Medizin - Open Access LMU - Teil 17/22

Age at menarche and its association with the metabolic syndrome and its components

The metabolic syndrome is a major public health challenge and identifies persons at risk for diabetes and cardiovascular disease. The aim of this study was to examine the association between age at menarche and the metabolic syndrome (IDF and NCEP ATP III classification) and its components. 1536 women aged 32 to 81 years of the German population based KORA F4 study were investigated. Data was collected by standardized interviews, physical examinations, and whole blood and serum measurements....

Complex interaction of sensory and motor signs and symptoms in chronic CRPS.

Spontaneous pain, hyperalgesia as well as sensory abnormalities, autonomic, trophic, and motor disturbances are key features of Complex Regional Pain Syndrome (CRPS). This study was conceived to comprehensively characterize the interaction of these symptoms in 118 patients with chronic upper limb CRPS (duration of disease: 43±23 months). Disease-related stress, depression, and the degree of accompanying motor disability were likewise assessed. Stress and depression were measured by Posttrauma...

Perspectives in Microvascular Fluid Handling: Does the Distribution of Coagulation Factors in Human Myocardium Comply with Plasma Extravasation in Venular Coronary Segments?

Background: Heterogeneity of vascular permeability has been suggested for the coronary system. Whereas arteriolar and capillary segments are tight, plasma proteins pass readily into the interstitial space at venular sites. Fittingly, lymphatic fluid is able to coagulate. However, heart tissue contains high concentrations of tissue factor, presumably enabling bleeding to be stopped immediately in this vital organ. The distribution of pro- and anti-coagulatively active factors in human heart ti...

Concomitant Carcinoma in situ in Cystectomy Specimens Is Not Associated with Clinical Outcomes after Surgery

Objective: The aim of this study was to externally validate the prognostic value of concomitant urothelial carcinoma in situ (CIS) in radical cystectomy (RC) specimens using a large international cohort of bladder cancer patients. Methods: The records of 3,973 patients treated with RC and bilateral lymphadenectomy for urothelial carcinoma of the bladder (UCB) at nine centers worldwide were reviewed. Surgical specimens were evaluated by a genitourinary pathologist at each center. Uni- and mult...

Are Treatment Preferences Relevant in Response to Serotonergic Antidepressants and Cognitive-Behavioral Therapy in Depressed Primary Care Patients? Results from a Randomized Controlled Trial Including a Patients' Choice Arm

Background Little is known about the influence of depressed patients' preferences and expectations about treatments upon treatment outcome We investigated whether better clinical outcome in depressed primary care patients is associated with receiving their preferred treatment Methods Within a randomized placebo-controlled single-centre 10-week trial with 5 arms (sertraline, placebo, cognitive-behavioral group therapy, CBT-G, moderated self-help group control, treatment with sertraline or CBT-...

Constrained pattern of viral evolution in acute and early HCV infection limits viral plasticity.

Cellular immune responses during acute Hepatitis C virus (HCV) and HIV infection are a known correlate of infection outcome. Viral adaptation to these responses via mutation(s) within CD8+ T-cell epitopes allows these viruses to subvert host immune control. This study examined HCV evolution in 21 HCV genotype 1-infected subjects to characterise the level of viral adaptation during acute and early HCV infection. Of the total mutations observed 25% were within described CD8+ T-cell epitopes or ...

Cord blood Vα24-Vβ11 natural killer T cells display a Th2-chemokine receptor profile and cytokine responses

Background: The fetal immune system is characterized by a Th2 bias but it is unclear how the Th2 predominance is established. Natural killer T (NKT) cells are a rare subset of T cells with immune regulatory functions and are already activated in utero. To test the hypothesis that NKT cells are part of the regulatory network that sets the fetal Th2 predominance, percentages of Vα24(+)Vβ11(+) NKT cells expressing Th1/Th2-related chemokine receptors (CKR) were assessed in cord blood. Furthermore...

