Graz, Austria

The Medical University of Graz is a university in Graz, Austria. Wikipedia.

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Kraigher-Krainer E.,Brigham and Women's Hospital | Shah A.M.,Brigham and Women's Hospital | Gupta D.K.,Brigham and Women's Hospital | Santos A.,Brigham and Women's Hospital | And 8 more authors.
Journal of the American College of Cardiology | Year: 2014

Objectives This study sought to determine the frequency and magnitude of impaired systolic deformation in heart failure with preserved ejection fraction (HFpEF). Background Although diastolic dysfunction is widely considered a key pathophysiologic mediator of HFpEF, the prevalence of concomitant systolic dysfunction has not been clearly defined. Methods We assessed myocardial systolic and diastolic function in 219 HFpEF patients from a contemporary HFpEF clinical trial. Myocardial deformation was assessed using a vendor-independent 2-dimensional speckle-tracking software. The frequency and severity of impaired deformation was assessed in HFpEF, and compared to 50 normal controls free of cardiovascular disease and to 44 age- and sex-matched hypertensive patients with diastolic dysfunction (hypertensive heart disease) but no HF. Among HFpEF patients, clinical, echocardiographic, and biomarker correlates of left ventricular strain were determined. Results The HFpEF patients had preserved left ventricular ejection fraction and evidence of diastolic dysfunction. Compared to both normal controls and hypertensive heart disease patients, the HFpEF patients demonstrated significantly lower longitudinal strain (LS) (-20.0 ± 2.1 and -17.07 ± 2.04 vs. -14.6 ± 3.3, respectively, p < 0.0001 for both) and circumferential strain (CS) (-27.1 ± 3.1 and -30.1 ± 3.5 vs. -22.9 ± 5.9, respectively; p < 0.0001 for both). In HFpEF, both LS and CS were related to LVEF (LS, R = -0.46; p < 0.0001; CS, R = -0.51; p < 0.0001) but not to standard echocardiographic measures of diastolic function (E' or E/E'). Lower LS was modestly associated with higher NT-proBNP, even after adjustment for 10 baseline covariates including LVEF, measures of diastolic function, and LV filling pressure (multivariable adjusted p = 0.001). Conclusions Strain imaging detects impaired systolic function despite preserved global LVEF in HFpEF that may contribute to the pathophysiology of the HFpEF syndrome. (LCZ696 Compared to Valsartan in Patients With Chronic Heart Failure and Preserved Left-ventricular Ejection Fraction; NCT00887588) © 2014 by the American College of Cardiology Foundation.

Heidari N.,Royal London Hospital | Lidder S.,Eastbourne District General Hospital | Grechenig W.,Medical University of Graz | Tesch N.P.,Medical University of Graz | Weinberg A.M.,Medical University of Graz
Journal of Orthopaedic Trauma | Year: 2013

BACKGROUND:: Posterolateral tibial plateau shear fractures often require buttress plating, which can be performed through a posterolateral approach. The purpose of this study was to provide accurate data about the inferior limit of dissection. METHODS:: Forty unpaired cadaver adult lower limbs were used. The anterior tibial artery was identified because it coursed through the interosseous membrane. The perpendicular distance from the lateral joint line and fibula head to this landmark was measured. RESULTS:: The anterior tibial artery coursed through the interosseous membrane at 46.3 ± 9.0 mm (range 27-62 mm) distal to the lateral tibial plateau and 35.7 ± 9.0 mm (range 17-50 mm) distal to the fibula head. CONCLUSIONS:: Displaced posterolateral tibial plateau fractures require anatomic reduction and stabilization with a buttress plate. This can be achieved by gaining access to the posterolateral tibial cortex. The distal limit of this dissection can be as little as 27 mm distal to the lateral tibial plateau. Dissection in this region should be carried out with caution. © 2013 by Lippincott Williams & Wilkins.

Regauer S.,Medical University of Graz | Eberz B.,General Gynecology Practice | Beham-Schmid C.,Medical University of Graz
APMIS | Year: 2015

Mast cell infiltrates in tissues of vulvodynia are common, but they have not been characterized for criteria of neoplastic mast cell disease or correlated with patient's concomitant diseases associated with increased mast cells. Formalin-fixed specimens of 35 patients with vulvodynia were evaluated immunohistochemically with antibodies to CD 3,4,8,20,117c and human mast cell tryptase, and for WHO-criteria of neoplastic mastocytosis (>25% spindled mast cell, CD25 expression, point mutations of the c-kit gene (D816V), and chronically elevated serum tryptase levels). Only 20/35 specimens showed a T-lymphocyte dominant inflammatory infiltrate on HE-stained sections, but all showed mast cells. 4/35 biopsies showed <10 mast cells/mm2, 15/35 specimens 40-60 mast cells/mm2 and 16/35 specimens >60 mast cells/mm2 (average 80/mm2). Control tissue contained typically <10 mast cells/mm2. Spindling, CD25-expression, c-kit gene mutations, or increased serum tryptase levels were not detected. 26/35 (74%) patients had concomitant autoimmune diseases, psoriasis, atopy, various allergies, preceding infections. Independent of the subtype of vulvodynia, the majority of mast cell rich biopsies with >40 mast cells/mm2 were classified as a secondary mast cell disorder reflecting an activated immune system in 75% of vulvodynia patients. Patients with increased mast cells may benefit from medical therapy targeting mast cells. © 2015 APMIS. Published by John Wiley & Sons Ltd.

Campiglio M.,Innsbruck Medical University | Di Biase V.,Innsbruck Medical University | Di Biase V.,Medical University of Graz | Tuluc P.,Innsbruck Medical University | And 2 more authors.
Journal of Cell Science | Year: 2013

Voltage-gated Ca2+ channels are multi-subunit membrane proteins that transduce depolarization into cellular functions such as excitation-contraction coupling in muscle or neurotransmitter release in neurons. The auxiliary b subunits function in membrane targeting of the channel and modulation of its gating properties. However, whether b subunits can reversibly interactwith, and thus differentially modulate, channels in the membrane is still unresolved. In the present study we applied fluorescence recovery after photobleaching (FRAP) of GFP-tagged a1 and b subunits expressed in dysgenic myotubes to study the relative dynamics of these Ca2+ channel subunits for the first time in a native functional signaling complex. Identical fluorescence recovery rates of both subunits indicate stable interactions, distinct recovery rates indicate dynamic interactions. Whereas the skeletal muscle β1a isoform formed stable complexes with CaV1.1 and CaV1.2, the non-skeletal muscle β2a and β4b isoforms dynamically interacted with both a1 subunits. Neither replacing the I-II loop of CaV1.1 with that of CaV2.1, nor deletions inthe proximal I-II loop, known to change the orientation of b relative to the a1 subunit, altered the specific dynamic properties of the b subunits. In contrast, a single residue substitution in the a interaction pocket of β1aM293A increased the FRAP rate threefold. Taken together,these findings indicate that in skeletal muscle triads the homologous β1a subunit forms a stable complex, whereas the heterologous β2a and β4b subunits form dynamic complexes with the Ca2+ channel. The distinct binding properties are not determined by differences in the I-II loop sequences of the a1 subunits, but are intrinsic properties of the b subunit isoforms. © 2013. Published by The Company of Biologists Ltd.

Puchwein P.,Medical University of Graz | Schildhauer T.A.,Medical University of Graz | Schoffmann S.,Medical University of Graz | Heidari N.,Royal London Hospital | And 2 more authors.
Journal of Shoulder and Elbow Surgery | Year: 2012

Background: Anatomically preshaped plates are increasingly used for stabilization of comminuted olecranon and Monteggia fractures. The purposes of this study were to investigate the morphology of the proximal ulna and to compare morphologic findings with geometry of 4 preshaped ulna plates. Materials and methods: Forty human elbows (mean age, 68 years; range, 21-98 years) were measured by 2 independent observers using 64-slice computed tomography scans and 3-dimensional measuring software. Results: Measurements showed a mean dorsal hook angle of 95.3° ± 9.0° (range, 74.7°-110.8°) with gender-specific differences (mean, 92.2° ± 8.1° in men and 98.3° ± 8.9° in women; P = .029); a mean distance from the tip of the olecranon to the proximal edge of the ulna of 24.7 ± 2.7 mm (range, 20-30.5 mm) with gender-specific differences (P = .00068); a mean varus angulation of 14.3° ± 3.6° (range, 5.8°-21.2°); and a mean anterior angulation (proximal ulna dorsal angulation) of 6.2° ± 2.7° (range, 1.0°-11.2°). The investigated plates offered a tolerable (± standard deviation) hook angle in 25% to 68%, an appropriate varus angulation in 0% to 20%, and an adequate anterior angulation in 23% to 88%. The intraclass correlation coefficient was between 0.74 and 0.91. Conclusion: The proximal ulna has a gender-specific and variable morphology. Some currently used anatomically preshaped proximal ulna plates differ significantly from these morphologic findings. In cases where reduction is not exactly possible, application of an "anatomically preshaped" plate may result in poor reduction. Especially in case of Monteggia fractures with instability of the radiocapitellar joint, surgeons could be misguided by plates that do not incorporate anterior angulation, resulting in subluxation of the radial head on the capitellum. © 2012 Journal of Shoulder and Elbow Surgery Board of Trustees.

Leebmann J.,General Hospital | Roeseler E.,Center for Nephrology | Julius U.,University Hospital | Heigl F.,MVZ Kempten Allgaeu | And 8 more authors.
Circulation | Year: 2013

Background-Lipoprotein(a) (Lp(a)) hyperlipoproteinemia is a major risk factor for cardiovascular disease, which is not affected by treatment of other cardiovascular risk factors. This study sought to assess the effect of chronic lipoprotein apheresis (LA) on the incidence of cardiovascular events in patients with progressive cardiovascular disease receiving maximally tolerated lipid-lowering treatment. Methods and Results-In a prospective observational multicenter study, 170 patients were investigated who commenced LA because of Lp(a)-hyperlipoproteinemia and progressive cardiovascular disease. Patients were characterized regarding plasma lipid status, lipid-lowering drug treatment, and variants at the LPA gene locus. The incidence rates of cardiovascular events 2 years before (y-2 and y-1) and prospectively 2 years during LA treatment (y+1, y+2) were compared. The mean age of patients was 51 years at the first cardiovascular event and 57 years at the first LA. Before LA, mean lowdensity lipoprotein cholesterol and Lp(a) were 2.56±1.04 mmolL-1 (99.0±40.1 mgdL-1) and Lp(a) 3.74±1.63 μmolL-1 (104.9±45.7 mgdL-1), respectively. Mean annual rates for major adverse coronary events declined from 0.41 for 2 years before LA to 0.09 for 2 years during LA (P<0.0001). Event rates including all vascular beds declined from 0.61 to 0.16 (P<0.0001). Analysis of single years revealed increasing major adverse coronary event rates from 0.30 to 0.54 (P=0.001) for y-2 to y-1 before LA, decline to 0.14 from y-1 to y+1 (P<0.0001) and to 0.05 from y+1 to y+2 (P=0.014). Conclusions-In patients with Lp(a)-hyperlipoproteinemia, progressive cardiovascular disease, and maximally tolerated lipid-lowering medication, LA effectively lowered the incidence rate of cardiovascular events. © 2013 American Heart Association, Inc.

Becker J.C.,Medical University of Graz | Andersen M.H.,University Hospital Herlev | Schrama D.,Medical University of Graz | Thor Straten P.,University Hospital Herlev
Cancer Immunology, Immunotherapy | Year: 2013

Solid tumors are more than an accumulation of cancer cells. Indeed, cancerous cells create a permissive microenvironment by exploiting non-transformed host cells. Thus, solid tumors rather resemble abnormal organs composed of the cancerous cells itself and the stroma providing the supportive framework. The stroma can be divided into the extracellular matrix consisting of proteoglycans, hyaluronic acid, and fibrous proteins, as well as stromal cells including mesenchymal and immune cells; moreover, it contains various peptide factors and metabolites. Here, we will focus on immune-modulating capacities of the tumor microenvironment. © 2013 Springer-Verlag Berlin Heidelberg.

Leonardis L.,University of Ljubljana | Auer-Grumbach M.,Medical University of Graz | Papic L.,Medical University of Graz | Zidar J.,University of Ljubljana
European Journal of Neurology | Year: 2012

Background and purpose: Mutations in atlastin-1 (ATL-1), a gene known to cause pure, early-onset autosomal dominant hereditary spastic paraplegia SPG3A, have been recently reported to cause hereditary sensory neuropathy I (HSN I). We describe the detailed clinical and electrophysiologic findings in the first family with ulcero-mutilating sensory neuropathy carrying the c. C1065A, p.N355K mutation in ATL-1. Methods: Detailed clinical and electrophysiologic studies were performed in affected and at-risk family members. Motor and sensory nerve conductions studies (NCS) were carried out in upper and lower limbs. ATL-1 was screened for mutations by direct sequencing. Results: Ten patients were found to carry the N355K mutation. With the exception of the two youngest patients, all had trophic skin changes in the feet consisting mainly of painless ulcers. Frequently, amputation of toes, feet, or even more proximal parts of the lower legs became necessary. A variable degree of increased muscle tone was observed in younger patients, whilst some older affected individuals only presented with hyperreflexia of patellar tendon reflexes. NCS revealed signs of an axonal motor and sensory neuropathies. Conclusions: Our family carrying the N355K ATL1 mutation, which was initially diagnosed as HSN I, enlarges the SPG3A phenotype. We therefore suggest that patients with HSN I excluded for more common causes of HSN I, and in particular, affected individuals who exhibit additional pyramidal tract features should also be screened for mutations in ATL1. © 2012 The Author(s) European Journal of Neurology © 2012 EFNS.

Mangge H.,Clinical Institute of Medical | Almer G.,Clinical Institute of Medical | Truschnig-Wilders M.,Clinical Institute of Medical | Schmidt A.,Medical University of Graz | And 2 more authors.
Current Medicinal Chemistry | Year: 2010

The development of atherosclerotic lesions leading to myocardial infarction (MI) or stroke encompasses a cascade of cellular and molecular events that can well be characterized as a chronic immune-mediated inflammation occurring preferentially in the biologic surrounding of the so called metabolic syndrome. Adipokines, chemokines, cytokines, and their receptors are critically involved in the initiation and perpetuation of atherosclerosis, and they play important roles at all levels in the pathogenesis of this disease. Metabolic risk profiles associated with sedentary lifestyle, obesity, especially intra-abdominal fat accumulation, insulin resistance, and dyslipidemia pave the way for a chronic, immunemediated vascular inflammation around vascular lipid deposits. In the present article, the impact of adiponectin, monocyte and T-cell associated cytokines (with emphasis on Neopterin), individual adipose tissue - distribution, and pleiotropic drug effects on the individual course of atherosclerosis and associated cardiovascular disease are reviewed. © 2010 Bentham Science Publishers Ltd.

Manacero S.A.,Clinic Ceneffi | Marschik P.B.,Medical University of Graz | Einspieler C.,Medical University of Graz
Early Human Development | Year: 2012

Background: It continues to be a challenge for clinicians to identify preterm infants likely to experience subsequent neurodevelopmental deficits. The Test of Infant Motor Performance (TIMP) and the assessment of spontaneous general movements (GMs) are the only reliable diagnostic and predictive tools for the functionality of the developing nervous system, if applied before term. Aim: To determine to what extent singular preterm assessments of motor performance can predict the neurodevelopmental outcome in 14-month olds. Methods: Thirty-seven preterm infants born < 34. weeks gestational age were recruited for the study at the NICU of the São Lucas University Hospital, Porto Alegre, RS, Brazil. At 34. weeks, their GMs were assessed; and the Test of Infant Motor Performance (TIMP) was applied. A prospective design was used to examine (A) the association between the GM assessment and the TIMP; and (B) the relation between GMs or the TIMP and the developmental status at 14. months, assessed by means of Alberta Infant Motor Scales (AIMS) and the Pediatric Evaluation of Disability Inventory (PEDI). Results: Nineteen infants (41%) had abnormal GMs; only one scored within the TIMP average range. Hence, GMs and TIMP were not related. Children with cramped-synchronized GMs at 34. weeks preterm had a lower AIMS centile rank than those with poor repertoire or normal GMs. There was a marginal association between cramped-synchronized GMs and a lower PEDI mobility score. Conclusions: A single preterm GM assessment is only fairly to moderately associated with the 14-month motor development. The TIMP is not suitable as a complementary assessment tool at such a young age. © 2011 Elsevier Ltd.

Facchinetti A.,University of Padua | Sparacino G.,University of Padua | Guerra S.,University of Padua | Mader J.K.,Medical University of Graz | And 6 more authors.
Diabetes Care | Year: 2013

OBJECTIVE-Reliability of continuous glucose monitoring (CGM) sensors is key in several applications. In this work we demonstrate that real-time algorithms can render CGM sensors smarter by reducing their uncertainty and inaccuracy and improving their ability to alert for hypo- and hyperglycemic events. RESEARCH DESIGN ANDMETHODS-The smart CGM (sCGM) sensor concept consists of a commercial CGM sensor whose output enters three software modules, able to work in real time, for denoising, enhancement, and prediction. These three software modules were recently presented in the CGM literature, and here we apply them to the Dexcom SEVEN Plus continuous glucosemonitor.We assessed the performance of the sCGM on data collected in two trials, each containing 12 patients with type 1 diabetes. RESULTS-The denoising module improves the smoothness of the CGM time series by an average of ∼57%, the enhancement module reduces the mean absolute relative difference from 15.1 to 10.3%, increases by 12.6% the pairs of values falling in the A-zone of the Clarke error grid, and finally, the prediction module forecasts hypo- and hyperglycemic events an average of 14 min ahead of time. CONCLUSIONS-We have introduced and implemented the sCGM sensor concept. Analysis of data from 24 patients demonstrates that incorporation of suitable real-time signal processing algorithms for denoising, enhancement, and prediction can significantly improve the performance of CGM applications. This can be of great clinical impact for hypo- and hyperglycemic alert generation as well in artificial pancreas devices. © 2013 by the American Diabetes Association.

Tomaschitz A.,Medical University of Graz | Pilz S.,Medical University of Graz | Ritz E.,University of Heidelberg | Meinitzer A.,Medical University of Graz | And 3 more authors.
European Heart Journal | Year: 2010

AimsEvidence has accumulated that elevated aldosterone levels are associated with increased risks of fatal cardiovascular (CV) events. With the present analysis, we aimed at evaluating prospectively whether plasma aldosterone correlates with all-cause and CV disease (CVD) mortality in a large cohort of patients.Methods and resultsMedian plasma aldosterone concentration (PAC) was 79.0 (48.0-124.0) pg/mL (normal range: 30-160) in 3153 patients [median age: 63.5 (56.3-70.6) years; 30.1 women] who had undergone coronary angiography. After a median follow-up of 7.7 (7.2-8.5) years, a total of 716 participants died [22.7; 454 (14.4) due to CV causes and 262 (8.3) due to non-CV causes]. In multivariable Cox proportional hazard analysis, adjusted for age, gender, antihypertensive treatment, and established CV risk factors, PAC levels stratified in quartiles were significantly associated with all-cause and CVD mortality. Compared with the reference (first) PAC quartile, hazard ratios (confidence interval 95) for the fourth, third, and second PAC quartiles were 1.30 (1.02-1.65, P = 0.033), 1.32 (1.04-1.68, P = 0.021), and 1.20 (0.93-1.54, P = 0.155) for total mortality and 1.58 (1.15-2.16, P = 0.004), 1.39 (1.01-1.90, P = 0.041), and 1.63 (1.20-2.20, P = 0.002) for CVD mortality, respectively. Analyses for specific causes of CV death revealed strong associations between PAC levels and higher risk for fatal stroke and sudden cardiac death. Conclusion In a large cohort of patients scheduled for coronary angiography, variation in PAC levels within the normal range is associated with increased all-cause and CVD mortality independent of major established CV risk factors. © 2009 The Author.

