0000000000088224
AUTHOR
Johannes Lotz
Placenta-derived CD95 ligand causes liver damage in hemolysis, elevated liver enzymes, and low platelet count syndrome.
Background & Aims: The HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome is a life-threatening complication during pregnancy. The associated liver disease may be severe, and maternal hepatic complications may progress to the point that transplantation becomes necessary. CD95 (APO-1, Fas)-mediated apoptosis of liver cells is one of the major pathogenic mechanisms during liver disease. The interaction of CD95 with its ligand, CD95L(FasL), induces apoptosis and thus the source of the death-inducing ligand is critical for understanding the pathomechanism of liver damage involving the CD95-system. Methods: Sera from HELLP patients were analyzed and used in cell culture experiment…
Postoperative Reduction of Fibrinolysis as a Prognostic Factor of Fatal Outcome
For the resection of an esophagus carcinoma a mortality rate of 2 to 30% was described, It is still unclear whether an abdominothoracic or transhiatal intervention is superior regarding the outcome. To investigate the prognostic value of fibrinolytic markers, plasmin-α2-antiplasmin (PAP) and D-dimer (DD) values were determined daily in the early postoperative period for 11days. In addition, the course of PAP and DD concentrations was compared with the method of esophagectomy. Of the 28 patients enclosed in the study, 5 died between day 10 and day 34 owing to adult respiratory distress syndrome and septicemia. The PAP and DD concentrations increased in survivors after surgery until day 5 an…
Increased CSF APPs- levels in patients with Alzheimer disease treated with acitretin
Objective: We investigated induction of α-secretase A disintegrin and metalloprotease 10 (ADAM10) by the synthetic retinoid acitretin (Neotigason; Actavis, Munchen-Riem, Germany) in patients with mild to moderate Alzheimer disease (AD) via measurement of CSF content of α-secretase–derived amyloid precursor protein (APPs-α). 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-α ratios calculated from the APPs-α levels after treatment and at baseline. We monitored safety and tolerability of the treatment. In addition, we assessed biomarkers such …
Metabolic Evaluation of 94 Patients 5 to 16 Years After Ileocecal Pouch (Mainz Pouch 1) Continent Urinary Diversion
PURPOSE In continent urinary diversion metabolic disturbances may be encountered in long-term followup. We evaluated metabolic consequences in patients with a minimum followup of 5 years after Mainz pouch 1 urinary diversion.At our institution continent urinary diversion using the ileocecal segment was performed between 1983 and 1995 in 458 patients. A total of 94 patients with an ileocecal pouch for a minimum of 5 years were reevaluated for metabolic changes. Median followup was 9.0 years. Routine laboratory parameters, blood gas analysis, vitamin B12, vitamin D25, cross-laps, bone specific alkaline phosphatase, osteocalcin and propeptide of type I collagen were obtained. Bone density was …
Activation of silent mating type information regulation 2 homolog 1 by human chorionic gonadotropin exerts a therapeutic effect on hepatic injury and inflammation
Incidence and prevalence of inflammatory liver diseases has increased over the last years, but therapeutic options are limited. Pregnancy induces a state of immune tolerance, which can result in spontaneous improvement of clinical symptoms of certain autoimmune diseases including autoimmune hepatitis (AIH). We investigated the immune-suppressive mechanisms of the human pregnancy hormone, chorionic gonadotropin (hCG), in the liver. hCG signaling activates silent mating type information regulation 2 homolog 1 (SIRT1), which deacetylates forkhead box o3 (FOXO3a), leading to repression of proapoptotic gene expression, because the immunosuppressive consequence attributed to the absence of caspas…
Influence of HMG-CoA reductase inhibitors on markers of coagulation, systemic inflammation and soluble cell adhesion.