Coupling of alpha(1)-Adrenoceptors to ERK1/2 in the Human Prostate

Introduction: alpha(1)-Adrenoceptors are considered critical for the regulation of prostatic smooth muscle tone. However, previous studies suggested further alpha(1)-adrenoceptor functions besides contraction. Here, we investigated whether alpha(1)-adrenoceptors in the human prostate may activate extracellular signal-regulated kinases (ERK1/2). Methods: Prostate tissues from patients undergoing radical prostatectomy were stimulated in vitro. Activation of ERK1/2 was assessed by Western blot a...

Arteriogenesis – Molecular Regulation, Pathophysiology and Therapeutics I

Crystal Structures of T. b. rhodesiense Adenosine Kinase Complexed with Inhibitor and Activator: Implications for Catalysis and Hyperactivation

Background: The essential purine salvage pathway of Trypanosoma brucei bears interesting catalytic enzymes for chemotherapeutic intervention of Human African Trypanosomiasis. Unlike mammalian cells, trypanosomes lack de novo purine synthesis and completely rely on salvage from their hosts. One of the key enzymes is adenosine kinase which catalyzes the phosphorylation of ingested adenosine to form adenosine monophosphate (AMP) utilizing adenosine triphosphate (ATP) as the preferred phosphoryl ...

Alpha-Lipoic Acid for the Prevention of Diabetic Macular Edema

Introduction: To evaluate the effect of alpha-lipoic acid (ALA) on the occurrence of diabetic macular edema. Methods: Randomized, double-blind, placebo-controlled, multicenter, multinational study. Patients were randomized to the treatment group with 600 mg ALA per day or the placebo group. Every 6 months stereo fundus photographs, HbA1c levels, and an ophthalmological examination were documented. The primary endpoint was the occurrence of clinically significant macular edema (CSME) within a ...

RANTES/CCL5 and risk for coronary events: results from the MONICA/KORA Augsburg case-cohort, Athero-Express and CARDIoGRAM studies.

The chemokine RANTES (regulated on activation, normal T-cell expressed and secreted)/CCL5 is involved in the pathogenesis of cardiovascular disease in mice, whereas less is known in humans. We hypothesised that its relevance for atherosclerosis should be reflected by associations between CCL5 gene variants, RANTES serum concentrations and protein levels in atherosclerotic plaques and risk for coronary events. We conducted a case-cohort study within the population-based MONICA/KORA Augsburg st...

Fibroblastic reticular cells from lymph nodes attenuate T cell expansion by producing nitric oxide.

Adaptive immune responses are initiated when T cells encounter antigen on dendritic cells (DC) in T zones of secondary lymphoid organs. T zones contain a 3-dimensional scaffold of fibroblastic reticular cells (FRC) but currently it is unclear how FRC influence T cell activation. Here we report that FRC lines and ex vivo FRC inhibit T cell proliferation but not differentiation. FRC share this feature with fibroblasts from non-lymphoid tissues as well as mesenchymal stromal cells. We identified...

Fifty-kDa Hyaluronic Acid Upregulates Some Epidermal Genes without Changing TNF-α Expression in Reconstituted Epidermis

Background: Due to its strong water binding potential, hyaluronic acid (HA) is a well-known active ingredient for cosmetic applications. However, based on its varying molecular size, skin penetration of HA may be limited. Recent studies have demonstrated that low-molecular-weight HA (LMW HA) may show a certain proinflammatory activity. We thus aimed to characterize an LMW-sized HA molecule that combines strong anti-aging abilities with efficient skin penetration but lacks potential proinflamm...

Dendritic Cells in Experimental Renal Inflammation - Part I

Dendritic cells (DCs) are bone marrow-derived professional antigen-presenting cells that act as master regulators of acquired and innate immune responses. While descriptions of cells with dendritic morphology in rodent kidneys date back to the early 1970s, a network of DCs in the mouse kidney has only recently been described. DCs acquire distinct phenotypic and functional characteristics depending on the microenvironment and the disease stages. Concomitantly, their communication with cells of...

Dendritic Cells in Human Renal Inflammation - Part II

Dendritic cells (DCs) are bone marrow-derived professional antigen-presenting cells that act as master regulators of acquired and innate immune responses. Here, we review the available information on their role in human renal inflammation. In the 1980s and early 1990s, major histocompatibility complex class II antigen-(HLA-DR) positive DCs were first described in normal human kidneys and in the interstitium of kidneys from patients with glomerulonephritis. Several DC subtypes were subsequentl...

