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Steib C.J.,Ludwig Maximilians University of Munich | Bilzer M.,Essex Pharma | Op Den Winkel M.,Ludwig Maximilians University of Munich | Pfeiler S.,Institute for Clinical Chemistry | And 4 more authors.
Hepatology | Year: 2010

The mechanisms underlying intrahepatic vasoconstriction are not fully elucidated. Here we investigated the Kupffer cell (KC)-dependent increase in portal pressure by way of actions of vasoconstrictive cysteinyl leukotrienes (Cys-LTs). Liver cirrhosis was induced in rats by bile duct ligation (BDL for 4 weeks; controls: sham-operation) and thioacetamide application (18 weeks). Infusion of leukotriene (LT) C4 or LTD4 in isolated perfused livers (20 nM, BDL and sham) demonstrated that LTC4 is a more relevant vasoconstrictor. In BDL animals the Cys-LT1 receptor inhibitor montelukast (1 μM) reduced the maximal portal perfusion pressure following LTC4 or LTD4 infusion. The infusion of LTC 4 or D4 in vivo (15 μg/kg b.w.) confirmed LTC 4 as the more relevant vasoconstrictor. Activation of KCs with zymosan (150 μg/mL) in isolated perfused BDL livers increased the portal perfusion pressure markedly, which was attenuated by LT receptor blockade (Ly171883, 20 μM). Cys-LTs in the effluent perfusate increased with KC activation but less with additional blockade of KCs with gadolinium chloride (10 mg/kg body weight, 48 and 24 hours pretreatment). KCs were isolated from normal rat livers and activated with zymosan or lipopolysaccharide at different timepoints. This resulted in an increase in Cys-LT production that was not influenced by preincubation with montelukast (1 μM). Infusion of LTC 4 (20 nM) and the thromboxane analog U46619 (0.1 μM) further enhanced portal pressure, indicating additive effects. Treatment with montelukast for 10 days resulted in an impressive reduction in the basal portal pressure and an attenuation of the KC-dependent increase in portal pressure. Conclusion: Activation of isolated KCs produced Cys-LTs. Infusion of Cys-LTs increased portal pressure and, vice versa, treatment with montelukast reduced portal pressure in rat liver cirrhosis. Therefore, montelukast may be of therapeutic benefit for patients with portal hypertension. Copyright © 2010 by the American Association for the Study of Liver Diseases.


Stein S.,University of Zürich | Stein S.,Zurich Center for Integrative Human Physiology | Lohmann C.,University of Zürich | Lohmann C.,Zurich Center for Integrative Human Physiology | And 20 more authors.
European Heart Journal | Year: 2010

Endothelial activation, macrophage infiltration, and foam cell formation are pivotal steps in atherogenesis. Our aim in this study was to analyse the role of SIRT1, a class III deacetylase with important metabolic functions, in plaque macrophages and atherogenesis. Methods and resultsUsing partial SIRT1 deletion in atherosclerotic mice, we demonstrate that SIRT1 protects against atherosclerosis by reducing macrophage foam cell formation. Peritoneal macrophages from heterozygous SIRT1 mice accumulate more oxidized low-density lipoprotein (oxLDL), thereby promoting foam cell formation. Bone marrow-restricted SIRT1 deletion confirmed that SIRT1 function in macrophages is sufficient to decrease atherogenesis. Moreover, we show that SIRT1 reduces the uptake of oxLDL by diminishing the expression of lectin-like oxLDL receptor-1 (Lox-1) via suppression of the NF-B signalling pathway. ConclusionOur findings demonstrate protective effects of SIRT1 in atherogenesis and suggest pharmacological SIRT1 activation as a novel anti-atherosclerotic strategy by reducing macrophage foam cell formation. © 2010 The Author.


PubMed | Hannover Medical School, Institute for Clinical Chemistry, Max Planck Institute of Psychiatry, University of Magdeburg and 3 more.
Type: Journal Article | Journal: Annals of neurology | Year: 2016

Autoantibodies (AB) against N-methyl-D-aspartate receptor subunit NR1 (NMDAR1) are highly seroprevalent in health and disease. Symptomatic relevance may arise upon compromised blood-brain barrier (BBB). However, it remained unknown whether circulating NMDAR1 AB appear in the cerebrospinal fluid (CSF). Of n = 271 subjects with CSF-serum pairs, 26 were NMDAR1 AB seropositive, but only 1 was CSF positive. Contrariwise, tetanus AB (non-brain-binding) were present in serum and CSF of all subjects, with CSF levels higher upon BBB dysfunction. Translational mouse experiments proved the hypothesis that the brain acts as an immunoprecipitator; simultaneous injection of NMDAR1 AB and the non-brain-binding green fluorescent protein AB resulted in high detectability of the former in brain and the latter in CSF.