Bentley M.,University of Montana | Nycz D.C.,University of Montana | Joglekar A.,University of Michigan | Joglekar A.,Evolvus Inc. | And 4 more authors.
Molecular Biology of the Cell | Year: 2010

The significance and extent of Ca2+ regulation of the biosynthetic secretory pathway have been difficult to establish, and our knowledge of regulatory relationships integrating Ca2+ with vesicle coats and function is rudimentary. Here, we investigated potential roles and mechanisms of luminal Ca2+ in the early secretory pathway. Specific depletion of luminal Ca2+ in living normal rat kidney cells using cyclopiazonic acid (CPA) resulted in the extreme expansion of vesicular tubular cluster (VTC) elements. Consistent with this, a suppressive role for vesicle-associated Ca2+ in COPII vesicle homotypic fusion was demonstrated in vitro using Ca2+ chelators. The EF-hand-containing protein apoptosis-linked gene 2 (ALG-2), previously implicated in the stabilization of sec31 at endoplasmic reticulum exit sites, inhibited COPII vesicle fusion in a Ca2+-requiring manner, suggesting that ALG-2 may be a sensor for the effects of vesicular Ca2+ on homotypic fusion. Immunoisolation established that Ca2+ chelation inhibits and ALG-2 specifically favors residual retention of the COPII outer shell protein sec31 on pre-Golgi fusion intermediates. We conclude that vesicle-associated Ca 2+, acting through ALG-2, favors the retention of residual coat molecules that seem to suppress membrane fusion. We propose that in cells, these Ca2+-dependent mechanisms temporally regulate COPII vesicle interactions, VTC biogenesis, cargo sorting, and VTC maturation. © 2010 by The American Society for Cell Biology.

De Boer R.A.,University of Groningen | Edelmann F.,University of Gottingen | Edelmann F.,German Center for Cardiovascular Research | Cohen-Solal A.,University Paris Diderot | And 4 more authors.
European Journal of Heart Failure | Year: 2013

In the last decades it has been appreciated that many patients with heart failure (HF) suffer from HF with preserved ejection fraction (HFpEF). The diagnosis and treatment of HFpEF is difficult, as we lack specific markers of the disease and no specific treatments have been identified. Galectin-3 has a strong relationship to several aspects of the pathophysiology of HF, especially myocardial fibrosis, the transition from compensated to decompensated HF, and co-morbidities such as renal disease and diabetes. Many of these traits are very commonly observed in patients with HFpEF, and this suggests that galectin-3 may be particularly important and useful in the study of HFpEF. This review summarizes our knowledge of the role of galectin-3 in fibrosis, specifically in experimental models of HF and HFpEF. Galectin-3 may be a marker and also a causal factor, and experimental studies suggested that galectin-3 may be a target for therapy in HFpEF. The detrimental effects of aldosterone may, in part, be conferred via galectin-3, and there are data to suggest that aldosterone blockers are of more benefit in patients with high levels of galectin-3. Furthermore, the relationship of galectin-3 to clinical correlates of developing HFpEF in human subjects is discussed, and the association between increased levels of galectin-3 and new-onset HF and mortality in the general population is highlighted. Additionally, the usefulness of galectin-3 in patients with established HFpEF is described. We conclude that galectin-3 may be useful for early detection, phenotyping, risk stratification, and therapeutic targeting of individuals with early or established HFpEF in which fibrosis is a major contributor to the disease. Finally, we propose areas of further research that should validate the role of galectin-3 in HFpEF. © 2013 Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2013. For permissions please email:

Pilz S.,Medical University of Graz | Tomaschitz A.,Medical University of Graz | Drechsler C.,University of Würzburg | Dekker J.M.,VU University Amsterdam | Marz W.,Medical University of Graz
Molecular Nutrition and Food Research | Year: 2010

Vitamin D deficiency is common among patients with myocardial diseases because sun-induced vitamin D production in the skin and dietary intake of vitamin D is often insufficient. Knockout mice for the vitamin D receptor develop myocardial hypertrophy and dysfunction. It has also been shown that children with rickets who suffered from severe heart failure could be successfully treated with supplementation of vitamin D plus calcium. In adults, almost all patients with heart failure exhibit reduced 25-hydroxyvitamin D levels, which are used to classify the vitamin D status. In prospective studies, vitamin D deficiency was an independent risk factor for mortality, deaths due to heart failure and sudden cardiac death. Several vitamin D effects on the electrophysiology, contractility, and structure of the heart suggest that vitamin D deficiency might be a causal factor for myocardial diseases. Data from interventional trials, however, are rare and urgently needed to elucidate whether vitamin D supplementation is useful for the treatment of myocardial diseases. In our opinion, the current knowledge of the beneficial effects of vitamin D on myocardial and overall health strongly argue for vitamin D supplementation in all vitamin D-deficient patients with or at high risk for myocardial diseases. © 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Hartmann H.,Hannover Medical School | Jakobs C.,VU University Amsterdam | Plecko B.,Medical University of Graz
Developmental Medicine and Child Neurology | Year: 2011

Pyridoxine-dependent epilepsy (PDE) is a treatable inborn error of metabolism with autosomal recessive inheritance. Antenatal and postnatal prophylactic administration of pyridoxine has been recommended to improve the developmental outcome in possible future pregnancies. We report on a male offspring of a second pregnancy at risk for PDE. While on prophylactic treatment with oral pyridoxine, the newborn developed encephalopathy and status epilepticus at age 14days. Seizures did not respond to parenteral pyridoxine and additional treatment with folinic acid. After treatment was changed to pyridoxal 5'-phosphate, the infant's condition improved. Antiquitin deficiency was excluded by biochemical and molecular genetic testing, and cofactor treatment was stopped on day26. He has since remained seizure-free with normal psychomotor development. In healthy newborns, high-dose treatment with pyridoxine may result in increased rather than decreased neuroexcitability. Postnatal prophylactic pyridoxine treatment of fetuses and neonates at risk for PDE should be limited to the shortest possible time, by either prenatal diagnosis or immediate postnatal biochemical and genetic testing. © The Authors. Developmental Medicine & Child Neurology © 2011 Mac Keith Press.

Hartler J.,Austrian Center of Industrial Biotechnology | Tharakan R.,Johns Hopkins University | Kofeler H.C.,Medical University of Graz | Thallinger G.G.,Austrian Center of Industrial Biotechnology
Briefings in Bioinformatics | Year: 2013

Lipidomics, the systematic study of the lipid composition of a cell or tissue, is an invaluable ccomplement to knowledge gained by genomics and proteomics research. Mass spectrometry provides a means to detect hundreds of lipids in parallel, and this includes low abundance species of lipids. Nevertheless, frequently occurring isobaric and isomeric lipid species complicate lipidomics analyses from an analytical and bioinformatics perspective. Various MS/MS strategies have evolved to resolve ambiguous identifications of lipid species, and these strategies have been supported by corresponding bioinformatics analysis tools. This review intends to familiarize readers with available bioinformatics MS/MS analysis tools and databases, the structural information obtainable from these, and their applicability to different MS/MS strategies. Finally, future challenges in detecting double bond positions are investigated from a bioinformatics perspective. © The Author 2012. Published by Oxford University Press.

Aberer W.,Medical University of Graz | Maurer M.,Charité - Medical University of Berlin | Reshef A.,Clinical Immunology and Angioedema Unit | Longhurst H.,Barts and the London Hospital | And 5 more authors.
Allergy: European Journal of Allergy and Clinical Immunology | Year: 2014

Background: Historically, treatment for hereditary angioedema (HAE) attacks has been administered by healthcare professionals (HCPs). Patient self-administration could reduce delays between symptom onset and treatment, and attack burden. The primary objective was to assess the safety of self-administered icatibant in patients with HAE type I or II. Secondary objectives included patient convenience and clinical efficacy of self-administration. Methods: In this phase IIIb, open-label, multicenter study, adult patients were trained to self-administer a single 30-mg icatibant subcutaneous injection to treat their next attack. Icatibant-naïve patients were treated by an HCP prior to self-administration. Evaluations included adverse event (AE) reporting, a validated questionnaire for convenience, and visual analog scale for efficacy. Results: A total of 151 patients were enrolled; 104 had an attack requiring treatment during the study, and 97 patients (19 naïve) were included in the self-administration cohort. Recurrence or worsening of HAE symptoms (22 of 97) was the most commonly reported AE; rescue medications including icatibant (N = 3) and C1-inhibitor concentrate (N = 6) were used in 13 cases. Overall, 89 of 97 patients used a single injection of icatibant. No serious AEs or hospitalizations were reported. Most patients (91.7%) found self-administration preferable to administration in the clinic. The median time to symptom relief (3.8 h) was comparable with results from controlled trials of icatibant. Conclusions: With appropriate training, patients were successfully able to recognize HAE attacks and decide when to self-administer icatibant. This, coupled with the patient-reported high degree of satisfaction, convenience and ease of use supports the adoption of icatibant self-administration in clinical practice. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Fritz J.S.,Pulmonary | Fritz J.S.,University of Pennsylvania | Blair C.,Gilead Sciences Inc. | Oudiz R.J.,University of California at Los Angeles | And 7 more authors.
Chest | Year: 2013

Background: Six-minute walk distance (6MWD) and brain natriuretic peptide (BNP) levels at baseline and after initiation of treatment have been associated with survival in patients with pulmonary arterial hypertension. Our objective was to determine the individual and additive ability of pretreatment and posttreatment 6MWD and BNP to discriminate 2-year survival in patients with pulmonary arterial hypertension. Methods: We included patients enrolled in two randomized clinical trials of ambrisentan who had 2-year follow-up (N 5 370). 6MWD and BNP were assessed before and after 12 weeks of treatment. Receiver operating characteristic curve analyses were performed to identify optimal cutoffs that defi ned subgroups with a high 2-year mortality. Classifi cation and regression tree analysis was used to determine the incremental prognostic value of combined assessments. Results: 6MWD at baseline and after 12 weeks of therapy were similarly discriminatory of 2-year survival (c-statistics 5 0.77 [95% CI 0.70-0.84] and 0.82 [95% CI 0.75-0.88], respectively), whereas change in 6MWD from baseline to week 12 was not discriminating. The same observation was true of BNP at baseline and after 12 weeks of therapy (c-statistics 5 0.68 [95% CI 0.60-0.76] and 0.74 [95% CI 0.66-0.82], respectively). After consideration of baseline 6MWD, there was no prognostic information added by the week 12 6MWD or BNP at either time point. Conclusions: 6MWD and BNP values at baseline or week 12 identifi ed a population with an elevated risk of death at 2 years. A repeat assessment of 6MWD or BNP after 12 weeks of ambrisentan therapy did not provide additional prognostic information beyond that obtained from baseline values. © 2013 American College of Chest Physicians.

Hoffmann J.,Ludwig Boltzmann Research Institute | Wilhelm J.,Justus Liebig University | Marsh L.M.,Ludwig Boltzmann Research Institute | Ghanim B.,Ludwig Boltzmann Research Institute | And 7 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2014

Rationale: The development of pulmonary hypertension (PH) in patients with idiopathic pulmonary fibrosis (IPF) or chronic obstructive pulmonary disease (COPD) is associated with increased morbidity. Objectives: To elucidate whether vascular remodeling in a wellcharacterized PH-COPD and PH-IPF patient cohort results from similar or divergent molecular changes. Methods: Vascular remodeling of donor, PH-COPD, and PH-IPF pulmonary arteries was assessed. Laser capture microdissected pulmonary artery profiles in combination with whole genome microarrays were performed. Measurements and Main Results: Pulmonary arteries from patients with COPD and IPF with PH exhibited remodeling of vascular layers and reduction of lumen area. Pathway analyses comparing normalized gene expression profiles obtained from patients with PH-IPF or PH-COPD revealed the retinol and extracellular matrix (ECM) receptor interaction to be the most perturbed processes. Within the ECM-receptor pathway, differential regulation of 5 out of the top 10 results (collagen, type III, α-1; tenascin C; collagen, type VI, α-3; thrombospondin 2; and von Willebrand factor) were verified by real-time polymerase chain reaction and immunohistochemical staining. Conclusions: Despite clinical and histologic vascular remodeling in all patients with PH-COPD and PH-IPF, differential gene expression pattern was present in pulmonary artery profiles. Several genes involved in retinol metabolism and ECM receptor interaction enable discrimination of vascular remodeling in PH-IPF or PH-COPD. This suggests that pulmonary arterial remodeling in PH-COPD and PHIPF is caused by different molecular mechanisms and may require specific therapeutic options. Copyright © 2014 by the American Thoracic Society.

Wehr E.,Medical University of Graz | Pilz S.,Medical University of Graz | Boehm B.O.,University of Ulm | Marz W.,University of Heidelberg | Obermayer-Pietsch B.,Medical University of Graz
Obesity | Year: 2011

Lipid accumulation product (LAP) is an emerging cardiovascular risk factor, which is calculated from waist circumference (WC) and triglyceride (TG) levels. The aim of this study was to elucidate the relationship between LAP and cardiovascular mortality as well as the presence of type 2 diabetes with respect to gender-specific differences. We determined WC and fasting TG levels and the cardiovascular and metabolic phenotypes coronary artery disease (CAD), hypertension, metabolic syndrome, and diabetes mellitus in 2,279 men and 875 postmenopausal women who were routinely referred to coronary angiography. The LAP was calculated as (WC (cm)-65) × (TG (mmol/l)) for men and as (WC (cm)-58) × (TG (mmol/l)) for women. LAP levels were independently associated with congestive heart failure mortality in all postmenopausal women and with all-cause mortality in diabetic postmenopausal women but not in men. Multivariable-adjusted hazard ratios (with 95% confidence intervals) for all-cause, cardiovascular, and congestive heart failure mortality in the third compared to the first LAP tertile were 4.28 (1.94-9.44; P<0.001), 3.47 (1.28-9.40; P = 0.015), and 10.77 (1.21-95.88; P = 0.033), respectively, in normal weight postmenopausal women, whereas no significant associations were found in men. LAP levels were highly associated with type 2 diabetes in all subjects, postmenopausal women, and men. High LAP values are predictive of mortality independently of other cardiovascular risk factors in normal weight and diabetic postmenopausal women but not in men. Type 2 diabetes (T2DM) was highly associated with LAP in women and men. Our study validates an inexpensive and simple risk profiling that may allow identifying postmenopausal women at high cardiovascular risk. © 2011 The Obesity Society.

Filippi M.,Vita-Salute San Raffaele University | Rocca M.A.,Vita-Salute San Raffaele University | De Stefano N.,University of Siena | Enzinger C.,Medical University of Graz | And 4 more authors.
Archives of Neurology | Year: 2011

Magnetic resonance imaging (MRI) is sensitive to focal multiple sclerosis (MS) lesions. For this reason, conventional MRI measures of the burden of disease derived from dual-echo, fluid-attenuated inversion recovery and postcontrast T1-weighted sequences are regularly used to monitor disease course in patients with confirmed MS and have been included in the diagnostic workup of patients in whom MS is suspected. Other quantitative magnetic resonance (MR)-based techniques with a higher pathological specificity (including magnetization transfer-MRI, diffusion tensor-MRI, and proton MR spectroscopy) have been extensively applied to measure disease burden within focal visible lesions and in the normal-appearing white matter and gray matter of MS patients at different stages of the disease. These methods, combined with functional imaging techniques, are progressively improving our understanding of the factors associated with MS evolution. More recently, the application of new imaging modalities capable of measuring pathological processes related to the disease that have been neglected in the past (eg, iron deposition and perfusion abnormalities) and the advent of high- and ultrahigh-field magnets have provided further insight into the pathobiological features of MS. After a brief summary of the main results obtained from the established and emerging MR methods, this review discusses the steps needed before the latter become suitable for widespread use in the MS research community. ©2011 American Medical Association. All rights reserved.

Hankey G.J.,Royal Perth Hospital | Eikelboom J.W.,McMaster University | Yi Q.,National Epidemiology and Surveillance | Lees K.R.,University of Glasgow | And 8 more authors.
The Lancet Neurology | Year: 2012

Background: Previous studies have suggested that any benefits of folic acid-based therapy to lower serum homocysteine in prevention of cardiovascular events might be offset by concomitant use of antiplatelet therapy. We aimed to establish whether there is an interaction between antiplatelet therapy and the effects of folic acid-based homocysteine-lowering therapy on major vascular events in patients with stroke or transient ischaemic attack enrolled in the vitamins to prevent stroke (VITATOPS) trial. Methods: In the VITATOPS trial, 8164 patients with recent stroke or transient ischaemic attack were randomly allocated to double-blind treatment with one tablet daily of placebo or B vitamins (2 mg folic acid, 25 mg vitamin B6, and 500 μg vitamin B12) and followed up for a median 3·4 years (IQR 2·0-5·5) for the primary composite outcome of stroke, myocardial infarction, or death from vascular causes. In our post-hoc analysis of the interaction between antiplatelet therapy and the effects of treatment with B vitamins on the primary outcome, we used Cox proportional hazards regression before and after adjusting for imbalances in baseline prognostic factors in participants who were and were not taking antiplatelet drugs at baseline and in participants assigned to receive B vitamins or placebo. We also assessed the interaction in different subgroups of patients and different secondary outcomes. The VITATOPS trial is registered with, number NCT00097669, and Current Controlled Trials, number ISRCTN74743444. Findings: At baseline, 6609 patients were taking antiplatelet therapy and 1463 were not. Patients not receiving antiplatelet therapy were more likely to be younger, east Asian, and disabled, to have a haemorrhagic stroke or cardioembolic ischaemic stroke, and to have a history of hypertension or atrial fibrillation. They were less likely to be smokers and to have a history of peripheral artery disease, hypercholesterolaemia, diabetes, ischaemic heart disease, and a revascularisation procedure. Of the participants taking antiplatelet drugs at baseline, B vitamins had no significant effect on the primary outcome (488 patients in the B-vitamins group [15%] vs 519 in the placebo group [16%]; hazard ratio [HR] 0·94, 95% CI 0·83-1·07). By contrast, of the participants not taking antiplatelet drugs at baseline, B vitamins had a significant effect on the primary outcome (123 in the B-vitamins group [17%] vs 153 in the placebo group [21%]; HR 0·76, 0·60-0·96). The interaction between antiplatelet therapy and the effect of B vitamins on the primary outcome was significant after adjusting for imbalance in the baseline variables (adjusted p for interaction=0·0204). Interpretation: Our findings support the hypothesis that antiplatelet therapy modifies the potential benefits of lowering homocysteine with B-vitamin supplementation in the secondary prevention of major vascular events. If validated, B vitamins might have a role in the prevention of ischaemic events in high-risk individuals with an allergy, intolerance, or lack of indication for antiplatelet therapy. Funding: Australia National Health and Medical Research Council, UK Medical Research Council, Singapore Biomedical Research Council, and Singapore National Medical Research Council. © 2012 Elsevier Ltd.