Associations between stress and migraine and tension-type headache: Results from a school-based study in adolescents from grammar schools in Germany

Introduction: Stress is considered the major contributor to migraine and tension-type headache in adolescents. Previous studies have focused on general stressors, whereas the aim of the present study was to investigate associations between individuals’ stressful experiences and different types of headache. Methods: Adolescents from 10th and 11th grades of grammar schools filled in questionnaires. Stressful experiences were measured with the Trier Inventory of Chronic Stress. Type of headach...

Der junge Krebspatient: Psychosoziale Probleme und Konzepte der Rehabilitation

Gene-disease network analysis reveals functional modules in mendelian, complex and environmental diseases

Scientists have been trying to understand the molecular mechanisms of diseases to design preventive and therapeutic strategies for a long time. For some diseases, it has become evident that it is not enough to obtain a catalogue of the disease-related genes but to uncover how disruptions of molecular networks in the cell give rise to disease phenotypes. Moreover, with the unprecedented wealth of information available, even obtaining such catalogue is extremely difficult. We developed a compr...

Determination of the proteolytic cleavage sites of the amyloid precursor-like protein 2 by the proteases ADAM10, BACE1 and γ-secretase.

Regulated intramembrane proteolysis of the amyloid precursor protein (APP) by the protease activities α-, β- and γ-secretase controls the generation of the neurotoxic amyloid β peptide. APLP2, the amyloid precursor-like protein 2, is a homolog of APP, which shows functional overlap with APP, but lacks an amyloid β domain. Compared to APP, less is known about the proteolytic processing of APLP2, in particular in neurons, and the cleavage sites have not yet been determined. APLP2 is cleaved by ...

Growth Pattern of Untreated Boys with Simple Virilizing Congenital Adrenal Hyperplasia Indicates Relative Androgen Insensitivity during the First Six Months of Life

Context: Mild forms of simple virilizing congenital adrenal hyperplasia (CAH) may be missed in newborn screening. In the pre-newborn-screening era, missed diagnosis of simple virilizing CAH was not infrequent in boys. Elevated adrenal androgens lead to accelerated growth and bone maturation. Traditional treatment of CA H consists of the suppression of ACTH through glucocorticoid replacement, in an attempt to reduce excessive androgen production. Objective: To retrospectively analyze early gro...

Development of a Sandwich ELISA to Measure Exposure to Occupational Cow Hair Allergens

Background: Cow hair and dander are important inducers of occupational allergies in cattle-exposed farmers. To estimate allergen exposure in farming environments, a sensitive enzyme immunoassay was developed to measure cow hair allergens. Methods: A sandwich ELISA was developed using polyclonal rabbit antibodies against a mixture of hair extracts from different cattle breeds. To assess the specificity of the assay, extracts from other mammalian epithelia, mites, molds and grains were tested. ...

Diacylglycerol regulates acute hypoxic pulmonary vasoconstriction via TRPC6

Background: Hypoxic pulmonary vasoconstriction (HPV) is an essential mechanism of the lung that matches blood perfusion to alveolar ventilation to optimize gas exchange. Recently we have demonstrated that acute but not sustained HPV is critically dependent on the classical transient receptor potential 6 (TRPC6) channel. However, the mechanism of TRPC6 activation during acute HPV remains elusive. We hypothesize that a diacylglycerol (DAG)-dependent activation of TRPC6 regulates acute HPV. Met...

AUC-RF: A New Strategy for Genomic Profiling with Random Forest

Objective: Genomic profiling, the use of genetic variants at multiple loci simultaneously for the prediction of disease risk, requires the selection of a set of genetic variants that best predicts disease status. The goal of this work was to provide a new selection algorithm for genomic profiling. Methods: We propose a new algorithm for genomic profiling based on optimizing the area under the receiver operating characteristic curve (AUC) of the random forest (RF). The proposed strategy implem...