Abstract Background: Beneath its lipid-lowering properties additional non-lipid effects of statin therapy are discussed. We therefore examined the impact of statins on laboratory markers of coagulation, inflammation and soluble cell adhesion to further explore these effects in 950 hospitalised patients with angiographically proven CAD. Methods and results: Although no significant differences were found in total cholesterol, LDL and HDL and triglyceride levels a statistically lower value in 277 statin-treated patients was found for von Willebrand factor [162(130/224) vs. 208(154/283)%, P =0.0001], leukocyte count [6.9(5.8/8.4) vs. 7.3(6.1/9.4)/nl, P =0.0005], high sensitive CRP [4.3(1.8/10.8…
Mean Platelet Volume and Arterial Stiffness - Clinical Relationship and Common Genetic Variability
AbstractVessel wall stiffening is an important clinical parameter, but it is unknown whether platelets, key elements in the pathogenesis of arterial thrombosis, are associated with arterial stiffness. The present studies sought to determine whether mean platelet volume (MPV), a potential marker of platelet activation, is linked to vascular elasticity as assessed by the augmentation index (AIx), in 15,010 individuals from the population-based Gutenberg Health Study. Multivariable analysis showed that MPV in both males (β 0.776; 95thCI [0.250;1.16]; p = 0.0024) and females (β 0.881[0.328;1.43]; p = 0.0018) is strongly associated with AIx. Individuals with MPV and AIx above the sex-specific me…
Interaction of Human Phagocytes with Pigmentless Aspergillus Conidia
ABSTRACT A defect in the pksP gene of Aspergillus fumigatus is associated with the loss of conidial pigmentation, a profound change of the conidial surface structure, and reduced virulence. The structural change of the conidial surface structure was not observed in similar A. nidulans wA mutants. Our data indicate that the pigment of both species is important for scavenging reactive oxygen species and for protection of conidia against oxidative damage.
Prognostic Influence of Pre-Operative C-Reactive Protein in Node-Negative Breast Cancer Patients
The importance of inflammation is increasingly noticed in cancer. The aim of this study was to analyze the prognostic influence of pre-operative serum C-reactive protein (CRP) in a cohort of 148 lymph node-negative breast cancer patients. The prognostic significance of CRP level for disease-free survival (DFS), metastasis-free survival (MFS) and overall survival (OS) was evaluated using univariate and multivariate Cox regression, also including information on age at diagnosis, tumor size, tumor grade, estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status, proliferation index (Ki67) and molecular subtype, as well as an assessment of the…
Vitamin metabolism in patients with a Mainz pouch I: long-term followup.
We assessed whether creation of the Mainz pouch I, which requires 24 to 36 cm. of terminal ileum and 12 cm. of ascending colon including the ileocecal valve, leads to metabolic disturbances.In 137 patients the levels of vitamins A, B1, B2, B6, B12, D and E, folic and bile acids, ammonia, and intracorpuscular vitamin B12 and folic acid were evaluated and a red blood count was performed. Patients were divided into children and adults, and into 3 groups according to number of years after surgery (2 or less, more than 2 to 4 and more than 4).In all patients the levels of vitamins A, B1, B2, B6, D and E, folic and bile acids, and ammonia as well as red blood count were within normal ranges. In t…
Rheopheresis in patients with ischemic diabetic foot syndrome: results of an open label prospective pilot trial.
: Rheopheresis is a specific application of membrane differential filtration, synonymous with double filtration plasmapheresis, for extracorporeal hemorheotherapy. Safety and efficacy of Rheopheresis for wound healing and skin oxygenation were investigated in patients with ischemic diabetic foot syndrome. Eight patients with type 2 diabetes mellitus and non-healing foot ulcers caused by severe ischemic diabetic foot syndrome were treated by a series of seven Rheopheresis sessions in a time span of 11 weeks. Wound healing had not been detectable under conditions of standardized wound care during at least 2 months. Wound status was classified by its morphology, severity and location, accordi…
Evaluation of an automated chromogenic substrate assay for the rapid determination of hirudin in plasma.
Abstract A fully mechanized chromogenic substrate assay method for the rapid and specific determination of recombinant hirudin (r-hirudin) in citrated plasma on clinical chemistry analyzers (Hitachi 911 and Cobas Mira) is described. In a first step, 12 μl sample volume is mixed with the chromogenic substrate. Due to the almost immediate action of hirudin the inhibitory reaction and the cleavage of the substrate is started simultaneously when bovine thrombin is added in excess. This excludes interferences by antithrombin III or heparin cofactor II. The change in absorbance/min is recorded at 405 nm. The measuring range is about 0.2 – 4.0 mg/l r-hirudin on both analyzers. Precision is charact…
Chronic Diarrhea in a 5-Year-Old Girl: Pitfall in Routine Laboratory Testing with Potentially Severe Consequences
A 5-year-old girl was referred because of recurrent watery diarrhea, abdominal pain, and flatulence. She was the second of 3 children. Her 10-year-old sister was normally developed and healthy. Her younger brother has meningomyelocele and hydrocephalus. At 1 year of age, the patient was admitted to the hospital for recurrent bronchitis, otitis media, food refusal, mild diarrhea, and abdominal distension since weaning. A sweat chloride analysis excluded cystic fibrosis. At that time, the patient’s laboratory results showed increased C-reactive protein (139 mg/L; reference interval, <5 mg/L) and moderate leukocytosis (14.6 × 109/L; reference interval, 4.5–13.5 × 109/L). Values for all other v…
Instruction of haematopoietic lineage choices, evolution of transcriptional landscapes and cancer stem cell hierarchies derived from an AML1-ETO mouse model.