Pilz S.,Medical University of Graz | Tomaschitz A.,Medical University of Graz | Drechsler C.,University of Würzburg | Ritz E.,University of Heidelberg | And 3 more authors.
European Heart Journal | Year: 2010

Aims Elevated parathyroid hormone (PTH) levels have been associated with increased cardiovascular risk in the general population. We aimed to elucidate whether PTH levels are associated with mortality and fatal cardiovascular events in patients referred for coronary angiography. Methods and results Intact PTH was measured in 3232 Caucasian patients from the LUdwigshafen RIsk and Cardiovascular Health (LURIC) study, who underwent coronary angiography at baseline (1997-2000). During a median follow-up time of 7.7 years, 742 patients died including 467 deaths due to cardiovascular causes. Unadjusted Cox proportional hazard ratios (HRs) (with 95 confidence intervals) in the fourth when compared to the first PTH quartile were 2.13 (1.75-2.60) for all-cause and 2.47 (1.92-3.17) for cardiovascular mortality. After adjustments for common cardiovascular risk factors, these HRs remained significant with 1.71 (1.39-2.10) for all-cause and 2.02 (1.55-2.63) for cardiovascular mortality. Among specific cardiovascular events we observed a particularly strong association of PTH with sudden cardiac death (SCD). The adjusted HR for SCD in the first vs. the fourth PTH quartile was 2.68 (1.71-4.22). Conclusion Our results among patients undergoing coronary angiography show that PTH levels are an independent risk factor for mortality and cardiovascular events warranting further studies to evaluate whether PTH modifying treatments reduce cardiovascular risk. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2010.

Dejaco C.,Medical University of Graz | Duftner C.,General Hospital of Kufstein | Wipfler-Freissmuth E.,Hospital of the Barmherzigen Bruder Marschallgasse | Weiss H.,General Hospital of the Elisabethinen | And 2 more authors.
Arthritis Care and Research | Year: 2013

Objective To compare ultrasound-verified joint inflammation between elderly-onset rheumatoid arthritis (EORA) and younger-onset rheumatoid arthritis (YORA) patients. Methods We conducted a retrospective analysis of 145 consecutive rheumatoid arthritis patients routinely assessed by sonography of wrists, metacarpophalangeal joints, and proximal interphalangeal joints, including semiquantitative scoring of synovial hypertrophy/effusion (SH/E) and power Doppler (PD) signals. Global ultrasound (GU) scores were calculated adding SH/E and PD results. EORA was defined by disease onset at age ≥60 years. Number of tender joints and swollen joints, global assessment of disease activity by physician or patient, Disease Activity Score in 28 joints (DAS28), Clinical Disease Activity Index (CDAI), and Simplified Disease Activity Index (SDAI) scores were recorded. Respective values for disease activity were accounted for in group comparisons using SPSS statistical software (version 18.0). Results Seventy patients were diagnosed with EORA (mean ± SD age 71.0 ± 7.3 years, 81.4% women) and 75 patients with YORA (mean ± SD age 46.8 ± 10.2 years, 86.7% women). EORA patients had higher GU scores (median 18.5 [interquartile range (IQR) 17.0] versus 12.0 [IQR 15.0], P = 0.009) and SH/E scores (median 12.0 [IQR 10.0] versus median 9.0 [IQR 9.0], P = 0.004) than patients with YORA. Patients with EORA were more likely to show PD signals in at least 1 joint than YORA patients (85% versus 72%; odds ratio 3.9 [95% confidence interval 1.3-11.5], P = 0.015). DAS28, CDAI, and SDAI scores did not differ between the groups. The sonographic pattern of joint involvement was similar in both groups, with active inflammation most commonly presenting at the wrists. Conclusion Ultrasound examination indicated higher inflammatory burden in EORA patients than in YORA patients despite similar clinical disease activity. © 2013 by the American College of Rheumatology.

Wehr E.,Medical University of Graz | Pilz S.,Medical University of Graz | Boehm B.O.,University of Ulm | Mrz W.,Medical University of Graz | And 2 more authors.
European Journal of Heart Failure | Year: 2011

Aims Accumulating evidence suggests that androgen deficiency is associated with cardiovascular disease. We aimed at evaluating whether total testosterone (TT) and free testosterone (FT) are associated with specific cardiovascular events. Methods and resultsWe measured TT and sex-hormone-binding globulin levels in 2078 men who were routinely referred for coronary angiography between 1997 and 2000. Free testosterone was calculated according to Vermeulen. Main outcome measures were Cox proportional hazard ratios (HRs) for sudden cardiac death, fatal myocardial infarction, death from congestive heart failure (CHF), as well as other cardiac deaths according to quartiles of TT and FT. The median follow-up time was 7.7 years. Multivariable adjusted HRs (with 95 confidence intervals) in the fourth compared with the first FT quartile and per 1 SD increase in FT for CHF mortality were 0.38 (0.170.87) and 0.37 (0.150.89), respectively. We observed no independent significant association of FT with sudden cardiac death, fatal myocardial infarction, or other cardiac death. There was no independent association of TT levels with cardiovascular events or cardiac disease. Conclusion Low levels of FT are independently associated with increased CHF mortality. © 2011 The Author.

Langsenlehner T.,Medical University of Graz | Renner W.,Medical University of Graz | Gerger A.,Medical University of Graz | Hofmann G.,Medical University of Graz | And 2 more authors.
Radiotherapy and Oncology | Year: 2011

Background and purpose: Polymorphisms in genes responsible for DNA damage signaling and repair might modulate DNA repair capacity and, therefore, affect cell and tissue response to radiation and influence individual radiosensitivity. The purpose of the present prospective investigation was to evaluate the association of single nucleotide polymorphisms in XRCC1 with radiation-induced late side effects in prostate cancer patients treated with radiotherapy. Material and methods: To analyze the role of XRCC1 polymorphisms for late toxicity 603 participants from the Austrian PROCAGENE study treated with three-dimensional conformal radiotherapy were included in the present investigation. Three non-synonymous candidate polymorphisms in the X-ray repair cross-complementing group 1 (XRCC1) gene (Arg194Trp; Arg280His; Arg399Gln) were selected and determined by 5́-nuclease (TaqMan) assays. Results: Within a median follow-up time of 35 months, 91 patients (15.7%) developed high-grade late toxicities (defined as late bladder and/or rectal toxicity RTOG ≥ 2). In a Kaplan-Meier analysis, carriers of the XRCC1 Arg280His polymorphism were at decreased risk of high-grade late toxicity (p = 0.022), in multivariate analysis including clinical and dosimetric parameters as potential confounders the XRCC1 Arg280His polymorphism remained a significant predictor for high-grade late toxicity (HR = 0.221, 95% CI 0.051-0.956; p = 0.043). No significant associations were found for the remaining polymorphisms. Conclusions: We conclude that the XRCC1 Arg280His polymorphism may be protective against the development of high-grade late toxicity after radiotherapy in prostate cancer patients. © 2011 Elsevier Ireland Ltd. All rights reserved.

Ljubojevic S.,Medical University of Graz | Bers D.M.,University of California at Davis
Journal of Cardiovascular Pharmacology | Year: 2015

Calcium (Ca2+) is a universal second messenger involved in the regulation of various cellular processes, including electrical signaling, contraction, secretion, memory, gene transcription, and cell death. In heart, Ca2+ governs cardiomyocyte contraction, is central in electrophysiological properties, and controls major signaling pathway implicated in gene transcription. How cardiomyocytes decode Ca2+ signal to regulate gene expression without interfering with, or being controlled by, "contractile" Ca2+ that floods the entire cytosol during each heartbeat is still elusive. In this review, we summarize recent findings on nuclear Ca2+ regulation and its downstream signaling in cardiomyocytes. We will address difficulties in reliable quantification of nuclear Ca2+ fluxes and discuss its role in the development and progression of cardiac hypertrophy and heart failure. We also point out key open questions to stimulate future work. Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved. Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this 5 article is prohibited.

Wascher T.C.,Medical University of Graz | Lindeman J.H.N.,Leiden University | Sourij H.,Medical University of Graz | Kooistra T.,TNO | And 2 more authors.
Molecular Medicine | Year: 2011

The possible contribution of tumor necrosis factor-α (TNF-α) to the development of obesity associated insulin resistance in humans is still controversial. Our study investigated the effect of TNF-α neutralization on insulin resistance in healthy, obese and insulin resistant men. We performed a prospective, randomized, double-blind placebo-controlled trial in nine young, healthy obese male subjects with metabolic syndrome and insulin resistance. Volunteers received three infusions (wks 0, 2 and 6) of infliximab or placebo. Insulin resistance was measured at baseline and after 70 d by homeostatic model assessment (HOMA) index as well as by minimal model analysis of an intravenous glucose tolerance test. Endothelial function was accessed before and after intervention by flow mediated dilation. Infliximab improved the inflammatory status as indicated by reduced high sensitivity C-reactive protein (hsCRP) and fibrinogen levels (2.77 ± 0.6 to 1.8 ± 0.5 μg/L, and 3.42 ± 0.18 to 3.18 ± 0.28 g/L; (day 0 and day 70, P = 0.020 and 0.037 respectively), but did not improve insulin resistance (HOMA index and intravenous glucose-tolerance test [ivGGT]) or endothelial function. Despite improvements in inflammatory status, chronic TNF-α neutralization does not improve insulin resistance or endothelial function in seemingly healthy, but obese, insulin-resistant volunteers. This study severely questions the proposal that TNF-α is a causative link between adiposity and insulin resistance. © 2011 The Feinstein Institute for Medical Research.

Giacomel J.,Spectrum | Zalaudek I.,Medical University of Graz | Zalaudek I.,Dermatology and Skin Cancer Unit
Dermatologic Clinics | Year: 2013

Dermoscopy (dermatoscopy or surface microscopy) is an ancillary dermatologic tool that in experienced hands can improve the accuracy of diagnosis of a variety of benign and malignant pigmented skin tumors. The early and more accurate diagnosis of nonpigmented, or pink, tumors can also be assisted by dermoscopy. This review focuses on the dermoscopic diagnosis of pink lesions, with emphasis on blood vessel morphology and pattern. A 3-step algorithm is presented, which facilitates the timely and more accurate diagnosis of pink tumors and subsequently guides the management for such lesions. © 2013 Elsevier Inc.

Krenn-Pilko S.,Medical University of Graz | Thurner E.-M.,Medical University of Graz | Stojakovic T.,Medical University of Graz | Pichler M.,University of Houston | And 3 more authors.
British Journal of Cancer | Year: 2014

Background:The elevation of the platelet-to-lymphocyte ratio (PLR), an easily applicable blood test based on platelet and lymphocyte counts has been associated with poor prognosis in patients with different types of cancer. The present study was aimed to investigate the prognostic significance of the preoperative PLR in a large cohort of breast cancer patients.Methods:Data from 793 consecutive non-metastatic breast cancer patients, treated between 1999 and 2004, were evaluated retrospectively. The optimal cutoff values for the PLR were calculated using receiver operating curve analysis. Cancer-specific survival (CSS), overall survival (OS) as well as distant metastasis-free survival (DMFS) were assessed using the Kaplan-Meier method. To evaluate the independent prognostic significance of PLR, multivariable Cox regression models were applied for all three different end points.Results:Univariable analysis revealed a significant association between the elevated preoperative PLR and CSS (hazard ratio (HR): 2.75, 95% confidence interval (CI): 1.57-4.83, P<0.001) that remained statistically significant in multivariable analysis (HR: 2.03, 95% CI: 1.03-4.02, P=0.042). An increased PLR was also significantly associated with decreased OS in univariable (HR: 2.45, 95% CI: 1.43-4.20, P=0.001) and in multivariable analysis (HR: 1.92, 95% CI: 1.01-3.67, P=0.047). Furthermore, univariable analysis showed a significant impact of increased PLR on DMFS (HR: 2.02, 95% CI: 1.18-3.44, P=0.010). Subgroup analysis revealed significant associations of the elevated PLR on the primary end point CSS for all breast cancer subtypes. This association retained its significance in multivariable analysis in patients with luminal B tumours (HR: 2.538, 95% CI: 1.043-6.177, P=0.040).Conclusions:In this study, we identified the preoperative PLR as an independent prognostic marker for survival in breast cancer patients. Independent validation of our findings is needed. © 2014 Cancer Research UK.

Pollheimer M.J.,Research Unit for Experimental and Molecular Hepatology | Pollheimer M.J.,Medical University of Graz | Fickert P.,Research Unit for Experimental and Molecular Hepatology | Fickert P.,Medical University of Graz
Clinical Reviews in Allergy and Immunology | Year: 2015

Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are immune-mediated cholangiopathies with enigmatic etiology and pathogenesis. They have distinct clinical, laboratory, immunological, and histomorphological characteristics. Well-characterized animal models for PBC and PSC are utterly needed to develop novel pathogenetic concepts and to study innovative treatment strategies. The aim of the current paper is to outline the characteristics of ideal PBC and PSC animal models and to contrast this with a real-life up-to-date overview of currently available mouse models. Although some of this models show several individual characteristics of PBC and PSC, it is obvious that all of them have substantial and important limitations. Nevertheless, some may be beneficial to study certain pathophysiological aspects. Potential cholangiopathy animal models should be systematically investigated in regard to elevated serum alkaline phosphatase, bilirubin, and bile acid levels; immunological abnormalities; and longitudinal studies in regard to their liver phenotype. We herein propose a common systematic workup for potential models based on the fact that there are some intriguing disease combinations in specific genetically modified mice and recommend a stepwise process in regard to model characterization with methodical harvesting and screening of numerous organs for potential concomitant diseases. Due to the complex nature of both cholangiopathies, it seems to be very likely that no single perfect PBC or PSC model will ever be generated. The models outlined herein will certainly help to clarify specific pathogenetic aspects and even more important may turn out to be suitable to test potential drugs for treatment. © 2014, Springer Science+Business Media New York.

Kurath S.,Medical University of Graz | Halwachs-Baumann G.,Hospital of Steyr | Muller W.,Medical University of Graz | Resch B.,Medical University of Graz
Clinical Microbiology and Infection | Year: 2010

To analyse current data on transmission of human cytomegalovirus (HCMV) via breast milk with subsequent symptomatic HCMV infection of the preterm infant and to report on long-term follow-up, a systematic literature review was performed using EMBASE, MEDLINE and CINAHL (January 1966 to December 2008) Studies were included for analysis if congenital HCMV infection was excluded and transmission via breast milk was either confirmed or strongly suspected. Twenty-six studies were included for analysis. Maternal HCMV-IgG-positivity was reported to be in the range 51.6-100% (median 81.6%), HCMV-IgG detection in breast milk in the range 67-97.2% (median 80%) and HCMV-positivity of the infants in the range 5.7-58.6%. Symptomatic HCMV disease occurred in 0-34.5% (median 3.7%) and severe sepsis-like syndrome in 0-13.8% (median 0.7%). Data on long-term outcome of preterm infants with symptomatic HCMV infection revealed a low risk for mild neurological and cognitive sequelae, without hearing impairment. Recommendations for high-risk preterm infants diverged markedly. The current data report low rates of symptomatic disease after transmission of HCMV via breast milk to the preterm infant without evidence of certain long-term sequelae. The results of our review do not support a general approach, either by avoidance or pasteurization of breast milk, in high-risk preterm infants. © 2010 The Authors. Journal Compilation © 2010 European Society of Clinical Microbiology and Infectious Diseases.

Liebisch G.,University of Regensburg | Vizcaino J.A.,European Bioinformatics Institute | Kofeler H.,Medical University of Graz | Trotzmuller M.,Medical University of Graz | And 4 more authors.
Journal of Lipid Research | Year: 2013

There is a need for a standardized, practical annotation for structures of lipid species derived from mass spectrometric approaches; i.e., for high-throughput data obtained from instruments operating in either high- or low-resolution modes. This proposal is based on common, officially accepted terms and builds upon the LIPID MAPS terminology. It aims to add defined levels of information below the LIPID MAPS nomenclature, as detailed chemical structures, including stereochemistry, are usually not automatically provided by mass spectrometric analysis. To this end, rules for lipid species annotation were developed that reflect the structural information derived from the analysis. For example, commonly used head group-specific analysis of glycerophospholipids (GP) by low-resolution instruments is neither capable of differentiating the fatty acids linked to the glycerol backbone nor able to define their bond type (ester, alkyl-, or alk-1-enyl-ether). This and other missing structural information is covered by the proposed shorthand notation presented here. Beyond GPs, we provide shorthand notation for fatty acids/acyls (FA), glycerolipids (GL), sphingolipids (SP), and sterols (ST). In summary, this defined shorthand nomenclature provides a standard methodology for reporting lipid species from mass spectrometric analysis and for constructing databases. Copyright © 2013 by the American Society for Biochemistry and Molecular Biology, Inc.

Bachmaier G.,Medical University of Graz
Neurology | Year: 2015

Objective: We investigated longitudinal changes in iron concentration in the subcortical gray matter (caudate nucleus, globus pallidus, putamen, thalamus) of patients with clinically isolated syndrome (CIS) and definite multiple sclerosis (MS) and their relation to clinical and other morphologic variables. Methods: We followed 144 patients (76 CIS; median Expanded Disability Status Scale [EDSS] 1.0 [interquartile range (IQR) 0.0-2.0]; 68 MS; median EDSS 2.0 [IQR 1.0-3.3]) clinically and with 3T MRI over a median period of 2.9 (IQR 1.3-4.0) years. Iron concentration was determined by R2∗ relaxometry at baseline and last follow-up. Results: At baseline, subcortical gray matter iron deposition was higher in MS compared to CIS. In CIS, R2∗ rates increased in the globus pallidus (p < 0.001), putamen (p < 0.001), and caudate nucleus (p < 0.001), whereas R2∗ rates in the thalamus decreased (p < 0.05). In MS, R2∗ rates increased in the putamen (p < 0.05), remained stable in the globus pallidus and caudate nucleus, and decreased in the thalamus (p < 0.01). Changes in R2∗ relaxation rates were unrelated to changes in the volume of respective structures, of T2 lesion load, and of disability. Conclusions: Iron accumulation in the basal ganglia is more pronounced in the early than later phases of the disease and occurs independent from other morphologic brain changes. Shortterm changes in iron concentration are not associated with disease activity or changes in disability. © 2015 American Academy of Neurology.

Regauer S.,Medical University of Graz | Reich O.,Medical University of Graz | Eberz B.,General Gynecology Practice
Journal of the American Academy of Dermatology | Year: 2014

Background: Vulvar squamous cell carcinomas (SCCs) arising in association with vulvar lichen planus (LP) are poorly documented. Objectives: We sought to present clinicopathological features of 38 patients (median age 61 years, range 39-90 years) with LP-associated vulvar SCCs. Methods: Evaluated were location of vulvar SCC and metastases at presentation, recurrences, survival, precursor lesions, presence of human papillomavirus DNA, p16ink4a, and p53 expression. Results: In all, 32 solitary (5 pT1a, 20 pT1b, 7 pT2) and 6 multifocal SCCs, located in the vestibulum (n = 20) and in nonhair-bearing modified and glycogenated mucosa (n = 18), arose in erosive (n = 13) and nonerosive (n = 25) LP. All SCCs were human papillomavirus DNA and p16ink4a negative. Sixteen of 38 (42%) women had inguinal metastases at presentation. Treatment was surgery with clear margins (36/38) and chemoradiation (2/38). Fourteen of 36 (39%) surgically treated patients developed between 1 and 5 new SCCs in the residual diseased mucosa. Of all recurrences, 68% developed within 12 months via precursors revealing various histologic features including elongated, but also flat rete ridges, basaloid and hypertrophic differentiation with inconsistent p53 expression. Fourteen of 38 (37%) patients died of SCCs. Limitations: Retrospective study and lack of a standardized treatment protocols are limitations. Conclusion: LP-associated SCCs were located in nonhair-bearing vulvar mucosa. Patients had a high rate of inguinal metastases, recurrent vulvar cancers in diseased mucosa, and disease-related death. ( J Am Acad Dermatol 2014;71:698-707.).