Analysis of IL2/IL21 Gene Variants in Cholestatic Liver Diseases Reveals an Association with Primary Sclerosing Cholangitis

Background/Aims: The chromosome 4q27 region harboring IL2 and IL21 is an established risk locus for ulcerative colitis (UC) and various other autoimmune diseases. Considering the strong coincidence of primary sclerosing cholangitis (PSC) with UC and the increased frequency of other autoimmune disorders in patients with primary biliary cirrhosis (PBC), we investigated whether genetic variation in the IL2/IL21 region may also modulate the susceptibility to these two rare cholestatic liver disea...

Differential cathelicidin expression in duodenal and gastric biopsies from Tanzanian and German patients.

Epithelial surfaces such as the gastrointestinal mucosa depend on expression of antimicrobial peptides like cathelicidin for immune defence against pathogens. The mechanisms behind mucosal cathelicidin regulation are incompletely understood. Cathelicidin expression was analysed in duodenal, antral and corpus/fundic mucosal biopsies from African and German patients. Additionally, cathelicidin expression was correlated with Helicobacter pylori (HP) infection and the inflammatory status of the m...

Biliary Bicarbonate Secretion Constitutes a Protective Mechanism against Bile Acid-Induced Injury in Man

Background: Cholangiocytes expose a striking resistance against bile acids: while other cell types, such as hepatocytes, are susceptible to bile acid-induced toxicity and apoptosis already at micromolar concentrations, cholangiocytes are continuously exposed to millimolar concentrations as present in bile. We present a hypothesis suggesting that biliary secretion of HCO(3)(-) in man serves to protect cholangiocytes against bile acid-induced damage by fostering the deprotonation of apolar bile...

Immediate-Type Hypersensitivity to Succinylated Corticosteroids

Background: Despite their frequent use, systemic corticosteroids have rarely elicited immediate-type reactions. Objective: We report two male patients, aged 26 and 70 years, respectively, with severe immediate-type hypersensitivity secondary to the administration of corticosteroids esterified with succinate. Methods: Skin tests, basophil activation tests and challenge tests were performed for diagnostic evaluation. Results: In both patients, immediate-type skin test reactions were found to me...

Analysis of the transcriptional program of developing induced regulatory T cells.

CD25+ regulatory T cells develop in the thymus (nTregs), but may also be generated in the periphery upon stimulation of naive CD4 T cells under appropriate conditions (iTregs). To gain insight into the mechanisms governing iTreg development, we performed longitudinal transcriptional profiling of CD25+ T cells during their differentiation from uncommitted naive CD4 T cells. Microarray analysis of mRNA from CD25+ iTregs early after stimulation revealed expression of genes involved in cell cycle...

Interaction of perceptual grouping and crossmodal temporal capture in tactile apparent-motion.

Previous studies have shown that in tasks requiring participants to report the direction of apparent motion, task-irrelevant mono-beeps can "capture" visual motion perception when the beeps occur temporally close to the visual stimuli. However, the contributions of the relative timing of multimodal events and the event structure, modulating uni- and/or crossmodal perceptual grouping, remain unclear. To examine this question and extend the investigation to the tactile modality, the current exp...

Distribution of country of origin in studies used in Cochrane Reviews.

Inclusion in systematic reviews is one important component in judging the potential impact of clinical studies upon practice and hence the 'value for money' of spending for clinical research. This study aims to quantify the distribution of countries of origin of clinical studies used in Cochrane Reviews (CRs), and to link these data to the size of a country and to its spending on research. Random sample of publications used for CRs published in Issue 1 2008 and of publications used in CRs in...

Label-free 3D visualization of cellular and tissue structures in intact muscle with second and third harmonic generation microscopy.

Second and Third Harmonic Generation (SHG and THG) microscopy is based on optical effects which are induced by specific inherent physical properties of a specimen. As a multi-photon laser scanning approach which is not based on fluorescence it combines the advantages of a label-free technique with restriction of signal generation to the focal plane, thus allowing high resolution 3D reconstruction of image volumes without out-of-focus background several hundred micrometers deep into the tissue...

Calculation of direct antiretroviral treatment costs and potential cost savings by using generics in the German HIV ClinSurv cohort.