The t(8;21) chromosomal translocation activates aberrant expression of the AML1-ETO (AE) fusion protein and is commonly associated with core binding factor acute myeloid leukaemia (CBF AML). Combining a conditional mouse model that closely resembles the slow evolution and the mosaic AE expression pattern of human t(8;21) CBF AML with global transcriptome sequencing, we find that disease progression was characterized by two principal pathogenic mechanisms. Initially, AE expression modified the lineage potential of haematopoietic stem cells (HSCs), resulting in the selective expansion of the myeloid compartment at the expense of normal erythro- and lymphopoiesis. This lineage skewing was foll…
Heterogeneous presentation of caspr2 antibody‐associated peripheral neuropathy – A case series
Contactin-associated protein 2-like (caspr2) antibodies have been discovered recently. Since then a multitude of patients with caspr2 antibodies presenting with different neurological symptoms have been reported. Here, we describe three patients with caspr2 antibodies with different types of pain/no pain in combination with peripheral neuropathy. The first patient, a 33-year-old woman, presented with erythromelalgia-like pain and autonomic symptoms; the second patient, a 58-year-old man, with paresthesia and pain while walking together with signs of peripheral motor neuron hyperexcitability in combination with optic neuritis, and the third patient, a 74-year-old man, without any pain but wi…
Defining normality in a European multinational cohort: Critical factors influencing the 99th percentile upper reference limit for high sensitivity cardiac troponin I
To establish and critically evaluate the 99th percentile upper reference limit (URL) for high-sensitivity cardiac troponin I (hs-cTnI) in a large healthy European cohort using different selection criteria.1368 presumably healthy individuals from 9 countries were evaluated with surrogate biomarkers for diabetes (glycated hemoglobin [HbA1c]48 mmol/mol), myocardial (B-type natriuretic peptide [BNP]35 pg/mL) and renal dysfunction (estimated glomerular filtration rate [eGFR]60 mL/min/1.73 m(2)), and dyslipidemia to refine the healthy cohort. The 99th percentile URLs were independently determined by the non-parametric and robust methods.The use of biomarker selection criteria resulted in a decrea…
The Influence of Oxidative Stress on Neurological Outcomes in Spontaneous Intracerebral Hemorrhage
Spontaneous intracerebral hemorrhage (ICH) causes, besides the primary brain injury, a secondary brain injury (SBI), which is induced, amongst other things, by oxidative stress (OS) and inflammation, determining the patient’s outcome. This study aims to assess the impact of OS in plasma and cerebrospinal fluid (CSF) on clinical outcomes in patients with ICH. A total of 19 ICH (volume >
Multi-site analytical evaluation of a chemiluminescent magnetic microparticle immunoassay (CMIA) for sirolimus on the Abbott ARCHITECT analyzer.
Objective This study evaluated a new chemiluminescent magnetic microparticle immunoassay (CMIA) for sirolimus on the ARCHITECT analyzer. Design and methods Patient and laboratory proficiency samples were tested at three European sites and one site in the United States. Results The CMIA total %CV's were all < 8% and the Limit of Quantification (LOQ) was < 1.52 ng/mL across the four sites. It cross-reacts to sirolimus metabolites F4 and F5 and showed no hematocrit interference over a range of 25% to 55%. Patient specimen correlations to three LC/MS/MS methods gave R ≥ 0.91 at three sites and mean biases of 14%, 25% and 39%. CMIA patient specimen correlations to the Abbott IMx gave R ≥ 0.94 at…
Alterations in lipid, carbohydrate and iron metabolism in patients with non-alcoholic steatohepatitis (NASH) and metabolic syndrome
NASH (non-alcoholic steatohepatitis) is considered the hepatic manifestation of the metabolic syndrome (MS). We aimed to analyze lipid, carbohydrate, and iron metabolism in NASH.37 patients with MS (17 M/20 F, 51+/-15 years), elevated transaminases; 25 patients had histologically proven NASH (NAS score≥5), 12 patients had toxic background (nonNASH). 37 age, sex, BMI-matched healthy controls. Lipid variables, LDL-subfractions, iron, ferritin, transferrin (T), transferrin saturation (TS), and hepcidin (H) were measured in patients/controls. Oral glucose tolerance tests were performed.NASH patients with steatosis gr. 2 and 3 (33% hepatic fat) had higher sd-LDL (mg/dl) concentrations than patie…
Kappa free light chains in cerebrospinal fluid as markers of intrathecal immunoglobulin synthesis.