Orendi K.,Medical University of Graz | Gauster M.,Medical University of Graz | Moser G.,Medical University of Graz | Meiri H.,Diagnostic Technologies Ltd. | Huppertz B.,Medical University of Graz
Reproduction | Year: 2010

Fusion of the trophoblast-derived choriocarcinoma cell line BeWo can be triggered by forskolin. BeWo cells are regularly used as a cell culture model to mimic in vivo syncytialisation of placental villous trophoblast. The β subunit of human chorionic gonadotropin (CGB), placental alkaline phosphatase as well as placental protein 13 (PP13, LGALS13) are exclusively expressed in the syncytiotrophoblast of the human placenta, and CGB is commonly used as a marker of syncytial differentiation. Here we tested the hypothesis that syncytial fusion precedes CGB and LGALS13 expression in trophoblast-derived BeWo cells. BeWo cells were cultured for 48 h in the presence or absence of forskolin and varying concentrations of H-89, a protein kinase A inhibitor that interferes with the forskolin-mediated pathway of syncytial fusion. LGALS13 and CGB expression were quantified by DELFIA and real-time PCR. Cell fusion was determined by morphological analysis and cell counting after immunofluorescence staining. In forskolin-stimulated BeWo cells that were hindered to fuse by treatment with H-89, levels of CGB protein expression were not altered, while LGALS13 protein and mRNA expression decreased significantly to control levels without forskolin. The LGALS13 protein expression data coincided with a significant decrease in syncytial fusion, while CGB protein expression was unaffected by rates of cell fusion and proliferation.We postulate that CGB protein expression is not necessarily linked to syncytial fusion, and thus CGB should be used with great caution as a marker of BeWo cell fusion. © 2010 Society for Reproduction and Fertility.

Geroldinger-Simic M.,Medical University of Vienna | Zelniker T.,Medical University of Vienna | Aberer W.,Medical University of Graz | Ebner C.,Allergy Clinic Reumannplatz | And 8 more authors.
Journal of Allergy and Clinical Immunology | Year: 2011

Background: Patients with birch pollen allergy often develop allergic reactions to plant foods. Objective: To evaluate the prevalence, main symptoms, and triggers of birch pollen-related food allergy and the role of food-specific IgG4 antibodies in food tolerance. Methods: Food-induced symptoms were evaluated in 225 individuals with birch pollen allergy by using a standardized questionnaire. IgE and IgG4 levels specific for the major birch pollen allergen Bet v 1 and birch profilin Bet v 2 and the Bet v 1 homologs in apple (Mal d 1) and hazelnut (Cor a 1) were quantified by ImmunoCAP. Mock-treated and IgG-depleted sera from patients tolerating hazelnuts in food challenges were compared for their inhibitory activity for binding of Cor a 1-IgE complexes to B cells. Results: In total, 73% of the study population experienced food allergy, which was perennial in 86% of the affected individuals. The oral allergy syndrome was the main clinical manifestation. However, more than 58% of the patients also experienced food-induced rhinoconjunctivitis. Apples and hazelnuts were identified as the most frequent triggers. Food allergy correlated with IgE reactivity to Bet v 1 but not to Bet v 2. Mal d 1-specific and Cor a 1-specific IgG4/IgE ratios were significantly higher in food-tolerant individuals than individuals with food allergy. Sera from IgG4-positive food-tolerant patients possessed IgG-dependent IgE-inhibitory activity. Conclusion: Birch pollen-related food allergy is highly prevalent and often perennial. High food allergen-specific IgG4/IgE ratios seem associated with food tolerance, potentially because specific IgG4 blocks IgE binding to food allergens. Thus, the presence of food allergen-specific IgG4 antibodies is no diagnostic marker for birch pollen-related food allergy. © 2010 American Academy of Allergy, Asthma and Immunology.

Laird J.R.,University of California at Davis | Schneider P.A.,Kaiser Permanente | Tepe G.,RodMed Klinikum | Brodmann M.,Medical University of Graz | And 9 more authors.
Journal of the American College of Cardiology | Year: 2015

Background Evidence from large, randomized, controlled peripheral artery disease trials reporting long-term outcomes using drug-coated balloons (DCBs) is limited. Previously, the DCB showed favorable 1-year outcomes compared with conventional percutaneous transluminal angioplasty (PTA), yet durability of the treatment effect with DCBs remains unknown. Objectives This study sought to investigate the longer-term outcomes of a paclitaxel-eluting DCB compared to PTA for femoropopliteal lesions. Methods We enrolled 331 patients with symptomatic (Rutherford 2 to 4) femoropopliteal lesions up to 18 cm in length. Patients were randomly assigned in a 2:1 ratio to treatment with DCB or PTA. The 24-month assessments included primary patency, freedom from clinically driven target lesion revascularization (CD-TLR), major adverse events, and quality of life and functional outcomes as assessed by the EuroQOL-5D quality-of-life questionnaire, walking impairment questionnaire, and 6-min walk test. Results At 24 months, patients treated with DCB showed significantly higher primary patency when compared with PTA (78.9% vs. 50.1%; p < 0.001). The rates of CD-TLR were 9.1% and 28.3% (p < 0.001) for the DCB and PTA groups, respectively. The overall mortality rate in the DCB group was 8.1% versus 0.9% in the PTA group (p = 0.008). There were no device- or procedure-related deaths and no major amputations in either group through 24-month follow-up. The rate of vessel thrombosis was low (1.5% DCB vs. 3.8% PTA; p = 0.243), with no new events reported between 1 and 2 years. Both groups showed similar functional improvement at 2 years, although DCB patients achieved this level of function with 58% fewer reinterventions. Conclusions The 24-month outcomes from the trial demonstrate a durable and superior treatment effect of DCB versus PTA with significantly higher primary patency, lower CD-TLR, and similar functional status improvement with fewer repeat interventions. (Randomized Trial of IN.PACT Admiral Drug Eluting Balloon vs Standard PTA for the Treatment of SFA and Proximal Popliteal Arterial Disease [INPACT SFA I]; NCT01175850; and IN.PACT Admiral Drug-Coated Balloon vs. Standard Balloon Angioplasty for the Treatment of Superficial Femoral Artery [SFA] and Proximal Popliteal Artery [PPA] [INPACT SFA II]; NCT01566461) © 2015 American College of Cardiology Foundation.

Wehr E.,Medical University of Graz | Pilz S.,Medical University of Graz | Boehm B.O.,University of Ulm | Marz W.,University of Heidelberg | Obermayer-Pietsch B.,Medical University of Graz
Clinical Endocrinology | Year: 2010

Objective Studies in rodents indicate a role of vitamin D in male reproduction, but the relationship between vitamin D and androgen levels in men is largely unexplored. We aimed to investigate the association of 25-hydroxyvitamin D [25(OH)D] levels with testosterone, free androgen index (FAI) and SHBG. Moreover, we examined whether androgen levels show a similar seasonal variation to 25(OH)D. Design In this cross-sectional study, 25(OH)D, testosterone and SHBG levels were assessed by immunoassay in 2299 men who were routinely referred for coronary angiography (1997-2000). Measurements Main outcome measures were associations of 25(OH)D levels with testosterone, SHBG and FAI. FAI was calculated as testosterone (nmoll)SHBG (nmoll) × 100. Results Men with sufficient 25(OH)D levels (≥30 gl) had significantly higher levels of testosterone and FAI and significantly lower levels of SHBG when compared to 25(OH)D insufficient (20-29·9 gl) and 25(OH)D-deficient (<20 gl) men (P < 0·05 for all). In linear regression analyses adjusted for possible confounders, we found significant associations of 25(OH)D levels with testosterone, FAI and SHBG levels (P < 0·05 for all). 25(OH)D, testosterone and FAI levels followed a similar seasonal pattern with a nadir in March (12·2 gl, 15·9 nmoll and 40·8, respectively) and peak levels in August (23·4 gl, 18·7 nmoll and 49·7, respectively) (P < 0·05 for all). Conclusion Androgen levels and 25(OH)D levels are associated in men and reveal a concordant seasonal variation. Randomized controlled trials are warranted to evaluate the effect of vitamin D supplementation on androgen levels. © 2010 Blackwell Publishing Ltd.

Mangge H.,Medical University of Graz | Stelzer I.,Medical University of Graz | Reininghaus E.Z.,Medical University of Graz | Postolache T.T.,University of Maryland Baltimore County | Fuchs D.,Innsbruck Medical University
Current Medicinal Chemistry | Year: 2014

Atherosclerosis (AS), a major pathologic consequence of obesity, is the main etiological factor of cardiovascular disease (CVD), which is the most common cause of death in the western world. A systemic chronic low grade immune- mediated inflammation (scLGI) is substantially implicated in AS and its consequences. In particular, proinflammatory cytokines play a major role, with Th1-type cytokine interferon- (IFN-) being a key mediator. Among various other molecular and cellular effects, IFN- activates the enzyme indoleamine 2,3-dioxygenase (IDO) in monocytederived macrophages, dendritic, and other cells, which, in turn, decreases serum levels of the essential amino acid tryptophan (TRP). Thus, people with CVD often have increased serum kynurenine to tryptophan ratios (KYN/TRP), a result of an increased TRP breakdown. Importantly, increased KYN/TRP is associated with a higher likelihood of fatal cardiovascular events. A scLGI with increased production of the proinflammatory adipokine leptin, in combination with IFN- and interleukin-6 (IL-6), represents another central link between obesity, AS, and CVD. Leptin has also been shown to contribute to Th1-type immunity shifting, with abdominal fat being thus a direct contributor to KYN/TRP ratio. However, TRP is not only an important source for protein production but also for the generation of one of the most important neurotransmitters, 5-hydroxytryptamine (serotonin), by the tetrahydrobiopterin-dependent TRP 5-hydroxylase. In prolonged states of scLGI, availability of free serum TRP is strongly diminished, affecting serotonin synthesis, particularly in the brain. Additionally, accumulation of neurotoxic KYN metabolites such as quinolinic acid produced by microglia, can contribute to the development of depression via NMDA glutamatergic stimulation. Depression had been reported to be associated with CVD endpoints, but it most likely represents only a secondary loop connecting excess adipose tissue, scLGI and cardiovascular morbidity and mortality. Accelerated catabolism of TRP is further involved in the pathogenesis of the anemia of scLGI. The pro-inflammatory cytokine IFN- suppresses growth and differentiation of erythroid progenitor cells, and the depletion of TRP limits protein synthesis and thus hemoglobin production, and, through reduction in oxygen supply, may contribute to ischemic vascular disease. In this review we discuss the impact of TRP breakdown and the related complex mechanisms on the prognosis and individual course of CVD. Measurement of TRP, KYN concentrations, and calculation of the KYN/TRYP ratio will contribute to a better understanding of the interplay between inflammation, metabolic syndrome, mood disturbance, and anemia, all previously described as significant predictors of an unfavorable outcome in patients with CVD. The review leads to a novel framework for successful therapeutic modification of several cardinal pathophysiological processes leading to adverse cardiovascular outcome. © 2014 Bentham Science Publishers.

The scientific literature in the area of laser acupuncture is rather large; however, the actual mechanisms and effects have not yet been proven in detail. Since the early days of laser acupuncture, there are still many open questions concerning technical parameters of this innovative technique. In this paper, we report about the most important technical parameters (wavelength, output power, power density, energy density, dose range, and continuous or pulsed laser) for laser acupuncture and present quantitative results for optimal laser stimulation, which allow eliciting reproducible effects in the periphery and in the brain. There are several position statements on laser acupuncture and also several review articles in scientific literature concerning clinical effectiveness of laser acupuncture. For example, the Australian Medical Acupuncture College stated recently that "the optimal energy density for laser acupuncture and biostimulation, based on current clinical experience, is 4J/cm 2". However, our results of previous research studies and of this paper clearly show that dose must be adjusted according to the individual responses. Copyright © 2012 Gerhard Litscher and Gerhard Opitz.

Bergmann O.,Karolinska Institutet | Zdunek S.,Karolinska Institutet | Felker A.,Karolinska Institutet | Salehpour M.,Uppsala University | And 16 more authors.
Cell | Year: 2015

Summary The contribution of cell generation to physiological heart growth and maintenance in humans has been difficult to establish and has remained controversial. We report that the full complement of cardiomyocytes is established perinataly and remains stable over the human lifespan, whereas the numbers of both endothelial and mesenchymal cells increase substantially from birth to early adulthood. Analysis of the integration of nuclear bomb test-derived 14C revealed a high turnover rate of endothelial cells throughout life (>15% per year) and more limited renewal of mesenchymal cells (<4% per year in adulthood). Cardiomyocyte exchange is highest in early childhood and decreases gradually throughout life to <1% per year in adulthood, with similar turnover rates in the major subdivisions of the myocardium. We provide an integrated model of cell generation and turnover in the human heart. Video Abstract © 2015 Elsevier Inc.

Burt A.D.,University of Adelaide | Lackner C.,Medical University of Graz | Tiniakos D.G.,Northumbria University
Seminars in Liver Disease | Year: 2015

Nonalcoholic fatty liver disease (NAFLD) comprises a spectrum of clinical and histopathological changes including simple steatosis, steatosis with inflammation, steatohepatitis, cirrhosis, and hepatocellular carcinoma. It was initially described in the context of drug-induced liver injury and acute liver disease following jejunoileal bypass surgery, but since the early 1980s it has been widely acknowledged as the hepatic manifestation of metabolic syndrome. It now represents a burgeoning public health crisis and is fast becoming the main indication for liver transplantation in some parts of the world. Its true incidence and prevalence are unknown, although estimates have been made from large imaging studies. Liver biopsy interpretation is still regarded as the gold standard for making accurate diagnoses in NAFLD, but sampling limitations are recognized. Furthermore, clear definitions for key histopathological components have been lacking, resulting in significant interobserver variations in making a diagnosis of steatohepatitis. In this review the authors consider some aspects of classification and variant forms of NAFLD such as that occurring in children. They provide an update on grading and staging systems and histopathological prognostic factors, and address the role of liver biopsy in contemporary clinical care of patients with NAFLD. © 2015 by Thieme Medical Publishers, Inc.

Millotti G.,University of Innsbruck | Samberger C.,Medical University of Graz | Frohlich E.,Medical University of Graz | Sakloetsakun D.,University of Innsbruck | Bernkop-Schnurch A.,University of Innsbruck
Journal of Materials Chemistry | Year: 2010

Thiomers are thiolated polymers with excellent mucoadhesive properties. The aim of this study was to synthesize a novel thiolated chitosan with higher reactivity in order to further improve mucoadhesion. For this purpose, 4-mercaptobenzoic acid was chosen to be covalently attached to chitosan. The aromatic structure of the ligand should exhibit a higher reactivity due to a comparatively low pKa value of the thiol group, which was determined to be 6.8. Mucoadhesion, in situ gelation, biocompatibility and toxicity were evaluated. Chitosan-4-mercaptobenzoic acid was proved to be 60-fold more mucoadhesive compared to unmodified chitosan. After 24 hours, the viscosity of the novel thiomer solution increased 2974-fold compared to unmodified chitosan and after 48 hours 4487-fold. Chitosan-4-mercaptobenzoic acid tablets disintegrated twice as slowly as unmodified chitosan. Furthermore, the novel thiomer proved to be biodegradable and to be non-toxic. Due to the above mentioned properties, chitosan-4-mercaptobenzoic acid is a promising excipient for oral formulations or in situ gelling formulations. © The Royal Society of Chemistry 2010.

Genser B.,University of Heidelberg | Genser B.,Federal University of Bahia | Silbernagel G.,University of Tübingen | De Backer G.,Ghent University | And 10 more authors.
European Heart Journal | Year: 2012

The impact of increased serum concentrations of plant sterols on cardiovascular risk is unclear. We conducted a systematic review and meta-analysis aimed to investigate whether there is an association between serum concentrations of two common plant sterols (sitosterol, campesterol) and cardiovascular disease (CVD). We systematically searched the databases MEDLINE, EMBASE, and COCHRANE for studies published between January 1950 and April 2010 that reported either risk ratios (RR) of CVD in relation to serum sterol concentrations (either absolute or expressed as ratios relative to total cholesterol) or serum sterol concentrations in CVD cases and controls separately. We conducted two meta-analyses, one based on RR of CVD contrasting the upper vs. the lower third of the sterol distribution, and another based on standardized mean differences between CVD cases and controls. Summary estimates were derived by fixed and random effects meta-analysis techniques. We identified 17 studies using different designs (four casecontrol, five nested casecontrol, three cohort, five cross-sectional) involving 11 182 participants. Eight studies reported RR of CVD and 15 studies reported serum concentrations in CVD cases and controls. Funnel plots showed evidence for publication bias indicating small unpublished studies with non-significant findings. Neither of our meta-analyses suggested any relationship between serum concentrations of sitosterol and campesterol (both absolute concentrations and ratios to cholesterol) and risk of CVD. Our systematic review and meta-analysis did not reveal any evidence of an association between serum concentrations of plant sterols and risk of CVD. © 2011 The Author.

Beltraminelli H.,Medical University of Graz | Beltraminelli H.,University of Basel | Mullegger R.,Hospital of Wiener Neustadt | Cerroni L.,Medical University of Graz
Journal of Cutaneous Pathology | Year: 2010

Background: Recently, Petrella et al. described four patients with an unusual CD8+ lymphoid proliferation arising on the ear. These cases do not correspond clearly to any recognized category of cutaneous T-cell lymphoma (CTCL) described in the World Health Organization (WHO)/European Organization for Research and Treatment of Cancer (EORTC) 2005 classification. Methods and Results: Three patients (all men; median age 64; range: 61-69) presented with plaques or small tumors localized on the ears. All lesions showed histopathologically a dense, diffuse infiltration of lymphocytes within the entire dermis without epidermotropism. Cytomorphology revealed predominance of medium-sized pleomorphic lymphocytes. Immunohistochemistry showed a cytotoxic phenotype (CD3 + /CD4 - /CD8 +). Polymerase chain reaction (PCR) analysis of the T-cell receptor (TCR)-gamma gene revealed a monoclonal rearrangement in two of three patients. Follow-up data of two patients were available; one is alive without skin or systemic manifestations of the disease after 28 months, whereas the other is alive with persistent skin disease after 7 months. Conclusions: Our observation confirms that some patients present with a peculiar lymphoid proliferation of small-medium pleomorphic cytotoxic lymphocytes located on the ear, probably representing a phenotypic variant of the cutaneous small/medium pleomorphic T-cell lymphoma (CSMPTCL). These cases should not be misinterpreted as a high-grade cytotoxic lymphoma. Beltraminelli H, Müllegger R, Cerroni L. Indolent CD8+ lymphoid proliferation of the ear: A phenotypic variant of the small-medium pleomorphic cutaneous T-cell lymphoma? Copyright © 2009 John Wiley & Sons A/S.

