude that a normal spirometry does not exclude presence of AATD related lung disease even in genotypes other than PI-ZZ. © 2016 Published by Elsevier Ltd.
PubMed | University of Tübingen, Clemenshospital Munster, University of Cologne, Marienklinik Bozen and 7 more.
Type: | Journal: Respiratory medicine | Year: 2016
Patients with alpha-1-antitrypsin deficiency (AATD) and a PI-ZZ genotype are at high risk to develop severe emphysema during adulthood. However, little is known about early stages of emphysema and disease manifestation in other PI-types. Spirometry is commonly used for monitoring although early manifestation of emphysema is suspected within the peripheral airways that are not accessible by forced expiratory manoeuvres. We hypothesized that the Lung Clearance Index (LCI) derived from multiple breath nitrogen-washout (N2-washout) is useful to bridge this diagnostic gap. Patients from age 4 years onward and different PI-types performed N2-washout and spirometry. Results were compared to controls. 193 patients (4-79 years, 75% PI-ZZ) and 33 controls (8-60 years) were included. Mean (SD) LCI in patients was 9.1 (3.1) and 6.3 (0.6) in controls (p0.001). 47% of adult patients with other than PI-ZZ genotypes and 39% of all patients with normal spirometry had abnormal LCIs. The LCI measured by N2-washout discriminates between patients with AATD and controls, reflects AATD related lung disease in all stages and appears to identify early peripheral lung changes in younger age than spirometry. We conclude that a normal spirometry does not exclude presence of AATD related lung disease even in genotypes other than PI-ZZ.
Goeppert B.,University of Heidelberg |
Schmidt C.R.,German Cancer Research Center |
Geiselhart L.,German Cancer Research Center |
Dutruel C.,German Cancer Research Center |
And 20 more authors.
Journal of Neuropathology and Experimental Neurology | Year: 2013
The scaffold protein A-kinase anchor protein 12 (AKAP12) exerts tumor suppressor activity and is downregulated in several tumor entities. We characterized AKAP12 expression and regulation in astrocytomas, including pilocytic and diffusely infiltrating astrocytomas. We examined 194 human gliomas and 23 normal brain white matter samples by immunohistochemistry or immunoblotting for AKAP12 expression. We further performed quantitative methylation analysis of the AKAP12 promoter by MassARRAY® of normal brain, World Health Organization (WHO) grade I to IV astrocytomas, and glioma cell lines. Our results show that AKAP12 is expressed in a perivascular distribution in normal CNS, strongly upregulated in tumor cells in pilocytic astrocytomas, and weakly expressed in diffuse astrocytomas of WHO grade II to IV. Methylation analyses revealed specific hypermethylation of AKAP12α promoter in WHO grade II to IV astrocytomas. Restoration experiments using 5-aza-2′- deoxycytidine in primary glioblastoma cells decreased AKAP12α promoter methylation and markedly increased AKAP12α mRNA levels. In summary, we demonstrate that AKAP12 is differentially expressed in human astrocytomas showing high expression in pilocytic but low expression in diffuse astrocytomas of all WHO-grades. Our results further indicate that epigenetic mechanisms are involved in silencing AKAP12 in diffuse astrocytomas; however, a tumor suppressive role of AKAP12 in distinct astrocytoma subtypes remains to be determined. © 2013 by the American Association of Neuropathologists, Inc.
Morikawa K.,University of Lausanne |
Morikawa K.,Showa University |
Gouttenoire J.,University of Lausanne |
Hernandez C.,Protein Analysis Facility |
And 11 more authors.
Hepatology | Year: 2014
The hepatitis C virus (HCV) NS3-4A protease is not only an essential component of the viral replication complex and a prime target for antiviral intervention but also a key player in the persistence and pathogenesis of HCV. It cleaves and thereby inactivates two crucial adaptor proteins in viral RNA sensing and innate immunity, mitochondrial antiviral signaling protein (MAVS) and TRIF, a phosphatase involved in growth factor signaling, T-cell protein tyrosine phosphatase (TC-PTP), and the E3 ubiquitin ligase component UV-damaged DNA-binding protein 1 (DDB1). Here we explored quantitative proteomics to identify novel cellular substrates of the NS3-4A protease. Cell lines inducibly expressing the NS3-4A protease were analyzed by stable isotopic labeling using amino acids in cell culture (SILAC) coupled with protein separation and mass spectrometry. This approach identified the membrane-associated peroxidase GPx8 as a bona fide cellular substrate of the HCV NS3-4A protease. Cleavage by NS3-4A occurs at Cys 11, removing the cytosolic tip of GPx8, and was observed in different experimental systems as well as in liver biopsies from patients with chronic HCV. Overexpression and RNA silencing studies revealed that GPx8 is involved in viral particle production but not in HCV entry or RNA replication. Conclusion: We provide proof-of-concept for the use of quantitative proteomics to identify cellular substrates of a viral protease and describe GPx8 as a novel proviral host factor targeted by the HCV NS3-4A protease. © 2013 by the American Association for the Study of Liver Diseases.