BACKGROUND/AIM OF THE STUDY: The study aimed to determine the cost impacts of antiretroviral drugs by analysing a long-term follow-up of direct costs for combined antiretroviral therapy, cART, -regimens in the nationwide long-term observational multi-centre German HIV ClinSurv Cohort. The second aim was to develop potential cost saving strategies by modelling different treatment scenarios. Antiretroviral regimens (ART) from 10,190 HIV-infected patients from 11 participating ClinSurv study ce...

Anti-GBM glomerulonephritis involves IL-1 but is independent of NLRP3/ASC inflammasome-mediated activation of caspase-1.

IL-1β and IL-18 are proinflammatory cytokines that contribute to renal immune complex disease, but whether IL-1β and IL-18 are mediators of intrinsic glomerular inflammation is unknown. In contrast to other cytokines the secretion of IL-1β and IL-18 requires a second stimulus that activates the inflammasome-ASC-caspase-1 pathway to cleave pro-IL-1β and -IL-18 into their mature and secretable forms. As the NLRP3 inflammasome and caspase-1 were shown to contribute to postischemic and postobstru...

CEACAM6 gene variants in inflammatory bowel disease.

The carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) acts as a receptor for adherent-invasive E. coli (AIEC) and its ileal expression is increased in patients with Crohn's disease (CD). Given its contribution to the pathogenesis of CD, we aimed to investigate the role of genetic variants in the CEACAM6 region in patients with inflammatory bowel diseases (IBD). In this study, a total of 2,683 genomic DNA samples (including DNA from 858 CD patients, 475 patients with ulcerat...

Lack of the long pentraxin PTX3 promotes autoimmune lung disease but not glomerulonephritis in murine systemic lupus erythematosus.

The long pentraxin PTX3 has multiple roles in innate immunity. For example, PTX3 regulates C1q binding to pathogens and dead cells and regulates their uptake by phagocytes. It also inhibits P-selectin-mediated recruitment of leukocytes. Both of these mechanisms are known to be involved in autoimmunity and autoimmune tissue injury, e.g. in systemic lupus erythematosus, but a contribution of PTX3 is hypothetical. To evaluate a potential immunoregulatory role of PTX3 in autoimmunity we crossed P...

Aplastic Crisis as Primary Manifestation of Systemic Lupus Erythematosus

Aplastic crisis is an unusual feature of systemic lupus erythematosus (SLE). We report the case of a 54-year-old woman presenting with both (extravascular) Coombs-positive hemolytic anemia and laboratory findings of bone marrow hyporegeneration with concomitant severe neutropenia. A bone marrow biopsy confirmed aplastic crisis. Diagnostic work-up revealed soaring titers of autoantibodies (anti-nuclear, anti-double-stranded DNA, anti-cardiolipin-IgM, and anti-beta 2-glykoprotein-IgM antibodies...

Entrapment of viral capsids in nuclear PML cages is an intrinsic antiviral host defense against varicella-zoster virus.

The herpesviruses, like most other DNA viruses, replicate in the host cell nucleus. Subnuclear domains known as promyelocytic leukemia protein nuclear bodies (PML-NBs), or ND10 bodies, have been implicated in restricting early herpesviral gene expression. These viruses have evolved countermeasures to disperse PML-NBs, as shown in cells infected in vitro, but information about the fate of PML-NBs and their functions in herpesvirus infected cells in vivo is limited. Varicella-zoster virus (VZV)...

Erythema Nodosum Associated with Myelodysplastic Syndrome: A Case Report

Chemo- and Thermosensory Responsiveness of Grueneberg Ganglion Neurons Relies on Cyclic Guanosine Monophosphate Signaling Elements

Neurons of the Grueneberg ganglion (GG) in the anterior nasal region of mouse pups respond to cool temperatures and to a small set of odorants. While the thermosensory reactivity appears to be mediated by elements of a cyclic guanosine monophosphate (cGMP) cascade, the molecular mechanisms underlying the odor-induced responses are unclear. Since odor-responsive GG cells are endowed with elements of a cGMP pathway, specifically the transmembrane guanylyl cyclase subtype GC-G and the cyclic nuc...