Farar J.,Medical University of Graz | Schussler G.,University of Innsbruck
Zeitschrift fur Psychosomatische Medizin und Psychotherapie | Year: 2011

Questions: Do some life story patterns exist, which are associated with depression? Can some life story factors be identified, which influence or determine a special kind of personality, predisposing to depression? Methods: Retrospective, cross sectional study with nonexperimental character, using a number of 60 nonmelancholic depressed patients. First, they were asked to give an interview on their life story. Then, they were asked to fill in questionnaires about personality, parental style of raising, clinical symptoms and personality disorders. Results: Significant correlations could be found between parental style of raising, a family history affected by depression, a dysfunctional household, the family composition, negative school experience and all investigated styles of personality. Further, clusters of personality, clusters of parental style of raising and clusters of specific life story factors could be detected. Discussion: Results show a strong relation between life story factors and personality styles, predisposing to depression and emphasize the importance of considering personality, when exploring special life story factors. Vice versa, actual personality styles can point to different patterns of life story and thus, show the relevance for the diagnostic and therapeutic process. © 2011 Vandenhoeck & Ruprecht GmbH & Co. KG, Göttingen.

Rocca M.A.,Vita-Salute San Raffaele University | Rocca M.A.,San Raffaele Scientific Institute | Amato M.P.,University of Florence | De Stefano N.,University of Siena | And 8 more authors.
The Lancet Neurology | Year: 2015

In patients with multiple sclerosis (MS), grey matter damage is widespread and might underlie many of the clinical symptoms, especially cognitive impairment. This relation between grey matter damage and cognitive impairment has been lent support by findings from clinical and MRI studies. However, many aspects of cognitive impairment in patients with MS still need to be characterised. Standardised neuropsychological tests that are easy to administer and sensitive to disease-related abnormalities are needed to gain a better understanding of the factors affecting cognitive performance in patients with MS than exists at present. Imaging measures of the grey matter are necessary, but not sufficient to fully characterise cognitive decline in MS. Imaging measures of both lesioned and normal-appearing white matter lend support to the hypothesis of the existence of an underlying disconnection syndrome that causes clinical symptoms to trigger. Findings on cortical reorganisation support the contribution of brain plasticity and cognitive reserve in limiting cognitive deficits. The development of clinical and imaging biomarkers that can monitor disease development and treatment response is crucial to allow early identification of patients with MS who are at risk of cognitive impairment. © 2015 Elsevier Ltd.

Pilz S.,Medical University of Graz | Pilz S.,VU University Amsterdam | Tomaschitz A.,Medical University of Graz | Drechsler C.,University of Würzburg | De Boer R.A.,University of Groningen
Kidney International Supplements | Year: 2011

Vitamin D deficiency is present in the vast majority of patients with chronic kidney disease (CKD), and correcting a poor vitamin D status is recommended as a treatment of CKD-mineral and bone disorders. In this review, we summarize the molecular and clinical data on the role of vitamin D status for heart diseases and its risk factors, with particular attention to patients with CKD. Experimental studies strongly suggest that vitamin D metabolism has a crucial role in myocardial and vascular pathophysiology. This is supported by observations of vitamin D receptor knockout mice, which suffer from myocardial hypertrophy and arterial hypertension with increased activity of the renin-angiotensin system. In the general population and in particular in CKD patients, a poor vitamin D status is associated with cardiovascular (CV) risk factors and preclinical manifestations of CV disease including coronary calcification. Poor vitamin D status is also associated with prevalent and incident CV diseases, such as heart failure and sudden cardiac death. Native as well as active vitamin D treatments improve CV risk profiles and exert beneficial effects on parameters of myocardial structure and function. Whether vitamin D therapy is effective for the prevention or treatment of CV disease remains to be proven in large-scale randomized controlled trials. Native vitamin D should, however, be supplemented in virtually all CKD patients with reduced 25-hydroxyvitamin D concentrations, and the promising data on antiproteinuric and cardioprotective effects of paricalcitol may extend the future indication spectrum for active vitamin D treatment.

Lallas A.,Skin Cancer Unit | Giacomel J.,Spectrum | Argenziano G.,Skin Cancer Unit | Garcia-Garcia B.,Hospital Universitario Central Of Asturias | And 4 more authors.
British Journal of Dermatology | Year: 2014

In addition to its well-documented value in improving the diagnosis of skin tumours, dermoscopy is continually gaining appreciation in the field of general dermatology. Dermoscopy has been shown to facilitate the clinical recognition of several inflammatory and infectious diseases, as well as their discrimination from skin tumours. Moreover, recent data indicate that it might also be profitable in assessing the outcome and adverse effects of various treatments. Application of dermoscopy should follow the standard procedure of acquiring information from patient history and clinically evaluating the number, location and morphology of the lesion(s). Four parameters should be assessed when applying dermoscopy in the realm of inflammatory and infectious diseases: (i) morphological vascular patterns; (ii) arrangement of vascular structures; (iii) colours; and (iv) follicular abnormalities, while the presence of other specific features (clues) should also be evaluated. It must be underlined that dermoscopic findings should always be interpreted within the overall clinical context of the patient, integrated with information from the history and the macroscopic examination. With new evidence continuously being gathered, the dermatoscope gradually acquires a role similar to the stethoscope of general practitioners, becoming an irreplaceable clinical tool for dermatologists. In this article, we provide a succinct summary of existing data on dermoscopy in general dermatology. Practical tips are suggested, which can assist clinicians in profitably utilizing and applying the available knowledge in their everyday practice. What's already known about this topic? Dermoscopy has well-documented value in improving the diagnosis of skin tumours. It is continually gaining appreciation in the field of general dermatology. What does this study add? We provide a succinct summary of existing data on dermoscopy in general dermatology. Practical tips are suggested, which can assist clinicians in profitably utilizing and applying the available knowledge in their everyday practice. © 2013 British Association of Dermatologists.

Silbernagel G.,Ludwigshafen Risk and Cardiovascular Study Non profit LLC | Silbernagel G.,University of Tübingen | Grammer T.B.,University of Heidelberg | Winkelmann B.R.,Cardiology Group Frankfurt Sachsenhausen | And 3 more authors.
Diabetes Care | Year: 2011

OBJECTIVE-Glycated hemoglobin has been suggested to be superior to fasting glucose for the prediction of vascular disease and death from any cause. The aim of the present work was to analyze and compare the predictive value of glycated hemoglobin and fasting glucose on all-cause and cause-specific mortality in subjects who underwent coronary angiography. RESEARCH DESIGN ANDMETHODS-We studied 2,686 participants of the Ludwigshafen Risk and Cardiovascular health study without a history of diabetes. The majority of this cohort had coronary artery disease. Glycated hemoglobin was measured at the baseline examination. The mean (± SD) duration of the follow-up for all-cause, cardiovascular, and cancer mortality was 7.54 ± 2.1 years. RESULTS-A total of 508 deaths occurred during the follow-up. Of those, 299 were accounted for by cardiovascular diseases and 79 by cancer. Baseline glycated hemoglobin was predictive of all-cause, cardiovascular, and cancer mortality. The multivariable-adjusted hazard ratios (HR) (95% CI) for glycated hemoglobin values of <5.0, 5.0-5.4, 5.5-5.9, 6.0-6.4, 6.5-7.4, and ≥7.5% for all-cause mortality were 1.36 (0.85-2.18), 1.00 (0.76-1.32), 1.00 (reference), 1.11 (0.88-1.41), 1.39 (1.07-1.82), and 2.15 (1.32-3.53), respectively. Similar J-shaped relationships were found between glycated hemoglobin and cardiovascular and cancer mortality. The associations of glycated hemoglobin with all-cause and cardiovascular mortality remained significant after inclusion of fasting glucose as a covariate. However, fasting glucose was not significantly related to mortality when adjusting for glycated hemoglobin. CONCLUSIONS-Glycated hemoglobin significantly and independently of fasting glucose predicts all-cause and cardiovascular mortality in whites at intermediate to high cardiovascular risk. © 2011 by the American Diabetes Association.

Blaber A.P.,Simon Fraser University | Goswami N.,Medical University of Graz | Bondar R.L.,Roberta Bondar Foundation | Kassam M.S.,Ryerson University
Stroke | Year: 2011

Background and Purpose- We investigated cerebral blood flow regulation in astronauts before and after flights. We hypothesized that autoregulation would be different before flight and after flight between nonfinishers and the finishers of a stand test. Methods- Twenty-seven astronauts from shuttle missions lasting 8 to 16 days underwent a 10-minute stand test: 10 days before flight, 1 to 2 hours and 3 days after landing. Mean blood flow velocity of the middle cerebral artery (MCA) was measured using transcranial Doppler; Mean arterial pressure was measured using a Finapres (Ohmeda, Englewood, CO) and was adjusted to the level of the MCA (BPMCA). Cross-spectral power, gain, phase, and coherence were determined for the relation between BPMCA and the cerebrovascular resistance index mean blood flow velocity/BPMCA. Results- BPMCA was reduced with stand (P<0.001). Differences between finishers and nonfinishers (P=0.011) and over test days (P=0.004) were observed. Cerebrovascular conductance was affected by stand (P<0.001), by group (P<0.001) with a group by stand, and test day interaction (P<0.01). Preflight data suggest that the nonfinishers were operating at a higher cerebral vasodilation than finishers for a given BPMCA, and on landing day the nonfinishers had a greater decrease in mean blood flow velocity as a function of BPMCA with standing compared to finishers and preflight. There was a significant interaction effect of gender over the test days and from supine to stand (P=0.035). Conclusions- Our results indicate that the cause of presyncope in astronauts may be related to a mismatch of cerebral blood flow with blood pressure. Astronaut gender may also play a role in susceptibility to orthostatic intolerance after flight. Copyright © 2011 American Heart Association. All rights reserved.

Jhund P.S.,Brigham and Women's Hospital | Jhund P.S.,University of Glasgow | Claggett B.,Brigham and Women's Hospital | Packer M.,University of Texas Southwestern Medical Center | And 8 more authors.
European Journal of Heart Failure | Year: 2014

Aims The first in class angiotensin receptor neprilysin inhibitor, LCZ696 has been shown to reduce levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), reduce left atrial size and improve New York Heart Association (NYHA) class in patients with heart failure with preserved ejection fraction (HFpEF). We examined whether the effects of LCZ696 were independent of systolic blood pressure (SBP) lowering. Methods and results In the Prospective comparison of ARNi (angiotensin receptor neprilysin inhibitor) with ARB (angiotensin receptor blocker) on Management Of heart failUre with preserved ejectioN fracTion (PARAMOUNT) trial 301 patients were randomly assigned to LCZ696 or valsartan. We examined the relationship between SBP lowering and LCZ696 on NT-proBNP level, left atrial size, NYHA class and estimated glomerular filtration rate (eGFR). By 12 weeks blood pressure was reduced by 9 mmHg (SD 15)/5 mmHg (SD 11) in patients receiving LCZ696 in comparison with 3 mmHg (SD 17)/2 mmHg (SD 12) in those receiving valsartan. The change in NT-proBNP was poorly correlated with change in SBP (LCZ696, r = 0.17, P = 0.06; valsartan, r = 0.05, P = 0.58) After adjustment for change in SBP, the ratio of change in NT-proBNP at 12 weeks for LCZ696 vs. valsartan was 0.76 (95% CI 0.63-0.93, P = 0.008), and similar to the ratio not adjusting for SBP (0.76, 95% CI 0.63-0.92, P = 0.006); P for interaction was 0.38). Similarly, reduction in left atrial volume index at 36 weeks, improvement in NYHA class and eGFR were all independent of the change in SBP. Conclusion In patients with HFpEF, the effect of the angiotensin receptor neprilysin inhibitor LCZ696 on NT-proBNP, left atrial volume, functional class, and eGFR was independent of reduction in SBP. © 2014 European Society of Cardiology.

Roscigno M.,Ospedali Riuniti di Bergamo | Heidenreich A.,RWTH Aachen | Lotan Y.,Southwestern Medical Center | Margulis V.,Southwestern Medical Center | And 3 more authors.
European Urology | Year: 2011

Context: The role of lymph node dissection (LND) in patients treated with radical nephroureterectomy (RNU) for upper tract urothelial cancer (UTUC) is still controversial. Objective: To analyze the impact of lymph node invasion on the outcome of patients, the staging, and the possible therapeutic role of LND in UTUC. Evidence acquisition: A Medline search was conducted to identify original articles, review articles, and editorials addressing the role of LND in UTUC. Keywords included upper tract urothelial neoplasms, lymphadenectomy, lymph node excision, lymphatic metastases, nephroureterectomy, imaging, and survival. Evidence synthesis: Regional nodes are frequently involved in UTUC and represent the most common metastatic site. Regional nodal status is a significant predictor of patient outcomes, especially in invasive disease. Therefore, select patients treated with RNU at high risk for regional nodal metastases should undergo LND to improve disease staging, which would identify those who could benefit from adjuvant systemic therapy. Several retrospective studies suggested the potential therapeutic role of LND in UTUC. An accurate LND could remove some nodal micrometastases not identified on routine pathologic examination, thus improving local control and cancer-specific survival. Radical surgery and LND might be curative in a subpopulation with limited nodal disease, as described in bladder cancer. A clear knowledge of the limits of LND and a template of LND for UTUC are still needed. Conclusions: An extended LND can provide better disease staging and may be curative in patients with limited nodal disease. However, current evidence is based on retrospective studies, which limits the ability to standardize either the indication or the extent of LND. Prospective trials are required to determine the impact of LND on survival in patients with UTUC and identify patients for a risk-adapted approach such as close follow-up or adjuvant chemotherapy. © 2011 European Association of Urology.

Reintam Blaser A.,Intensive Care | Reintam Blaser A.,University of Tartu | Deane A.M.,Royal Adelaide Hospital | Deane A.M.,University of Adelaide | Fruhwald S.,Medical University of Graz
Current Opinion in Critical Care | Year: 2015

Purpose of review To summarize existing evidence on definition, epidemiology, mechanisms, risk factors, consequences, outcome and management of diarrhoea in the critically ill. Recent findings In health, diarrhoea is defined as the passage of three or more loose or liquid stools per day. In the critically ill, the diagnosis is yet to be formalized and reported prevalence of diarrhoea varies according to the definition used. Recent studies estimate the prevalence between 14 and 21% and describe risk factors for diarrhoea in critically ill patients. The precipitant of diarrhoea always needs to be identified, as targeted therapies are important for several causes. Although the majority of patients with diarrhoea require only supportive care, it is always essential to exclude, or confirm and treat infectious diarrhoea. There is little evidence to support delaying or withdrawing provision of enteral nutrition in patients with diarrhoea, and we recommend continuing enteral nutrition whenever possible. However, the consequences of diarrhoea-hypovolaemia, electrolyte disturbances, malnutrition, skin lesions and contamination of wounds-should be avoided or at least recognized promptly. Summary A definition of diarrhoea and a practical approach to identify the precipitant and to manage diarrhoea in critically ill patients are proposed. © Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Cicardi M.,University of Milan | Aberer W.,Medical University of Graz | Banerji A.,Massachusetts General Hospital | Bas M.,TU Munich | And 9 more authors.
Allergy: European Journal of Allergy and Clinical Immunology | Year: 2014

Angioedema is defined as localized and self-limiting edema of the subcutaneous and submucosal tissue, due to a temporary increase in vascular permeability caused by the release of vasoactive mediator(s). When angioedema recurs without significant wheals, the patient should be diagnosed to have angioedema as a distinct disease. In the absence of accepted classification, different types of angioedema are not uniquely identified. For this reason, the European Academy of Allergy and Clinical Immunology gave its patronage to a consensus conference aimed at classifying angioedema. Four types of acquired and three types of hereditary angioedema were identified as separate forms from the analysis of the literature and were presented in detail at the meeting. Here, we summarize the analysis of the data and the resulting classification of angioedema. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Agency: Cordis | Branch: FP7 | Program: CP | Phase: ICT-2011.5.2 | Award Amount: 5.47M | Year: 2013

The Go-Smart project will build a generic open-source software simulation environment for planning of image guided percutaneous Minimally Invasive Cancer Treatment (MICT). MICT includes radiofrequency ablation (RFA), cryoablation, microwave ablation (MW), transarterial chemoembolisation (TACE), brachytherapy (BT), and prospectively, irreversible electroporation (IRE). Beside of TACE each type of MICT uses needles that are inserted into the tumour tissue and the tissue is destroyed through heating, cooling, and application of an electric field or radiation. These treatments are often combined with TACE. The commonalities between the different procedures allow for the development of a generic, reusable, robust simulation environment with the relevant physics and physiology needed to correctly predict the result of MICT in terms of lesion size and shape. The environment will incorporate patient data and appropriate physiological models to simulate tissue response to heat, cooling, hypoxia, radiation, or electrical pulses. The models will account for multi-scale physiological dependencies between a full organ, its anatomical structures and tissue properties down to the cellular level. The software environment will be open-ended with extendable interfaces to allow clinicians to add further patient data collected before, during and after MICTs. This data will be used by the research community to refine the existing physiological tissue models thus transforming the environment into a user-driven growing info-structure. The Go-Smart environment will allow the Interventional Radiologists (IR) to select an optimal type of MICT by simulating the personalised result of the different treatments and medical protocols in patient specific conditions. Bringing different MICTs into a unified simulation environment is a unique approach and will promote their systematic comparison and establish much needed common standards and protocols for MICT in Europe.

Agency: Cordis | Branch: H2020 | Program: CSA | Phase: INFRASUPP-6-2014 | Award Amount: 2.04M | Year: 2015

B3Africa - Bridging Biobanking and Biomedical Research across Europe and Africa will dramatically improve and facilitate the development of better predictive, preventive and personalized healthcare worldwide. The rapidly evolving African biobanks are an invaluable resource: The African population has the greatest genomic diversity on the planet and represents an incredible resource of information to advance biomedical research. B3Africa aims to implement a cooperation platform and technical informatics framework for biobank integration between Africa and Europe. The collaboration harmonizes the ethical and legal framework, biobank data representation and bioinformatics pipelines for sharing data and knowledge among biobanks and allowing access for researchers from both continents. Main actors from the relevant initiatives including Human Heredity and Health in Africa project (H3Africa), European Biobanking and Biomolecular Resources research infrastructure (BBMRI-ERIC) and LMIC Biobank and Cohort Network (BCNet) collaborate in B3Africa to address the following objectives: Defining an ethical and regulatory framework for biobank data sharing between Europe and Africa Defining data models for representing biobank and research data based on existing best practices, standards and ontologies Designing an informatics platform using existing open-source software (with eBioKit and BiBBox as essential modules) integrating workflows for biobank applications Implementation of an education and training system for information and capacity building Validating the B3Africa concept with existing biobanks from both continents B3Africa will provide the critical mass to maximise efficiency in biomedical research, supports defragmentation through integration and allows efficient leverage of existing biobanks and e-infrastructures in Europe and Africa. The technical informatics framework will be designed for easy upscaling and integration with other research infrastructures.