Drey M.,Friedrich - Alexander - University, Erlangen - Nuremberg | Krieger B.,Friedrich - Alexander - University, Erlangen - Nuremberg | Sieber C.C.,Friedrich - Alexander - University, Erlangen - Nuremberg | Bauer J.M.,Friedrich - Alexander - University, Erlangen - Nuremberg | And 3 more authors.
Journal of the American Medical Directors Association | Year: 2014

Objectives: Sarcopenia, age-related muscle wasting, is associated with increased morbidity and mortality in the affected individuals. The pathogenesis of sarcopenia is not yet fully understood. A multifactorial concept is currently favored. The reduced number of motor units as a potential mechanism of muscle mass loss is explored in the present study. Design: This is a cross-sectional study. Setting: The participants were community-dwelling older adults. Participants: The participants were sarcopenic (75) and nonsarcopenic (74) according to the criteria of the European Working Group on Sarcopenia in Older People aged 65 to 94 years. Measurements: The motor unit number index (MUNIX) of the hypothenar muscle was used to assess the number and size [motor unit size index (MUSIX)] of motor units. Results: The participants with pathologic MUNIX and MUSIX (n= 23) are significantly more frequently sarcopenic (n= 17, P= .029) than nonsarcopenic (n= 6). The participants with pathologic MUNIX and MUSIX (n= 23) had significantly less muscle mass than the nonsarcopenic controls (P < .001). After adjusting for age and sex, only gait speed has shown no difference between the 2 groups. Pearson's correlation coefficient between MUSIX and the reciprocal value of MUNIX is 0.87 (P < .001). Conclusions: Sarcopenia induced by a small number of motoneurons can be identified by applying the MUNIX method to the hypothenar muscle. An enlargement of motor units because of motoneuron loss seems to preserve physical performance. © 2014 American Medical Directors Association, Inc.


Drey M.,Friedrich - Alexander - University, Erlangen - Nuremberg | Zech A.,University of Hamburg | Freiberger E.,Friedrich - Alexander - University, Erlangen - Nuremberg | Bertsch T.,Institute for Clinical Chemistry | And 4 more authors.
Gerontology | Year: 2012

Background: It has been unclear which training mode is most effective and feasible for improving physical performance in the risk group of prefrail community-dwelling older adults. Objective: The purpose of the present study was to compare the effects of strength training (ST) versus power training (PT) on functional performance in prefrail older adults. This study was registered at clinicaltrials.gov as NCT00783159. Methods: 69 community-dwelling older adults (>65 years) who were prefrail according to the definition of Fried were included in a 12-week exercise program. The participants were randomized into an ST group, a PT group and a control group. All participants were supplemented with vitamin D 3 orally before entering the intervention period. The primary outcome was the global score on the Short Physical Performance Battery (SPPB). Secondary outcomes were muscle power, appendicular lean mass (aLM) measured by dual energy X-ray absorptiometry and self-reported functional deficits (Short Form of the Late-Life Function and Disability Instrument, SF-LLFDI). Results: Regarding changes in the SPPB score during the intervention, significant heterogeneity between the groups was observed (p = 0.023). In pair-wise comparisons, participants in both training groups significantly (PT: p = 0.012, ST: 0.009) increased their SPPB score (PT: Δ mean = 0.8, ST: Δ mean = 1.0) compared to the control group, with no statistical difference among training groups (p = 0.301). No statistical differences were found in changes in aLM (p = 0.769), muscle power (p = 0.308) and SF-LLFDI (p = 0.623) between the groups. Muscle power significantly increased (p = 0.017) under vitamin D 3 intake. Conclusions: In prefrail community-dwelling adults, PT is not superior to ST, although both training modes resulted in significant improvements in physical performance. With regard to dropout rates, ST appears to be advantageous compared to PT. The high prevalence of vitamin D 3 deficiency and the slight improvement of physical performance under vitamin D 3 supplementation among study participants underline the relevance of this approach in physical exercise interventions. © 2011 S. Karger AG, Basel.