Abstract Background: Intrathecal immunoglobulin synthesis is observed in several inflammatory disorders of the central nervous system, but its detection by current laboratory tests is either tedious or relatively insensitive. We assessed the diagnostic accuracy of an assay for κ free light chains (κFLC) in cerebrospinal fluid (CSF) and serum, and compared it with traditional tests for intrathecal immunoglobulin synthesis. Methods: κFLCs were measured by nephelometry in CSF/serum pairs from 112 patients. Samples were excluded if blood contamination of CSF as a result of traumatic lumbar puncture (n = 12) or monoclonal bands in both CSF and serum (n = 5) were present. The remaining sample pai…
Reference Values for a Homogeneous Ferritin Assay and Traceability to the 3rd International Recombinant Standard for Ferritin (NIBSC Code 94/572)
Abstract Reference values for two ferritin assays (Tina-quant®a Ferritin, Enzymun®, both Roche Diagnostics, Mannheim, Germany) were established (136 males and 139 females). To rule out inflammation as well as iron deficiency in the reference population, subjects with the C-reactive protein concentration < 5 mg/l, and zinc protoporphyrin < 40 µmol/mol heme and the soluble transferrin receptor < 3 mg/l were selected. Taking into account latent iron deficiency as well as hereditary hemochromatosis the 5–95 percentile range was as follows: male, 27–365 μg/l; female, 13–148 μg/l for Tina-quant®a and 12–151 μg/l for Enzymun®. The Tinaquant® a Ferritin assay showed a very good correlation…
Cerebrospinal Fluid Tau Protein Levels and <sup>18</sup>F-Fluorodeoxyglucose Positron Emission Tomography in the Differential Diagnosis of Alzheimer’s Disease
<i>Aims:</i> In this study, we aimed to compare cerebrospinal fluid (CSF) levels of total tau (t-tau), phosphorylated tau (p-tau<sub>181</sub>) and positron emission tomography with <sup>18</sup>F-fluorodeoxyglucose (FDG-PET) in the differential diagnosis of Alzheimer’s disease (AD) under clinical conditions. <i>Method:</i> In a cross-sectional, blinded, single-center study, we examined a sample of 75 unselected memory clinic patients with clinical diagnoses of dementia of Alzheimer type (DAT; n = 24), amnestic mild cognitive impairment (MCI; n = 16), other dementias (n = 13) and nondemented controls (n = 22). Discriminative accuracy, sensitiv…
Hepatocellular Hyperplasia, Plasmacytoma Formation, and Extramedullary Hematopoiesis in Interleukin (IL)-6/Soluble IL-6 Receptor Double-Transgenic Mice
Cytokines interact not only with membrane anchored receptors, but also with specific soluble receptors which circulate in the bloodstream. In general, soluble cytokine receptors such as soluble tumor necrosis factor receptor, soluble interleukin 1 receptor, and soluble interleukin 4 receptor compete with their membrane-bound counterparts for the ligands and therefore act as antagonists. In contrast, soluble receptors for cytokines of the interleukin-6 (IL-6) family complex with their ligands act agonistically. Interestingly, the complex of IL-6 and the soluble interleukin 6 receptor (sIL-6R) activates target cells that do not express the membrane-bound IL-6R and therefore cannot respond to …
Distribution of HOMA-IR in a population-based cohort and proposal for reference intervals
Abstract Objectives Insulin resistance (IR) is a hallmark of type 2 diabetes mellitus (DM). The homeostatic model assessment of insulin resistance (HOMA-IR) provides an estimate for IR from fasting glucose and insulin serum concentrations. The aim of this study was to obtain a reference interval for HOMA-IR for a specific insulin immunoassay. Methods The Gutenberg Health Study (GHS) is a population-based, prospective, single-center cohort study in Germany with 15,030 participants aged 35–74 years. Fasting glucose, insulin, and C-peptide were available in 10,340 participants. HOMA-IR was calculated in this group and three reference subgroups with increasingly more stringent inclusion criteri…
Apolipoprotein A1 in Cerebrospinal Fluid Is Insufficient to Distinguish Alzheimer's Disease from Other Dementias in a Naturalistic, Clinical Setting.