Agency: Cordis | Branch: H2020 | Program: CSA | Phase: INFRADEV-2-2015 | Award Amount: 1.44M | Year: 2016

ERINHA2 aims to complete the work carried out during the first preparatory phase (PP1) - ERINHA - in order to reach the financial, administrative and technical maturity necessary to complete the establishment of the Research Infrastructre and ensure that the operation phase can begin in 2018. ERINHA2 will therefore finalise the decision to use the status of an association and prepare the necessary legal document to register the RI depending on the country voted on to host the Central Coordinating Unit. ERINHA2 will prepare all procedures and protocols (human resources, IPR, ethics) needed to effectively operate the RI. The financial and business plans prepared in ERINHA (PP1) will updated and presented to national and international stakeholders to obtain their agreement to fund the infrastructure. An overarching group of activities - WP5, Stakeholders and commitment - will aim to accompany all partner countries in their efforts to obtain agreements and funding. This WP5 will ensure all relevant stakeholders and potential users are informed of the progress, services and benefits of ERINHA. The utlimate outcome of ERINHA2 will be the signtature of the ERINHA statutes among the founding countries to officially establish the RI and enter into the construction phase.

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2013.2.4.2-3 | Award Amount: 3.85M | Year: 2013

More than 14 million Europeans suffer from heart failure (HF), of which more than 50 % have HF with preserved left ventricular (LV) ejection fraction (EF) (HFPEF, diastolic heart failure). HFPEF is the only cardiovascular disease with increasing prevalence and incidence, affecting 10-20% of the elderly and contributing substantially to hospitalizations of elderly HF patients. Currently, no medical treatment has been shown to be effective and the economic, social and personal burden of HFPEF is enormous; this disease constitutes one of the most pressing unmet clinical needs. A cardinal feature of HFPEF is exercise intolerance. The pathophysiology of exercise intolerance in HFPEF depends on multiple factors in heart, endothelium and skeletal muscles. From a pathophysiological point of view, exercise could by far outweigh any pharmacological intervention in this heterogeneous syndrome, since lifestyle dependent risk factor, physical inactivity, and physical deconditioning underlay and contribute to HFPEF. OptimEx will focus on the cardiovascular effects of exercise training as primary and secondary prevention of HFPEF. We will combine in vivo and in vitro studies in man and rats in serial experiments that will advance our understanding of fundamental cellular and molecular mechanisms underpinning dose-dependent exercise-induced changes in the heart, blood vessels and skeletal muscles. This research is aimed to tackle one of the major health problems the developed world faces with its ageing societies and increasing prevalence of the HFPEF and will support sustainable health systems in EU member states through improvements in the clinical management of a common and disabling disease. The project is therefore highly relevant to improve the health of European citizens and important to promote healthy ageing and preventing disease.

Agency: Cordis | Branch: H2020 | Program: CSA | Phase: PHC-34-2014 | Award Amount: 939.72K | Year: 2015

ASSESS CT will contribute to better semantic interoperability of eHealth services in Europe, in order to optimise care and to minimise harm in delivery of care. In a joint one-year effort, the ASSESS CT consortium will investigate the fitness of the clinical terminology SNOMED CT as a potential standard for EU-wide eHealth deployments, scrutinising clinical, technical, financial, and organisational aspects. Unbiased towards SNOMED CT adoption, the ASSESS CT project will employ established evaluation approaches from social science. It will scrutinise adoption against two alternative scenarios: to abstain from actions at the EU level, or to devise an EU-wide semantic interoperability framework without SNOMED CT. ASSESS CT will review the current state of SNOMED CT through survey and focus group, regarding its use by IHTSDO members and the fulfilment of semantic interoperability use cases, the relationship with EU-wide recommendations, known technical and organisational drawbacks, and maintenance of the terminology. A series of studies using sampled clinical data will provide new evidence about conceptual and term coverage for selected languages, as well as technical fitness in manual and automated semantic annotation scenarios. The consortium will also analyse the impact of SNOMED CT adoption from a socio-economic viewpoint, encompassing management, business, organisational, and governance aspects. Validation of all working tasks, both political and domain-specific, will be secured through four large workshops with a list of distinguished experts assembled in an Expert Panel, Committee of MS Representatives, and national focus groups. Sufficient budget is reserved, also for coordination across the parallel H2020 Call PHC34 projects. Concrete strategy recommendations will be delivered to both MS, the EC, and SDOs about how SNOMED CT can scale up successful adoption and contribute to building a EU eHealth Interoperability Framework.

Agency: Cordis | Branch: FP7 | Program: CP | Phase: ICT-2013.5.2 | Award Amount: 3.71M | Year: 2014

The ClinicIMPPACT proposal builds upon the successful completion of the IMPPACT project (Grant No. 223877, completed in February 2012) that resulted in the creation of a physiological radio-frequency ablation (RFA) model for liver cancer treatment. This preliminary RFA model has been tested in porcine animal studies with extensive histological workup and in a clinical study using patient data for retrospective simulations.\nThe main objectives of this proposal are: (i) to bring the existing IMPPACT RFA model for liver cancer treatment into clinical practice; (ii) to verify and refine the model in a small clinical study; (iii) to develop the model into a real-time patient-specific RFA planning and support system for Interventional Radiologists (IR) under special consideration of their clinical workflow needs; (iv) to establish a corresponding training procedure for IRs; (v) to evaluate the practicality and benefit of the model for routine clinical purposes by analyzing user surveys and running expert forums.\nThe proposed RFA planning and support tool is therefore unique as it offers a validated software environment, where IRs can interact during the RFA treatment with the virtual tumour ablation through the extensive use of simulation and visualisation technology.

Agency: Cordis | Branch: FP7 | Program: CP-CSA-Infra-PP | Phase: INFRA-2010-2.2.8 | Award Amount: 4.79M | Year: 2010

In the context of the emerging and re-emerging infectious diseases involving highly pathogenic microorganisms, European countries have to be well-prepared to face such threats. However, the Biosafety Level 4 (BSL4) capacity in Europe is not sufficient enough to cover the efficient development of diagnosis, prophylactic and therapeutics means against these pathogens. Moreover, there is no global coordination of activities and harmonization of practice in this field. Therefore, the ERINHA project proposes the creation of a top world-class BSL4 research infrastructure that will address the actual European capacity sparseness. The project plans to conduct five main actions which are: (i) Building additional BSL4 areas in several existing BSL4 laboratories, (ii) Building BSL4 laboratories in strategically selected EU countries that are lacking one, (iii) Building a support infrastructure around BSL4 laboratories mainly dedicated to host scientific visitors and staff, (iv) Setting-up the user access to the ERINHA infrastructure, (v) Establishing coordination capacities for efficient dispatching and control of all activities. For 46 months, the ERINHA Preparatory Phase will focus on (i) Identifying relevant sites in Europe for new BSL4 constructions or major upgrades, (ii) Getting political and financial commitments from National, European or International concerned entities to support construction, (iii) Establishing a secured and validated financial plan for construction, (iv) Defining and implementing an appropriate governance and legal framework, (v) Harmonising and disseminating common procedures related to L4 biological resources, biosafety and biosecurity management, (iv) Defining and implementing joint training programs to operate in BSL4 facilities, (vii) Identifying the ERINHAs users and establishing rules for access. These achievements will allow the ERINHA project to reach the legal, financial and technical maturity to proceed to the construction phase.

Agency: Cordis | Branch: H2020 | Program: RIA | Phase: PHC-24-2015 | Award Amount: 18.47M | Year: 2016

The management of febrile patients is one of the most common and important problems facing healthcare providers. Distinction between bacterial infections and trivial viral infection on clinical grounds is unreliable, and as a result innumerable patients worldwide undergo hospitalization, invasive investigation and are treated with antibiotics for presumed bacterial infection when, in fact, they are suffering from self-resolving viral infection. We aim to improve diagnosis and management of febrile patients, by application of sophisticated phenotypic, transcriptomic (genomic, proteomic) and bioinformatic approaches to well characterised large-scale, multi-national patient cohorts already recruited with EU funding. We will identify, and validate promising new discriminators of bacterial and viral infection including transcriptomic and clinical phenotypic markers. The most accurate markers distinguishing bacterial and viral infection will be evaluated in prospective cohorts of patients reflecting the different health care settings across European countries. By linking sophisticated new genomic and proteomic approaches to careful clinical phenotyping, and building on pilot data from our previous studies we will develop a comprehensive management plan for febrile patients which can be rolled out in healthcare systems across Europe.

Agency: Cordis | Branch: H2020 | Program: CSA | Phase: SC1-HCO-02-2016 | Award Amount: 2.08M | Year: 2017

Molecular in vitro diagnostics and biomedical research have allowed great progress in personalised medicine but further progress is limited by insufficient guidelines for pre-analytical workflow steps (sample collection, preservation, storage, transport, processing etc.) as well as by insufficient quality assurance of diagnostic practice. This allows using compromised patients samples with post collection changes in cellular and extra-cellular biomolecules profiles thus often making diagnostic test results unreliable or even impossible. To tackle this, SPIDA4P aims to generate and implement a comprehensive portfolio of 22 pan-European pre-analytical CEN/Technical Specifications and ISO/International Standards, addressing the important pre-analytical workflows applied to personalized medicine. These will also applicable to biomarker discovery, development and validation as well as to biobanks. Corresponding External Quality Assurance (EQA) Schemes will be developed and implemented as well, aiming to survey the resulting quality of samples and diagnostic practice. SPIDIA4P will ensure stakeholder organisations involvements as well as training, education, and counselling as additional major foci of the project. The consortium will closely coordinate with large European public research consortia to obtain access to research and validation studies data serving as evidence for the new standards developments and achieved improvements of diagnosis, patient stratification and prognosis of disease outcome. At this crucial moment in the development of personalised medicine, SPIDIA4P proposes a coordination and support action that reunites 19 highly experienced partners in international standardisation for in vitro diagnostics, coming from private industry including SMEs, public institutions and from one official European Standards Organisation. This strong consortium is balanced and empowered to maximise the impacts of in vitro diagnostics on personalised medicine.

Agency: Cordis | Branch: FP7 | Program: CP-IP | Phase: KBBE.2011.2.2-03 | Award Amount: 11.56M | Year: 2012

Nutrition during early development has an important impact on later health, particularly through greater obesity risk, as demonstrated by FP6 EARNEST. EarlyNutrition explores the current key hypotheses on likely causes and pathways to prevention of early life origins of obesity (specifically adiposity) and associated disorders. We bring extraordinary expertise and study populations of 470,000 individuals to investigate: The fuel mediated in utero hypothesis The accelerated postnatal weight gain hypothesis The mismatch hypothesis. Scientific and technical expertise in placental biology, epigenetics and metabolomics will provide understanding at the cellular and molecular level, and refined strategies for intervention in pregnancy and early post natal life to prevent obesity. Using existing cohort studies, ongoing and novel intervention studies and a basic science programme, we will provide the scientific foundations for evidence based recommendations for optimal EarlyNutrition that incorporate long-term health outcomes, focusing on 4 Target Groups: women before pregnancy; pregnant women; infants (incl. breastfeeding); young children. Evidence is produced from animal and placental studies (Theme 1; T1), prospective cohort studies (T2), and randomised controlled trials in pregnant women and infants (T3). T4 covers scientific strategic integration, recommendation development and dissemination, including systematic reviews and behaviour change approaches. A strong multi-disciplinary team of international leaders in the field including collaborators from USA and Australia achieves balance and complementarity. The projects impact comprises definitive evidence on early nutrition effects on health, enhanced EU and global policies, major economic benefits through obesity prevention and value-added nutritional products, and practical recommendations on optimal nutrition in Target Groups. Wide dissemination will be achieved through active engagement with stakeholders.

Agency: Cordis | Branch: H2020 | Program: RIA | Phase: INFRAIA-1-2014-2015 | Award Amount: 10.23M | Year: 2015

The Europlanet 2020 Research Infrastructure (EPN2020-RI) will address key scientific and technological challenges facing modern planetary science by providing open access to state-of-the-art research data, models and facilities across the European Research Area. Its Transnational Access activities will provide access to world-leading laboratory facilities that simulate conditions found on planetary bodies as well as specific analogue field sites for Mars, Europa and Titan. Its Virtual Access activities will make available the diverse datasets and visualisation tools needed for comparing and understanding planetary environments in the Solar System and beyond. By providing the underpinning facilities that European planetary scientists need to conduct their research, EPN2020-RI will create cooperation and effective synergies between its different components: space exploration, ground-based observations, laboratory and field experiments, numerical modelling, and technology. EPN2020-RI builds on the foundations of successful FP6 and FP7 Europlanet programmes that established the Europlanet brand and built structures that will be used in the Networking Activities of EPN2020-RI to coordinate the European planetary science communitys research. It will disseminate its results to a wide range of stakeholders including industry, policy makers and, crucially, both the wider public and the next generation of researchers and opinion formers, now in education. As an Advanced Infrastructure we place particular emphasis on widening the participation of previously under-represented research communities and stakeholders. We will include new countries and Inclusiveness Member States, via workshops, team meetings, and personnel exchanges, to broaden/widen/expand and improve the scientific and innovation impact of the infrastructure. EPN2020-RI will therefore build a truly pan-European community that shares common goals, facilities, personnel, data and IP across national boundaries

Agency: Cordis | Branch: FP7 | Program: CP-IP | Phase: HEALTH-2007-1.2-5 | Award Amount: 13.82M | Year: 2008

In vitro diagnostics have allowed a great deal of progress in medicine but are limited by two factors: (a) the lack of guidelines in collection, handling, stabilisation and storage of biosamples which limits the reproducibility of subsequent diagnoses, and (b) its scale is restrained to the cellular level. To address this first point, this IP, SPIDIA, built of clinicians, academics, tool and assay developers, aims to develop quality guidelines for molecular in vitro diagnostics and to standardize the pre-analytical workflow in related procedures. Regarding the second point, SPIDIA aims to develop modern pre-analytical tools for diagnostics improving the stabilisation, handling and study of free biomolecules within blood, plasma, serum, tissues and tumours. Recent discoveries have revealed that RNA, DNA or proteins, released from pathological sites, like tumour cells or Alzheimers disease (AD) brain lesions, into the blood or as a secondary blood based response to the disease can serve as biomarkers for early and reliable molecular diagnosis of such debilitating diseases. Further discoveries have shown that the cellular profiles of these molecules and structures in clinical samples can change during transport and storage thus making clinical assay results and pharmaceutical research unreliable or even impossible. It will therefore be a decisive prerequisite for future and current diagnostic assays to develop standards and new technologies, tools and devices that eliminate the human error in the pre-analytical steps of in vitro diagnostics. At this crucial moment in the development of molecular diagnostics, SPIDIA proposes an IP that reunites 7 private research companies (including 4 SMEs), 1 private research institute, 6 public research organisms, including universities, hospitals and biobanks, one management SME and an official European Standards Organisation. This strong consortium is balanced and empowered to maximise the impacts of in vitro diagnostics on human health.

Agency: Cordis | Branch: FP7 | Program: CSA-CA | Phase: HEALTH.2013.4.1-5 | Award Amount: 2.34M | Year: 2013

The overall goal of InterConnect is to establish a global network that will facilitate the co-ordination of population research on the interaction between genetic and environmental factors in the aetiology of obesity and diabetes. We aim to establish mechanisms for identification and classification of studies and the data that they hold and create a forum for harmonization of methods as a foundation for optimizing the use of existing data for the study of gene-environment interaction. We aim to establish a funders forum and a forum for stakeholders and bring these groups together with subject-specific researchers and methodologists to create an appropriately governed framework for sharing existing data, harmonizing the addition of new data and planning new studies. With the involvement of strong funders and stakeholders fora in InterConnect from the outset, the project will provide a network to link, co-ordinate and eventually integrate EU funded research activities with those in other continents. InterConnect will provide a forum for exchange of information and best practice between projects. This will be relevant both to the research community and also the funders. The engagement of stakeholders and our dissemination programme will ensure that the knowledge that is ultimately gained through collaborative work in this network will be translated into policy, social and economic benefits. Through its work on an ethical and legal framework, InterConnect will create a sustainable framework that will facilitate data sharing that is transparent and dynamic.

Agency: Cordis | Branch: FP7 | Program: CP-CSA-Infra | Phase: INFRA-2007-2.2-01 | Award Amount: 7.16M | Year: 2008

The Preparatory Phase for a pan-European Biobanking and Biomolecular Resources Research Infrastructure (BBMRI) will focus on technical, legal, governance, and financial issues to prepare to construct BBMRI, building on existing biobanks, resources and technologies, specifically complemented with innovative components and properly embedded into European scientific, ethical, legal and societal frameworks, provide the concept for a key resource to increase excellence and efficacy in biomedical sciences, drug development and public health, expand and secure competitiveness of European research and industry in a global context, develop a sustainable financial framework. Biomedical quality-assessed samples and data as well as biomolecular resources and molecular analysis tools are essential for academic and industry-driven research to treat and prevent human diseases. Although currently established national biobanks and biomolecular resources are a unique European strength, valuable collections typically suffer from fragmentation of the European biobanking-related research community. This hampers the collation of biological samples and data from different biobanks required to achieve sufficient statistical power. Moreover, it results in duplication of effort and jeopardises sustainability due to the lack of long-term funding. BBMRI will comprise: biobanks of different formats (collections of blood, DNA, tissue, etc., together with medical, environmental, life-style and follow-up data), biomolecular resources (antibody and affinity binder collections, ORF clone collections, siRNA libraries, proteins, cellular resources etc.), enabling technologies and high-throughput analysis platforms and molecular tools to decipher gene, protein and metabolite functions and their interactions, harmonized standards for sample collection, storage, preanalytics and analysis harmonized databases and biocomputing infrastructure, ethical, legal and societal

Agency: Cordis | Branch: FP7 | Program: CP-IP | Phase: KBBE.2013.2.2-03 | Award Amount: 7.95M | Year: 2013

Vitamin D deficiency has significant implications for human health and impacts on healthy growth and development and successful aging. Fundamental knowledge gaps are barriers to implementing a safe and effective public health strategy to prevent vitamin D deficiency and optimize status. ODIN will provide the evidence to prevent vitamin D deficiency in Europe and improve nutrition and public health through food. By establishing an internationally standardized analytical platform for 25OHD, ODIN will measure the distribution of circulating 25OHD and describe the prevalence of vitamin D deficiency in Europe. Using available biobanks and databases from National nutrition surveys ODIN will delineate the relative contributions of sun and dietary sources of vitamin D to circulating 25OHD. In support of planned EFSA revisions of vitamin D recommendations, ODIN will carry out three RCT in pregnant women, children and teenagers and a fourth RCT in ethnic immigrant groups to provide experimental data to specify vitamin D intake requirements. Using dietary modeling, innovative food-based solutions to increase vitamin D in the food supply through a combination of bio-fortification of meats, fish, eggs, mushrooms and yeast will be developed and ODIN will test the efficacy and safety of these products in food-based RCT varying in scale from small product-specific trials to a large total diet study in vulnerable indigenous and immigrant sub-groups. ODIN has assembled the largest critical mass of prospective adult, pregnancy and birth cohort studies to date and will conduct meta-analyses and individual subject-level meta-regression analyses to integrate standardized data on vitamin D status, a priori defined clinical endpoints and genotype to examine relationships between vitamin D and human health, including beneficial and adverse effects, on perinatal outcomes, bone growth and body composition and allergic disease in children and cardiovascular disease and mortality in adults.