PubMed | University of Tübingen, Robert Bosch GmbH, University of Würzburg, University of Lübeck and 7 more.
Type: Journal Article | Journal: Leukemia | Year: 2016
Approximately 15% of follicular lymphomas (FLs) lack breaks in the BCL2 locus. The aim of this study was to better define molecular and clinical features of BCL2-breakpoint/t(14;18)-negative FLs. We studied the presence of BCL2, BCL6 and MYC breaks by fluorescence in situ hybridization and the expression of BCL2, MUM1, CD10, P53 and Ki67 in large clinical trial cohorts of 540 advanced-stage FL cases and 116 early-stage disease FL patients treated with chemotherapy regimens and radiation, respectively. A total of 86% and 53% of advanced- and early-stage FLs were BCL2-breakpoint-positive, respectively. BCL2 was expressed in almost all FLs with BCL2 break and also in 86% and 69% of BCL2-breakpoint-negative advanced- and early-stage FLs, respectively. CD10 expression was significantly reduced in BCL2-breakpoint-negative FLs of all stages and MUM1 and Ki67 expression were significantly increased in BCL2-break-negative early-stage FLs. Patient characteristics did not differ between FLs with and without BCL2 breaks and neither did survival times in advanced-stage FLs. These results suggest that the molecular profile differs to some extent between FLs with and without BCL2 breaks and support the notion that FLs with and without BCL2 breaks belong to the same lymphoma entity.
Stahmeyer J.T.,Hannover Medical School |
Stahmeyer J.T.,German Liver Foundation |
Rossol S.,Hannover Medical School |
Bert F.,Krankenhaus Nordwest |
And 10 more authors.
European Journal of Gastroenterology and Hepatology | Year: 2014
Background Viral hepatitis is major a public health problem affecting millions of people worldwide. Estimates assume 400 000-500 000 people chronically infected with hepatitis C virus (HCV) in Germany. Long-term consequences are the development of liver cirrhosis and hepatocellular carcinoma. The aim of the study was to assess the costs for treating patients with chronic HCV in Germany. Methods We conducted a retrospective multicenter observational study. The design was approved by an ethics committee, and patients were asked for their informed consent. Patients were grouped in four different health states. Healthcare utilization data were extracted from doctor files of six medical centers in Germany. Results Data of 315 patients with chronic HCV were analyzed. The mean age was 49.4 years, 57.5% were male and 67.9% had a genotype 1 infection. The most common routes of transmission were injection drug use (39.0%) and infection through blood products (15.9%). The average total cost was €19 147 including ambulatory care and diagnostics (€1686), pharmaceuticals (€14 875), inpatient care (€1293), and sick leave (€1293). For patients in stable health states (mild and moderate HCV, compensated cirrhosis), costs did not differ significantly and were mainly influenced by antiviral treatment. For patients with decompensated cirrhosis, inpatient care accounted for the largest part of the costs. Conclusion Treatment of HCV patients involves high costs, mainly associated with the length of antiviral therapy. Viral eradication can prevent severe disease stages, which are associated with high costs. It is necessary to follow current guidelines and monitor patients closely to avoid unnecessary costs. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Haselbach S.,Goethe University Frankfurt |
Maurer J.,Goethe University Frankfurt |
Vogel V.,Goethe University Frankfurt |
Harder S.,University Hospital Frankfurt Am |
And 6 more authors.
Clinical Chemistry and Laboratory Medicine | Year: 2013
Background: Heparin is the standard drug for anticoagulation treatment and is used in many cardiac surgical interventions to prevent blood clotting. The anticoagulation status is controlled by various clotting tests. However, these tests depend on parameters like temperature, hemodilution etc. and are thus not applicable for a direct monitoring of the heparin concentration. The aim of this prospective study was to test a novel light scattering assay (LiSA) for the direct determination of heparin concentration during cardiopulmonary bypass (CPB) surgery and to compare the heparin concentrations with routinely determined activated clotting time (ACT). Methods: The patient group consisted of 50 patients undergoing coronary bypass surgery with CPB. The coagulation status was monitored by the measurement of ACT, which was performed approximately every 30 min during surgery. Parallel to each ACT measurement, the heparin concentration was measured by LiSA. Results: For 70% of the patients, ACT and heparin concentration measured by LiSA correlated reasonably over the entire time course of the intervention. For 30% of the patients, an insufficient correlation or even no correlation at all was observed. Conclusions: This study showed that LiSA enables the determination of intra-operative heparin levels. The lack of correlation between ACT and heparin concentration in a substantial group of patients shows that monitoring of heparin concentration is important. A more precise blood coagulation management, in particular, a precise administration of heparin and protamine, should be based on a combination of the measurement of heparin concentration and of ACT, but not on ACT alone.