Hegglin A.,Geriatrische Klinik | Schoch O.D.,Multidisciplinary Center for Sleep Medicine | Korte W.,Institute for Clinical Chemistry | Korte W.,University of Bern | And 4 more authors.
Sleep and Breathing | Year: 2012

Objectives: The aim of this study was to assess serum tumor necrosis factor alpha (TNFA) concentrations 8 months of continuous positive airway pressure (CPAP) therapy. Design: This study used prospective, observational clinical trial. Patients: Sixty-six patients with newly diagnosed sleep apnea syndrome (12 women, 54 men), age 52.3±9.8 (mean±SD) with a body mass index of 29.7±4.4 and an apnea-hypopnea index of 39.7±26.8, were studied. Intervention CPAP was administered for a mean of 7.8± 1.3 months. Measurements and results: TNFA concentrations using an ultrasensitive ELISA assay at baseline and follow-up. TNFA decreased in men with high (5.2±1.7 h/night, -0.46±1.1 ng/l, p=0.001) and with low (2.5±1.0 h/night -0.63±0.77 ng/l, p=0.001) adherence but not in women. Average number of hours of CPAP use correlated positively with delta TNFA (R 2 0.08, p=0.04) Conclusion: Long-term CPAP positively affects TNFA even in men with poor adherence to CPAP. © Springer-Verlag 2011.


Drey M.,Friedrich - Alexander - University, Erlangen - Nuremberg | Sieber C.C.,Friedrich - Alexander - University, Erlangen - Nuremberg | Bauer J.M.,Friedrich - Alexander - University, Erlangen - Nuremberg | Bauer J.M.,Geriatric Center Oldenburg | And 9 more authors.
Experimental Gerontology | Year: 2013

Introduction: Sarcopenia is considered to be an enormous burden for both the individuals affected and for society at large. A multifactorial aetiology of this geriatric syndrome has been discussed. Amongst other pathomechanisms, the degeneration of the neuromuscular junction (NMJ) may be of major relevance. The intact balance between the pro-synaptic agent agrin and the anti-synaptic agent neurotrypsin ensures a structurally and functionally intact NMJ. Excessive cleavage of the native motoneuron-derived agrin by neurotrypsin into a C-terminal Agrin Fragment (CAF) leads to functional disintegration at the NMJ and may consecutively cause sarcopenia. The present study evaluates the hypothesis that CAF serum concentration is a potential marker for the loss of appendicular lean mass in older adults. It also explores how CAF concentration is influenced by vitamin D supplementation and physical exercise. Method: Serum was taken from 69 (47 female) prefrail community-dwelling older adults participating in a training intervention study to measure the CAF concentration using the Western blot technique. All participants were supplemented orally with vitamin D3 before the training intervention period commenced. Appendicular lean mass (aLM) was evaluated by dual energy X-ray absorptiometry. Multiple linear regression models were used to identify factors significantly associated with CAF concentration. Results: Appendicular lean mass, age and sex were identified as significant explanatory factors for CAF concentration. Gait speed and hand grip strength were not associated with CAF concentration. Male participants showed a strong correlation (r = - 0.524) between CAF serum concentration and aLM, whereas this was not the case (r = - 0.219) in females. Vitamin D supplementation and physical exercise were significantly associated with a reduction in CAF concentration, especially in participants with initially high CAF concentrations. Conclusions: C-terminal Agrin Fragment could be a potential marker for identifying sarcopenia in a subgroup of affected individuals in the future. The decline of muscle mass seems to be a CAF-associated process in males, whereas the situation in females may be more complex and multifactorial. CAF concentration is reduced by vitamin D supplementation and physical exercise and therefore suggests a potentially positive effect on NMJs. Further prospective studies of sarcopenic patients in addition to muscle biopsy and electromyographical investigations are planned to verify the external validity of the CAF concept. © 2012 Elsevier Inc.