Agency: Cordis | Branch: FP7 | Program: CP-IP | Phase: HEALTH.2012.2.1.1-1-C | Award Amount: 17.68M | Year: 2012

Despite examples of excellent practice, rare disease (RD) research is still mainly fragmented by data and disease types. Individual efforts have little interoperability and almost no systematic connection between detailed clinical and genetic information, biomaterial availability or research/trial datasets. By developing robust mechanisms and standards for linking and exploiting these data, RD-Connect will develop a critical mass for harmonisation and provide a strong impetus for a global trial-ready infrastructure ready to support the IRDiRC goals for diagnostics and therapies for RD in close collaboration with the successful A/B projects. It will build on and transform the current state-of-the-art across databases, registries, biobanks, bioinformatics, and ethical considerations to develop a quality-assured and comprehensive integrated hub/platform in which complete clinical profiles are combined with -omics data and sample availability for RD research. The integrated, user-friendly RD-Connect platform, built on efficient informatics concepts already implemented in international research infrastructures for large-scale data management, will provide access to federated databases/registries, biobank catalogues, harmonised -omics profiles, and cutting-edge bioinformatics tools for data analysis. All patient data types will be linked via the generation of a unique identifier (RD-ID) developed jointly with the US NIH. The RD-Connect platform will be one of the primary enablers of progress in IRDiRC-funded research and will facilitate gene discovery, diagnosis and therapy development. RD-Connect has the RD field at its heart and brings together partners with a strong track record in RD research (gene discovery and development of innovative treatments), as well as committed IRDiRC funding partners and representatives of all major international RD initiatives (EU/US/AU/JP) spanning patient organisations, research and public health, to maximise impact to RD patients

Agency: Cordis | Branch: FP7 | Program: CP-CSA-Infra | Phase: INFRA-2011-2.3.2. | Award Amount: 13.73M | Year: 2012

The ESFRI infrastructures in Biological and BioMedical Sciences face substantial challenges in accessing and sharing data and resources. The BioMedBridges consortium brings together the six established ESFRI infrastructures with common goals to define, implement and deliver data interoperability across the biological and biomedical domains. The first objective is to ensure that interoperable standards are available across all data resources and services shared by two of more ESFRI infrastructure. The identified standards will be implemented to enable data interoperation between ESFRI projects in biomedical sciences. Public data in life sciences will be freely accessible through these standard interoperable services. Private data, however, is a major concern in this domain, for medical information or for data with intellectual property issues. Where projects need to share sensitive data, standards for secure and restricted access will be identified and implemented. BioMedBridges is a practical solution to the data interoperability requirements of infrastructures in the biological and biomedical domains. A suite of use cases will guide the development and deployment of standards and services with emphasis on the issues arising between specific projects. These may cover the exchange of biomedical and genetic data, linking mouse model organism data with human clinical information, and the deposition of large volumes of data from one project to another. BioMedBridges is inclusive of emerging infrastructures which can contribute additional data classes and challenges such as bioimaging, ecosystems, small molecules and infectious diseases. The ESFRI infrastructures leading BioMedBridges are ELIXIR, BBMRI, EATRIS, ECRIN, InfraFrontier and INSTRUCT.

Agency: Cordis | Branch: FP7 | Program: CSA-CA | Phase: SiS-2009-;SiS-2009- | Award Amount: 906.08K | Year: 2011

EURECNET is a network that brings together national REC associations, networks or comparable initiatives but also other bodies relevant in the field of research involving human participants like National Ethics Councils and the European Commissions ethical review system. Such a network forms the infrastructural basis to promote awareness of specific working practices of RECs across Europe, to enhance the shared knowledge base of European RECs, to support coherent reviews and opinions and to meet new challenges and emerging ethical issues. The central objective of EURECNET as a Coordinating Action is to foster the already existing network of European REC networks (in short EUREC). In particular, the contribution of EURECNET aims at five different levels: - fostering a sustainable infrastructure for European RECs (including a statute and a secretariat) to promote exchange and cooperation and to allow for international cooperation; - gathering information on RECs in Europe to build a basis for mutual exchange - collecting and evaluating training materials for REC members to enhance the quality of review; - conducting capacity building to facilitate the development of national REC networks (as future partners of EUREC); - identifying emerging ethical issues to develop common solutions for challenges posed by new technologies and scientific methodologies.

Agency: Cordis | Branch: FP7 | Program: CP-CSA-Infra | Phase: INFRA-2010-1.1.13 | Award Amount: 13.42M | Year: 2011

The objective of this project is the integration of world class high-throughput sequencing and genotyping facilities that will provide sequencing and genotyping technologies and data analysis methodologies to the scientific community. The European Sequencing and Genotyping Infrastructure (ESGI) will enable external users to generate data rapidly and to acquire knowledge efficiently. By providing access to the ESGI facilities in order to benefit from the sequencing and genotyping technologies, there will be an outreach and sustainable impact for the scientific community in the area of biological and medical research to generate new knowledge. The ESGI will optimise European research programs and foster transnational collaborations. In general, the ESGI will defragment and thereby strengthen the European research capacities in genetics and genomics and improve the knowledge transfer from large genomics centers among themselves and to external expert groups or scientists who are focusing on specific research questions. Our aim is to apply and improve new high-throughput nucleic acids analysis technologies for a broad range of genetic and systems biology studies using well-phenotyped samples, for example those derived from standardised European biobanks and animal facilities. In particular, massively-parallel sequencing technologies are essential components of modern biomedical research and are ready to reveal molecular and cellular pathways underlying complex traits and common diseases. As the European Strategy Forum for Research Infrastructures (ESFRI) pointed out in the past, the development of an efficient infrastructure for sequencing and genotyping is of crucial importance to position Europe as one of the world-leading regions for genetics, genomics and systems biology research and thus a contribution to the European Research Area.

Agency: Cordis | Branch: FP7 | Program: CP-IP | Phase: HEALTH.2011.2.1.1-3 | Award Amount: 17.32M | Year: 2011

Bacterial infection is the major cause of disability and death in children worldwide. We will use meningococcal disease (MD) as a model to understand genetic factors underlying susceptibility and severity of childhood bacterial infection which will then be applied to other childhood infections. We have established cohorts of patients with MD in Central and Southern Europe (CE,SE), UK and Africa as well as cohorts with other bacterial infections. We have established an inter-disciplinary team with expertise in Infectious Diseases, Immunogenetics, Bio-informatics, Microbiology, Public Health and Vaccinology including SME and industrial partners. We have already undertaken a genome wide study (GWAS) to identify genes causing susceptibility to meningococcal disease in a UK cohort. We identified complement factor H (fH) and fH-related (fHr) genes controlling MD susceptibility. This finding is fundamental to prevention as vaccines containing the MD fH receptor are undergoing trials. We will undertake GWAS on the CE, and SE MD cohorts, allowing meta analysis, and cross validation, and undertake GWAS on 2,500 Meningococcal Vaccine recipients. We will use next generation sequencing to identify the causal variants within the fH/fHr region and other regions implicated by pathway and severity analyses of the three MD GWAS and vaccine GWAS. We will match bacterial and host genetic variation and identify mechanisms of action of fH variants and other genes controlling susceptibility and severity using RNA expression, functional analyses and animal models. We will identify Mendelian defects and rare mutations as well as copy number variation and epi-genetic effects using next generation sequencing and RNA sequencing in extreme phenotype cohorts with MD , pneumococcal ,staphylococcal and salmonella disease. The study will identify mechanisms underlying susceptibility, provide new targets for treatment and prevention, and identify those at risk of disease or poor outcome.

Agency: Cordis | Branch: FP7 | Program: CP-IP | Phase: KBBE.2013.2.2-02 | Award Amount: 13.01M | Year: 2013

Emerging evidence indicates that the gut microbiome contributes to our ability to extract energy from the diet and influences development and function of the immune, endocrine and nervous systems, which regulate energy balance and behaviour. This has led to hypothesize that developing microbiome-based dietary interventions can be cost-effective measures to prevent diet-related and behavioural disorders. Yet this approach is restricted in practice by a lack of understanding of the specific species that contribute to these disorders and their interactions with host and lifestyle determinants. To progress beyond the state of the art, the MyNewGut proposal aims to: (1) shed light on the contribution of the human microbiome to nutrient metabolism and energy expenditure; (2) identify microbiome-related features that contribute to or predict obesity and associated disorders in human epidemiological studies; (3) understand how the microbiome is influenced by environmental factors and its role in brain and immune development and function in humans; and (4) provide proof-of-concept of the disease risk-reduction potential of dietary intervention with new foods/ingredients targeting the gut microbiome in humans. To this end, a translational multidisciplinary research strategy will be developed, combining experts in omic-technologies and all other scientific disciplines required. Consequently, the MyNewGut proposal will contribute to developing new approaches to prevent diet-related diseases (metabolic syndrome and obesity) and behavioural disorders through lifestyle changes, intake of pro- and prebiotics and semi-personalised and innovative food products. This will ultimately contribute to increasing the competitiveness of the European food industry and provide consumers with reliable claims on foods. Results will also help inform new strategies on public health, support EU legislation and improve the position of the EU in the field of food-related disease prevention.

Alcaraz I.,Autonomous University of Madrid | Cerroni L.,Medical University of Graz | Rutten A.,Dermatohistopathologische Gemeinschaftspraxis | Kutzner H.,Dermatohistopathologische Gemeinschaftspraxis | Requena L.,Autonomous University of Madrid
American Journal of Dermatopathology | Year: 2012

Skin metastases occur in 0.6%-10.4% of all patients with cancer and represent 2% of all skin tumors. Skin metastases from visceral malignancies are important for dermatologists and dermatopathologists because of their variable clinical appearance and presentation, frequent delay and failure in their diagnosis, relative proportion of different internal malignancies metastasizing to the skin, and impact on morbidity, prognosis, and treatment. Another factor to take into account is that cutaneous metastasis may be the first sign of clinically silent visceral cancer. The relative frequencies of metastatic skin disease tend to correlate with the frequency of the different types of primary cancer in each sex. Thus, women with skin metastases have the following distribution in decreasing order of frequency of primary malignancies: breast, ovary, oral cavity, lung, and large intestine. In men, the distribution is as follows: lung, large intestine, oral cavity, kidney, breast, esophagus, pancreas, stomach, and liver. A wide morphologic spectrum of clinical appearances has been described in cutaneous metastases. This variable clinical morphology included nodules, papules, plaques, tumors, and ulcers. From a histopathologic point of view, there are 4 main morphologic patterns of cutaneous metastases involving the dermis, namely, nodular, infiltrative, diffuse, and intravascular. Generally, cutaneous metastases herald a poor prognosis. The average survival time of patients with skin metastases is a few months. In this article, we review the clinicopathologic and immunohistochemical characteristics of cutaneous metastases from internal malignancies, classify the most common cutaneous metastases, and identify studies that may assist in diagnosing the origin of a cutaneous metastasis. Copyright © 2012 by Lippincott Williams & Wilkins.

Tantry U.S.,Sinai Hospital of Baltimore | Bonello L.,Aix - Marseille University | Aradi D.,Heart Center Balatonfured | Price M.J.,Scripps Research Institute | And 19 more authors.
Journal of the American College of Cardiology | Year: 2013

Dual antiplatelet therapy with aspirin and a P2Y12 receptor blocker is a key strategy to reduce platelet reactivity and to prevent thrombotic events in patients treated with percutaneous coronary intervention. In an earlier consensus document, we proposed cutoff values for high on-treatment platelet reactivity to adenosine diphosphate (ADP) associated with post-percutaneous coronary intervention ischemic events for various platelet function tests (PFTs). Updated American and European practice guidelines have issued a Class IIb recommendation for PFT to facilitate the choice of P2Y 12 receptor inhibitor in selected high-risk patients treated with percutaneous coronary intervention, although routine testing is not recommended (Class III). Accumulated data from large studies underscore the importance of high on-treatment platelet reactivity to ADP as a prognostic risk factor. Recent prospective randomized trials of PFT did not demonstrate clinical benefit, thus questioning whether treatment modification based on the results of current PFT platforms can actually influence outcomes. However, there are major limitations associated with these randomized trials. In addition, recent data suggest that low on-treatment platelet reactivity to ADP is associated with a higher risk of bleeding. Therefore, a therapeutic window concept has been proposed for P2Y 12 inhibitor therapy. In this updated consensus document, we review the available evidence addressing the relation of platelet reactivity to thrombotic and bleeding events. In addition, we propose cutoff values for high and low on-treatment platelet reactivity to ADP that might be used in future investigations of personalized antiplatelet therapy. © 2013 by the American College of Cardiology Foundation.

Vieth M.,Institute of Pathology | Langner C.,Medical University of Graz | Neumann H.,Friedrich - Alexander - University, Erlangen - Nuremberg | Takubo K.,Tokyo Metropolitan Hospital
Pathology Research and Practice | Year: 2012

Most clinicians and researchers agree that Barrett's esophagus (BE) is a precancerous condition which, however, is not easily defined. Whether goblet cells must be present or not is a matter of debate and definitions vary worldwide. Although the use of the term " columnar metaplasia" tends to circumvent these issues, it can also be subdivided into those with and without goblet cells. There is some evidence that Barrett's esophagus results from a multistep process in which goblet cells are a secondary event. Hence, Barrett's adenocarcinoma has recently been shown to originate from areas lacking goblet cells. The histological diagnosis of neoplasia is often hampered by marked interobserver variation. New endoscopic techniques allow for local resections of neoplasia with curative intent. Pathologists should know which pieces of information gastroenterologists need for management options: surveillance versus therapy such as endoscopic resection with or endoscopic ablation without histological specimen. The most important information for gastroenterologists is whether there is neoplasia or not; if any, they need to know the grade (low grade, high grade, carcinoma) and risk factors (vessel permeation, poor differentiation, resection complete in case of endoscopic resection, depth of infiltration). © 2012 Elsevier GmbH.

Wiesner T.,Sloan Kettering Cancer Center | Murali R.,Sloan Kettering Cancer Center | Murali R.,Medical University of Graz | Fried I.,Sloan Kettering Cancer Center | And 7 more authors.
American Journal of Surgical Pathology | Year: 2012

We recently reported that germline mutations in BAP1 cause a familial tumor syndrome characterized by high penetrance for melanocytic tumors with distinct clinical and histologic features. Melanocytic neoplasms in affected individuals harbored BRAF mutations, showed loss of BAP1 expression, and histologically resembled so-called "atypical Spitz tumors" (ASTs). ASTs are an ill-defined and probably heterogenous group of melanocytic tumors that display histologic features seen in both Spitz nevi and melanomas. Their biological behavior cannot be reliably predicted. In view of the histologic similarities of the familial tumors and ASTs, we hypothesized that a subset of ASTs might harbor genetic alterations seen in the familial tumors. To address this hypothesis, we analyzed 32 sporadic ASTs for BRAF mutations and for BAP1 expression. Nine (28%) sporadic ASTs showed loss of BAP1 expression, of which 8 (89%) had concomitant BRAF mutations. Only 1 of the BAP1-positive ASTs (4%) had a BRAF mutation (P<0.0001). BRAF-mutated, BAP1-negative tumors were primarily located in the dermis and were composed entirely or predominantly of epithelioid melanocytes with abundant amphophilic cytoplasm and well-defined cytoplasmic borders. Nuclei were commonly vesicular and exhibited substantial pleomorphism and conspicuous nucleoli. The combination of BRAF mutation and loss of nuclear BAP1 expression thus characterizes a subset of ASTs with distinct histologic features. The typical morphology of these tumors and BAP1 immunohistochemistry provide pathologic clues that will enable accurate identification of this subset. Future studies are necessary to determine whether this subset has a predictable clinical behavior. © 2012 by Lippincott Williams & Wilkins.

Zittermann A.,Ruhr University Bochum | Iodice S.,Italian National Cancer Institute | Pilz S.,Medical University of Graz | Grant W.B.,Nutrition and Health Research Center | And 3 more authors.
American Journal of Clinical Nutrition | Year: 2012

Background: Low vitamin D status may increase mortality risk. Objective: We used nonparametric ("highest compared with lowest"categories) and parametric (>2 categories) statistical models to evaluate associations of 25-hydroxyvitamin D [25(OH)D] serum concentrations and mortality in observational studies among general populations. Design: We searched PubMed, EMBASE, Web of Science, and reference lists for relevant articles. We included studies that contained data on relative risks (RRs) for mortality for different 25(OH)D concentrations, which included a corresponding measure of uncertainty, and this yielded 14 prospective cohort studies that involved 5562 deaths out of 62,548 individuals. We applied logtransformed RRs and CIs, adjusted for the maximal number of confounding variables. In the parametric model, which is based on 11 studies and 59,231 individuals, we used the lowest quantile as the reference category. Results: For "highest compared with lowest" categories of 25(OH)D, the estimated summary RR of mortality was 0.71 (95% CI: 0.50, 0.91). In the parametric model, the estimated summary RRs (95% CI) of mortality were 0.86 (0.82, 0.91), 0.77 (0.70, 0.84), and 0.69 (0.60, 0.78) for individuals with an increase of 12.5, 25, and 50 nmol 25(OH)D serum values/L, respectively, from a median reference category of ∼27.5 nmol/L. There was, however, no significant decrease in mortality when an increase of ∼87.5 nmol/L above the reference category occurred. Conclusion: Data suggest a nonlinear decrease in mortality risk as circulating 25(OH)D increases, with optimal concentrations ∼75-87.5 nmol/L. © 2012 American Society for Nutrition.

Sundgot-Borgen J.,Norwegian School of Sport Sciences | Meyer N.L.,University of Colorado at Colorado Springs | Lohman T.G.,University of Arizona | Ackland T.R.,University of Western Australia | And 3 more authors.
British Journal of Sports Medicine | Year: 2013

A focus on low body weight and body fat content, combined with regulations in some weight-sensitive sports, are considered risk factors for extreme dieting, eating disorders (EDs) and related health consequences among athletes. At present there are, from a health perspective, no generally accepted optimum values for body weight or percentage of fat mass in different sports and there is no 'gold standard' method for body composition assessment in athletes. On the basis of health considerations as well as performance, medical support teams should know how to approach elite athletes who seek to achieve an unrealistic body composition and how to prevent restrictive eating practices from developing into an ED. In addition, these teams must know when to raise the alarm and how to advice athletes who are affected by extreme dieting or clinical EDs. However, there is no consensus on when athletes struggling with extreme dieting or EDs should be referred for specialist medical treatment or removed from competition. Based on the present review, we conclude that there is a need for (1) sport-specific and gender-specific preventive programmes, (2) criteria for raising alarm and 'does not start' (DNS) for athletes with EDs and (3) modifications to the regulations in some sports. Further, the key areas for research identified include the development of standard methods for body composition assessment in elite athletes; screening measures for EDs among athletes; development and testing of prevention programmes; investigating the short and long-term effects of extreme dieting; and EDs on health and performance.