Apolipoprotein A1 (ApoA1) is the major protein component of the high-density lipoprotein and involved in cholesterol transport. Disruption of cholesterol homeostasis has been identified as a contributing factor for Alzheimer's disease (AD). Moreover, polymorphisms of ApoA1 have been associated with higher risk of disease onset and cognitive decline. Therefore, ApoA1 has been suggested as a biomarker in AD. Here, we tested a small cohort of AD and non-AD dementia patients and measured levels of ApoA1 in cerebrospinal fluid. Our results indicate that ApoA1 might not be applicable to distinguish AD from other forms of dementia.
Immunonephelometric determination of the C4b-binding protein.
A fully mechanised immunonephelometric method for the rapid and specific determination of C4b-binding protein (C4b-BP) in citrated plasma is described. The method utilizes commercially available rabbit antiserum against human C4b-BP and a nephelometer analyser. A single determination can be performed within 6 min, requiring 80 microliters sample volume. The measuring range is about 10 to 200% of normal C4b-BP. Precision is characterized by intraassay coefficients of variation between 1.5% and 2.8%, and interassay coefficients of variation between 4.0% and 4.6% for the same C4b-BP concentrations. The nephelometry of C4b-BP was correlated with electroimmunodiffusion (Laurell technique; r = 0.…
Neurofilament light chain levels reflect outcome in a patient with glutamic acid decarboxylase 65 antibody–positive autoimmune encephalitis under immune checkpoint inhibitor therapy
Neurological immune-mediated side effects are rare but often severe complications of immune checkpoint inhibitor (ICI) treatment. This report describes a severe case of nivolumab/ipilimumab-associated glutamic acid decarboxylase 65-positive autoimmune encephalitis. It proposes neurofilament light chain levels, a biomarker indicating axonal damage, in the cerebrospinal fluid and serum as a putative novel biomarker for this diagnostically and therapeutically challenging entity with an often unfavorable outcome. Additionally, we provide an overview of previous reports of patients developing autoimmune encephalitis under ICI treatment.
False-Positive LSD Drug Screening Induced by a Mucolytic Medication
Since the early 1990s, the ingestion of lysergic acid diethylamide (LSD) as an inexpensive alternative to amphetamine derivatives has once again become widespread (1)(2). Consequently, screening of LSD has gained importance in clinical routine. The drug screening of a patient with a severe craniocerebral trauma showed a positive LSD screening by the homogeneous immunoassay CEDIA® DAU LSD (Boehringer Mannheim). In spite of the 3-h half-life of LSD in plasma (3), the drug screening remained positive for several days. These samples …
Endothelin-1 modulates the expression of adhesion molecules on fibroblast-like synovial cells (FLS)
Endothelin-1 is known to possess various biological properties. In the present study we have investigated the effects of Endothelin-1 (Et-1) on the expression of adhesion molecules ICAM-1, VCAM-1 and CD-44 by fibroblast-like synoviocytes. Cultured fibroblast-like synoviocytes were treated with Et-1 in the absence or presence of C1306, a specific endothelin-A-receptor antagonist. Cell surface expression of ICAM-1, VCAM-1 and CD-44 was determined by immunofluorescence studies, Cyto-ELISA and FACS-analysis. ICAM-1, VCAM-1 and CD-44 were constitutively expressed on cultured FLS. After incubation with Et-1 the expression of ICAM-1, VCAM-1 and CD-44 increased. The level of expression of adhesion …
C1-ESTERASE INHIBITOR REVERSES FUNCTIONAL CONSEQUENCES OF SUPERIOR MESENTERIC ARTERY ISCHEMIA/REPERFUSION BY LIMITING REPERFUSION INJURY AND RESTORING MICROCIRCULATORY PERFUSION
Activated complement contributes significantly to reperfusion injury after ischemia. This study explores functional consequences of C1-esterase inhibitor (C1-INH) treatment after superior mesenteric artery occlusion (SMAO)/ reperfusion using intravital microscopy. Thirty anesthetized, spontaneously breathing, male Sprague-Dawley rats underwent SMAO for 60 min followed by reperfusion (4 h). C1-esterase inhibitor (100 and 200 IU/kg body weight) or saline (0.9%) was given as a single bolus before reperfusion. Sham-operated animals (n = 10) without SMAO served as controls.Systemichemodynamicsweremonitoredcontinuously,arterial bloodgasesanalyzedintermittently, andleukocyte/ endothelial interacti…