Boeer K.,Institute for Clinical Chemistry | Reinhofer M.,Institute for Clinical Chemistry | Losche W.,FSU Jena
Platelets | Year: 2010

Wnhole blood aggregometry on the is a simple, fast and standardized method and it is widely used to assess platelet function under antiplatelet therapy. Reference ranges and a cut-off value as a measure of ASA response were established by measuring arachidonic acid induced aggregation (ASPI-test) in healthy volunteers and cardiac patients after and used to classify patients as ASA responders or non-responders. However, assessing the platelet function is highly affected by pre-analytical and analytical conditions and often reduced aggregation by TRAP induced aggregation (TRAP-test) is seen, rendering the samples difficult for interpretation of the ASPI-test and the responder status to ASA. We hypothesised that in this simplified model any preanalytical factor has the same effect on TRAP-testing as on ASPI-testing and that by calculating the ratio between a defined, normal TRAP-test result and the TRAP-test result measured for the individual patient this ratio could be applied to the measured ASPI-test thereby reaching a more valid discrimination between ASA responders and -non-responders. TRAP- and ASPI-test were performed in blood from ASA-treated volunteers and controls on Multiplate™ before an after pneumatic tube delivery as a model to stimulate shear stress induced platelet activation and aggregation. The calculated, normalised ASPI test result after tube delivery did not differ significantly from the initial ASPI test result although tube delivery had a significant impact on the measured ASPI test result. If applied to patients samples a definite judgement on the ASA response status of patients with reduced "general platelet activatability" could be given. Normalisation of the ASPI-test result using the TRAP-test result may provide a method to judge on the ASA response status in patients with decreased initial "general platelet activatability". © 2010 Informa UK Ltd All rights reserved.


Endres K.,Institute for Clinical Chemistry | Fahrenholz F.,Institute for Clinical Chemistry | Lotz J.,Johannes Gutenberg University Mainz | Hiemke C.,Institute for Clinical Chemistry | And 5 more authors.
Neurology | Year: 2014

Objective: We investigated induction of a-secretase A disintegrin and metalloprotease 10 (ADAM10) by the synthetic retinoid acitretin (Neotigason; Actavis, München-Riem, Germany) in patients with mild to moderate Alzheimer disease (AD) via measurement of CSF content of a-secretase-derived amyloid precursor protein (APPs-a). Methods: Twenty-one patients clinically diagnosed with mild to moderate AD received acitretin (30 mg per day) or placebo in a 4-week double-blind study. Primary endpoint was the difference of CSF APPs-a ratios calculated from the APPs-a levels after treatment and at baseline. We monitored safety and tolerability of the treatment. In addition, we assessed biomarkers such as b-amyloid 42 (Ab42) under treatment conditions. Results: The acitretin group showed a significant increase in CSF APPs-a levels compared with the placebo group (difference 0.38, 95% confidence interval 0.03-0.72, p 5 0.035) within this rather short treatment period. The synthetic retinoid acitretin was overall safe and well tolerated. Conclusions: Our pilot study highlights that acitretin is able to enhance the nonamyloidogenic APP processing in human patients. Clinical consequences of this regulation should be investigated in larger and longer trials in patients with AD to evaluate acitretin's potential to serve as a novel therapeutic drug. Classification of evidence: This study provides Class III evidence that in patients with AD, oral acitretin increases CSF APPs-a levels. © 2014 American Academy of Neurology.


Khan N.,Institute for Clinical Chemistry | Khan N.,Kohat University of Science and Technology | Asif A.R.,Institute for Clinical Chemistry
Mediators of Inflammation | Year: 2015

Human gastrointestinal tract is covered by a monolayer of specialized epithelial cells that constitute a protective barrier surface to external toxic and infectious agents along with metabolic and digestive functions. Intercellular junctions, among epithelial cells, such as desmosomes, adherens, gap, and tight junctions (TJs), not only provide mechanical integrity but also limit movement of molecules across the monolayer. TJ is a complex structure composed of approximately 35 different proteins that interact with each other at the apical side of two adjacent epithelial cells. Claudin family proteins are important members of TJ with so far 24 known isoforms in different species. Claudins are structural proteins of TJ that help to control the paracellular movement by forming fence and barrier across the epithelial monolayer. Altered function of claudins is implicated in different form of cancers, inflammatory bowel diseases (IBDs), and leaky diarrhea. Based on their significant role in the molecular architecture of TJ, diversity, and disease association, further understanding about claudin family proteins and their genetic/epigenetic regulators is indispensable. © 2015 Niamat Khan and Abdul R. Asif.

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