Estimates of Outcomes Up to Ten Years after Stroke: Analysis from the Prospective South London Stroke Register

Background: Although stroke is acknowledged as a long-term condition, population estimates of outcomes longer term are lacking. Such estimates would be useful for planning health services and developing research that might ultimately improve outcomes. This burden of disease study provides population-based estimates of outcomes with a focus on disability, cognition, and psychological outcomes up to 10 y after initial stroke event in a multi-ethnic European population. Methods and Findings: Dat...

Ethik und Ökonomie in der Onkologie

Chitin modulates innate immune responses of keratinocytes.

Chitin, after cellulose the second most abundant polysaccharide in nature, is an essential component of exoskeletons of crabs, shrimps and insects and protects these organisms from harsh conditions in their environment. Unexpectedly, chitin has been found to activate innate immune cells and to elicit murine airway inflammation. The skin represents the outer barrier of the human host defense and is in frequent contact with chitin-bearing organisms, such as house-dust mites or flies. The effect...

Missing Heritability in the Tails of Quantitative Traits? A Simulation Study on the Impact of Slightly Altered True Genetic Models

Objective: Genome-wide association studies have identified robust associations between single nucleotide polymorphisms and complex traits. As the proportion of phenotypic variance explained is still limited for most of the traits, larger and larger meta-analyses are being conducted to detect additional associations. Here we investigate the impact of the study design and the underlying assumption about the true genetic effect in a bimodal mixture situation on the power to detect associations. ...

Aerosolized BC-819 inhibits primary but not secondary lung cancer growth.

Despite numerous efforts, drug based treatments for patients suffering from lung cancer remains poor. As a promising alternative, we investigated the therapeutic potential of BC-819 for the treatment of lung cancer in mouse tumor models. BC-819 is a novel plasmid DNA which encodes for the A-fragment of Diphtheria toxin and has previously been shown to successfully inhibit tumor growth in human clinical study of bladder carcinoma. In a first set of experiments, we examined in vitro efficacy of...

NCAM1, TACR1 and NOS Genes and Temperament: A Study on Suicide Attempters and Controls

Suicide, one of the leading causes of death among young adults, seems to be plausibly modulated by both genetic and personality factors. The aim of this study was to dissect the potential association between genetics and temperament in a sample of 111 suicide attempters and 289 healthy controls. We focused on 4 genes previously investigated in association with suicide on the same sample: the nitric oxide synthase 1 and 3 (NOS1 and NOS3), the neuronal cell adhesion molecule 1 (NCAM1), and the ...

Exposure to moderate air pollution during late pregnancy and cord blood cytokine secretion in healthy neonates.

Ambient air pollution can alter cytokine concentrations as shown in vitro and following short-term exposure to high air pollution levels in vivo. Exposure to pollution during late pregnancy has been shown to affect fetal lymphocytic immunophenotypes. However, effects of prenatal exposure to moderate levels of air pollutants on cytokine regulation in cord blood of healthy infants are unknown. In a birth cohort of 265 healthy term-born neonates, we assessed maternal exposure to particles with ...

O-methylguanine-DNA methyltransferase (MGMT) mRNA expression predicts outcome in malignant glioma independent of MGMT promoter methylation

Background: We analyzed prospectively whether MGMT (O(6)-methylguanine-DNA methyltransferase) mRNA expression gains prognostic/predictive impact independent of MGMT promoter methylation in malignant glioma patients undergoing radiotherapy with concomitant and adjuvant temozolomide or temozolomide alone. As DNA-methyltransferases (DNMTs) are the enzymes responsible for setting up and maintaining DNA methylation patterns in eukaryotic cells, we analyzed further, whether MGMT promoter methylatio...

Failure of Urine Dipsticks to Detect Ketosis in Rats

Variants of the human PPARG locus and the susceptibility to chronic periodontitis

Apart from its regulatory function in lipid and glucose metabolism, peroxisome proliferator-activated receptor (PPAR)γ has impact on the regulation of inflammation and bone metabolism. The aim of the study was to investigate the association of five polymorphisms (rs10865710, rs2067819, rs3892175, rs1801282, rs3856806) within the PPARG gene with chronic periodontitis. The study population comprised 402 periodontitis patients and 793 healthy individuals. Genotyping of the PPARG gene polymorphis...