Kleber M.E.,University of Heidelberg | Delgado G.,University of Heidelberg | Grammer T.B.,University of Heidelberg | Silbernagel G.,University of Bern | And 6 more authors.
Journal of the American Society of Nephrology | Year: 2015

Obesity and diets rich in uric acid-raising components appear to account for the increased prevalence of hyperuricemia in Westernized populations. Prevalence rates of hypertension, diabetes mellitus, CKD, and cardiovascular disease are also increasing.We used Mendelian randomization to examine whether uric acid is an independent and causal cardiovascular risk factor. Serum uric acid was measured in 3315 patients of the Ludwigshafen Risk and Cardiovascular Health Study. We calculated a weighted genetic risk score (GRS) for uric acid concentration based on eight uric acid-regulating single nucleotide polymorphisms. Causal odds ratios and causal hazardratios (HRs)were calculatedusing a two-stage regression estimatewith theGRS as the instrumental variable to examine associations with cardiometabolic phenotypes (cross-sectional) and mortality (prospectively) by logistic regression and Cox regression, respectively. Our GRS was not consistently associated with any biochemical marker except for uric acid, arguing against pleiotropy. Uric acid was associated with a range of prevalent diseases, including coronary artery disease. Uric acid and the GRS were both associated with cardiovascular death and sudden cardiac death. In a multivariate model adjusted for factors including medication, causal HRs corresponding to each 1-mg/dl increase in genetically predicted uric acid concentration were significant for cardiovascular death (HR, 1.77; 95% confidence interval, 1.12 to 2.81) and sudden cardiac death (HR, 2.41; 95% confidence interval, 1.16 to 5.00). These results suggest that high uric acid is causally related to adverse cardiovascular outcomes, especially sudden cardiac death. Copyright © 2015 by the American Society of Nephrology.

Pilz S.,VU University Amsterdam | Pilz S.,Medical University of Graz | Rutters F.,VU University Amsterdam | Nijpels G.,VU University Amsterdam | And 6 more authors.
Diabetes Care | Year: 2014

OBJECTIVE Accumulating evidence suggests an association between insulin sensitivity and albuminuria, which, even in the normal range, is a risk factor for cardiovascular diseases.We evaluated whether insulin sensitivity is associated with albuminuria in healthy subjects. RESEARCH DESIGN AND METHODS We investigated 1,415 healthy, nondiabetic participants (mean age 43.9 6 8.3 years; 54.3% women) fromthe RISC (Relationship between Insulin Sensitivity and Cardiovascular Disease) study, of whom 852 participated in a follow-up examination after 3 years. At baseline, insulin sensitivity was assessed by hyperinsulinemic- euglycemic clamps, expressed as the M/I value. Oral glucose tolerance test-based insulin sensitivity (OGIS), homeostasis model assessment of insulin resistance (HOMA-IR), and urinary albumin-to-creatinine ratio (UACR) were determined at baseline and follow-up. RESULTS Microalbuminuria (UACR ≥30 mg/g) was present in fewer than 2% at either study visit. After multivariate adjustments, there was no cross-sectional association between UACR and any measure of insulin sensitivity. Neither OGIS nor HOMA-IR was significantly associated with follow-up UACR, but in a multivariate regression analysis, baseline M/I emerged as an independent predictor of UACR at follow-up (β-coefficient 20.14; P = 0.001). CONCLUSIONS In healthy middle-aged adults, reduced insulin sensitivity, assessed by hyperinsulinemic-euglycemic clamp, is continuously associated with a greater risk of increasing albuminuria. This finding suggests that reduced insulin sensitivity either is simply related to or might causally contribute to the initial pathogenesis of albuminuria. © 2014 by the American Diabetes Association.

Fajkovic H.,Landesklinikum St. Poelten | Klatte T.,Medical University of Vienna | Nagele U.,Landeskrankenhaus Hall in Tirol | Dunzinger M.,Landeskrankenhaus Vocklabruck | And 3 more authors.
World Journal of Urology | Year: 2013

Introduction: Through evolution in technology, endoscopic treatment has gained popularity for the treatment of upper tract urothelial carcinoma (ENDO-UTUC). Methods: A total of 20 patients with ENDO-UTUC were compared to 178 treated by radical nephroureterectomy (RNU) for a pTa-1 UTUC, and a systematic review was performed. Results: Mean age for ENDO-UTUC was 71. 9 ± 16. 0 years, and tumor features were favorable (90 % papillary, 14 low grade, 11 pTa). All ENDO-UTUC were performed ureteroscopically. Mean follow-up was 20. 4 ± 30 months. The 5-year overall survival (OS) rate was 45 %. Local (LR) and bladder recurrence (BR) was 25 and 15 %. Time to definitive treatment was longer, ASA higher, LR rates higher, OS lower for ENDO-UTUC (all p < 0. 001), but no difference was recorded for BR (p = 0. 056) and cancer-specific survival (CSS) (p = 0. 364). Postoperative kidney function (KF) was better in the ENDO-UTUC (p = 0. 048), though preoperative KF showed no difference. The maximal level of evidence was 3b, patients were highly selected, numbers of patients were low, and ASA scores high. OS was rather low and CSS high. LR rate was high (61 %) and BR rate moderate (39 %) for ureteroscopic and 36 and 28 %, respectively, for percutaneous approach. Conclusions: LR for ENDO-UTUC is high. In high-grade UTUC, oncological outcome is worse. RNU is associated with a significant loss of KF, but LR is rare. ENDO-UTUC is reserved for selected cases if elective. In imperative cases, it has to be balanced between KF, morbidity of the procedure, risk of operation and tumor control. ENDO-UTUC is not necessarily underused in Austria, because of lack in evidence, but 41 % of all RNU were performed in pTa/pTis/pT1 lesions. © 2012 Springer-Verlag.

Bishop M.J.,King's College London | Vigmond E.J.,University of Bordeaux 1 | Plank G.,Medical University of Graz | Plank G.,University of Oxford
American Journal of Physiology - Heart and Circulatory Physiology | Year: 2013

Electrophysiological heterogeneity in action potential recordings from healthy intact hearts remains highly variable and, where present, is almost entirely abolished at fast pacing rates. Consequently, the functional importance of intrinsic action potential duration (APD) heterogeneity in healthy ventricles, and particularly its role during rapidly activating reentrant arrhythmias, remain poorly understood. By incorporating both transmural and apicobasal APD heterogeneity within a biventricular rabbit computational model and comparing with an equivalent homogeneous model, we directly investigated the functional importance of intrinsic APD heterogeneity under fast pacing and arrhythmogenic protocols. Although differences in APD were significantly modulated at the tissue level during pacing and further reduced as pacing frequency increased, small differences were still noticeable. Such differences were further marginally accentuated/ attenuated via electrotonic effects relative to wavefront propagation directions. The remaining small levels of APD heterogeneity under the fastest pacing frequencies resulted in arrhythmia initiation via heterogeneous conduction block, in contrast to complete block in the homogeneous model. Such induction mechanisms were more evident during premature stimuli at slower paced rhythms where intrinsic heterogeneity remained to a greater degree. During sustained arrhythmias, however, intrinsic heterogeneity made little difference to overall reentrant behavior, either visually, or in terms of duration, metrics quantifying filament/phase singularity dynamics, and global electrocardiogram characteristics. These findings suggest that, despite being important during arrhythmia initiation, intrinsic electrophysiological heterogeneity plays little functional role during rapid pacing and sustained arrhythmia dynamics in the healthy ventricle and thus questions the need to incorporate such detail in computational models when simulating rapid arrhythmias. © 2013 the American Physiological Society.

Tong J.,University of Graz | Schriefl A.J.,University of Graz | Cohnert T.,Medical University of Graz | Holzapfel G.A.,University of Graz | Holzapfel G.A.,KTH Royal Institute of Technology
European Journal of Vascular and Endovascular Surgery | Year: 2013

Objective: The main purpose of the present study is the investigation of gender differences in the biomechanical properties, thrombus age, mass fraction and key clinical factors of abdominal aortic aneurysms (AAAs). Materials and methods: A total of 90 AAA samples (78 males and 12 females) were harvested from open surgical aneurysm repairs. Biaxial extension and peeling tests were performed to characterise the biaxial mechanical responses and to determine dissection properties of both the intraluminal thrombi (ILTs) and the thrombus-covered walls. Relative thrombus age was determined by characterising the ILT histological microstructure. Mass fraction analyses quantified dry weight percentages of elastin and collagen within the AAA walls. Moreover, we statistically compared clinical factors between male and female. Results: The luminal layers of the female thrombi and the female AAA walls showed a significantly lower tissue stiffness (modulus) in the longitudinal direction when compared to males. Gender differences were also shown in the dissection properties of the intima-media composite within the AAA walls, in which a statistically significantly lower energy to propagate a dissection was quantified for females than for males. Moreover, 82% of female thrombi were relatively older (ILT age phases III and IV), twice that of male thrombi (43%). A pronounced lower elastin content was identified for the intima-media composites of male AAA walls, whereas female AAA walls had significantly lower dry weight percentages of collagen. Regarding clinical factors, nicotine pack years, serum creatinine and AAA expansion rate were found to be much higher for male patients. Conclusion: These findings may help to explain higher risks for AAA growth in males and the ruptures of smaller-sized AAAs in females. © 2012 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.

Pilz S.,Medical University of Graz | Pilz S.,VU University Amsterdam | Iodice S.,Italian National Cancer Institute | Zittermann A.,Ruhr University Bochum | And 2 more authors.
American Journal of Kidney Diseases | Year: 2011

Background: Vitamin D deficiency, assessed as low 25-hydroxyvitamin D (25[OH]D) level, is highly prevalent in patients with chronic kidney disease (CKD) and is associated with various adverse health outcomes. Whether low 25(OH)D levels in patients with CKD are an independent risk factor for mortality remains to be studied in detail, and this was the objective of our work. Study Design: A systematic review and meta-analysis of prospective observational studies. Setting & Population: Patients with CKD. CKD was diagnosed mainly as decreased estimated glomerular filtration rate. Selection Criteria for Studies: We performed a systematic literature search in MEDLINE, ISI, and EMBASE to identify prospective studies reporting on 25(OH)D levels and mortality. Predictor: 25(OH)D serum concentrations. Outcome: All-cause mortality. Results: 10 studies with an overall sample of 6,853 patients with CKD were included. Relative risk of mortality per 10-ng/mL (25-nmol/L) increase in 25(OH)D level was 0.86 (95% CI, 0.82-0.91), with no indication of publication bias or significant heterogeneity (I2 =15%; P = 0.3). Summary estimates for CKD cohorts with and without dialysis treatment showed homogeneous results (P = 0.9). Limitations: Results may be limited by heterogeneity, unconsidered confounders, and the observational design of the studies. Furthermore, publication bias by unpublished null findings on the association of 25(OH)D level and mortality cannot be ruled out and ascertainment of CKD was based largely on estimated glomerular filtration rate. Conclusions: Higher 25(OH)D levels are associated with significantly improved survival in patients with CKD. Whether treatment of low 25(OH)D level using natural vitamin D supplementation improves survival in patients with CKD remains to be elucidated in randomized controlled trials. © 2011 National Kidney Foundation, Inc.

Weisbecker H.,University of Graz | Pierce D.M.,University of Graz | Regitnig P.,Medical University of Graz | Holzapfel G.A.,University of Graz | Holzapfel G.A.,KTH Royal Institute of Technology
Journal of the Mechanical Behavior of Biomedical Materials | Year: 2012

Many treatments for cardiovascular diseases include an endovascular insertion of stents or stent grafts into arteries, a procedure which may cause high tissue stresses and even damage in the arterial wall. In order to study such problems by using finite element methods, both appropriate constitutive models and experimental data on human tissue samples are required. Layer-specific experimental data for human tissue tested up to the supra-physiological loading range are rare in the literature. In this study, intact and layer-separated experimental data from uniaxial extension tests are presented for human thoracic and abdominal aortas with non-atherosclerotic intimal thickening undergoing supra-physiological loading. A novel pseudo-elastic damage model, proposed to describe discontinuous softening in aortic arterial tissues, is fit to the obtained experimental data. Fitting of the model with and without consideration of damage accumulation in the non-collagenous matrix material reveals that tissue damage is primarily related to the collagen fiber fabric. By employing the fit model, the effect of aortic tissue pre-conditioning on the material parameters from the resulting data fits is evaluated. Histological examination of the collagen fibers under different applied stretches is used to gain more insights into the structural changes of the tissue under supra-physiological loading. © 2012 Elsevier Ltd.

Hofstetter J.,ETH Zurich | Martinelli E.,Medical University of Graz | Weinberg A.M.,Medical University of Graz | Becker M.,ETH Zurich | And 3 more authors.
Corrosion Science | Year: 2015

The biodegradation of ultrahigh-purity Mg (XHP Mg, Fe≈2ppm) was tested in vitro in NaHCO3/CO2-buffered simulated body fluid and in vivo in the femur of rats. The in vitro degradation rate, which was evaluated using an also here described newly designed hydrogen evolution testing setup, is with ≈10±3μm/y very low and shows very good agreement with in vivo data. The results for XHP Mg are also compared with in vitro tests on high-purity Mg (Fe≈37ppm) in the as-cast and annealed states. The less pure specimens exhibit significantly higher degradation rates due to the formation of Fe-containing precipitates during casting and annealing. © 2014 Elsevier Ltd.

Lopez-Garcia P.,University of the Basque Country | Boeker M.,Albert Ludwigs University of Freiburg | Illarramendi A.,University of the Basque Country | Schulz S.,Albert Ludwigs University of Freiburg | Schulz S.,Medical University of Graz
Journal of the American Medical Informatics Association | Year: 2012

Objectives: To study ontology modularization techniques when applied to SNOMED CT in a scenario in which no previous corpus of information exists and to examine if frequency-based filtering using MEDLINE can reduce subset size without discarding relevant concepts. Materials and Methods: Subsets were first extracted using four graph-traversal heuristics and one logic-based technique, and were subsequently filtered with frequency information from MEDLINE. Twenty manually coded discharge summaries from cardiology patients were used as signatures and test sets. The coverage, size, and precision of extracted subsets were measured. Results: Graph-traversal heuristics provided high coverage (71-96% of terms in the test sets of discharge summaries) at the expense of subset size (17-51% of the size of SNOMED CT). Pre-computed subsets and logic-based techniques extracted small subsets (1%), but coverage was limited (24-55%). Filtering reduced the size of large subsets to 10% while still providing 80% coverage. Discussion: Extracting subsets to annotate discharge summaries is challenging when no previous corpus exists. Ontology modularization provides valuable techniques, but the resulting modules grow as signatures spread across subhierarchies, yielding a very low precision. Conclusion: Graph-traversal strategies and frequency data from an authoritative source can prune large biomedical ontologies and produce useful subsets that still exhibit acceptable coverage. However, a clinical corpus closer to the specific use case is preferred when available.

Requena L.,Autonomous University of Madrid | Cerroni L.,Medical University of Graz | Kutzner H.,Dermatopathologie Friedrichshafen
Dermatologic Clinics | Year: 2012

A large number of foreign substances may penetrate the skin for both voluntary and involuntary reasons. The voluntary group includes the particulate materials used in tattoos and cosmetic fillers, whereas the involuntary group is almost always caused by accidental inclusion of external substances secondary to cutaneous trauma. This article focuses on the histopathologic findings seen in cutaneous reactions to exogenous agents, with special emphasis on the microscopic morphology of the external particles in recognizing specifically the involved substance (something that is becoming increasingly important in the event of litigation). © 2012 Elsevier Inc.

Ackland T.R.,University of Western Australia | Lohman T.G.,University of Arizona | Sundgot-Borgen J.,Norwegian School of Sport Sciences | Maughan R.J.,Loughborough University | And 3 more authors.
Sports Medicine | Year: 2012

Quantifying human body composition has played an important role in monitoring all athlete performance and training regimens, but especially so in gravitational, weight class and aesthetic sports wherein the tissue composition of the body profoundly affects performance or adjudication. Over the past century, a myriad of techniques and equations have been proposed, but all have some inherent problems, whether in measurement methodology or in the assumptions they make. To date, there is no universally applicable criterion or 'gold standard' methodology for body composition assessment. Having considered issues of accuracy, repeatability and utility, the multi-component model might be employed as a performance or selection criterion, provided the selected model accounts for variability in the density of fat-free mass in its computation. However, when profiling change in interventions, single methods whose raw data are surrogates for body composition (with the notable exception of the body mass index) remain useful. © 2012 Adis Data Information BV. All rights reserved.

Tong J.,University of Graz | Cohnert T.,Medical University of Graz | Regitnig P.,Medical University of Graz | Holzapfel G.A.,University of Graz | Holzapfel G.A.,KTH Royal Institute of Technology
European Journal of Vascular and Endovascular Surgery | Year: 2011

Objective: The intraluminal thrombus (ILT) present in the majority of abdominal aortic aneurysms (AAAs) plays an important role in aneurysm wall weakening. Studying the age-dependent elastic properties of the ILT and the thrombus-covered wall provides a better understanding of the potential effect of ILT on AAA remodelling. Materials and methods: A total of 43 AAA samples (mean age 67 ± 6 years) including ILT and AAA wall was harvested. Biaxial extension tests on the three individual ILT layers and the thrombus-covered wall were performed. Histological investigations of the thrombi were performed to determine four different age phases, and to correlate with the change in the mechanical properties. A three-dimensional material model was fitted to the experimental data. Results: The luminal layers of the ILT exhibit anisotropic stress responses, whereas the medial and the abluminal layers are isotropic materials. The stresses at failure in the equibiaxial protocol continuously decrease from the luminal to the abluminal side, whereby cracks, mainly oriented along the longitudinal direction, can be observed in the ruptured luminal layers. The thrombi in the third and fourth phases contribute to wall weakening and to an increase of the mechanical anisotropy of their covered walls. The material models for the thrombi and the thrombus-covered walls are in excellent agreement with the experimental data. Conclusion: Our results suggest that thrombus age might be a potential predictor for the strength of the wall underneath the ILT and AAA rupture. © 2011 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.

Charli-Joseph Y.,National Institute of Health science and Nutrition | Cerroni L.,Medical University of Graz | Leboit P.E.,University of California at San Francisco
American Journal of Surgical Pathology | Year: 2015

Cutaneous lymphomas of both B cells and less commonly T cells can exceptionally exhibit spindle-cell morphology. Less than 30 spindle-cell B-cell lymphomas of the skin have been described, mostly before the adoption of detailed immunohistochemistry, and thus initially interpreted as variants of diffuse large B-cell lymphoma (DLBCL). Furthermore, some authors suggest that cutaneous spindle-cell B-cell lymphomas (cSCBCLs) may behave more aggressively than their conventional morphologic counterparts and may thus merit more aggressive treatment. Herein we describe the largest case series of cSCBCL analyzed to date to characterize their clinicopathologic and immunohistochemical features and clarify their subtype according to the current WHO/EORTC classification scheme. Twenty-four cSCBCLs arose in 18 male and 6 female individuals with a mean age of 55 years, mostly on the head (12/24), trunk (8/24), and lower extremities (4/24). Histopathologic features were similar for all cases. Neoplasms involved the entire dermis and focally the subcutis. The neoplastic infiltrates comprised a mixture of medium-sized, visually prominent spindled cells (15%; up to 85% of the infiltrate) arranged in a fascicular pattern around nodular aggregates and admixed in a random manner between centrocyte/centroblast-like cells within these nodular collections. Immunohistochemical support for a follicular center cell origin was present in 22/24 cases, 1 was consistent with DLBCL-leg type and 1 defied precise classification, best fitting with intermediate-grade DLBCL-other. Our findings reinforce the concept that most cSCBCLs are variants of low-grade B-cell lymphomas of follicle center cell origin and not intermediate-grade variants of DLBCL. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Bishop M.J.,King's College London | Plank G.,Medical University of Graz | Plank G.,University of Oxford
Frontiers in Physiology | Year: 2014

Light scattering during optical imaging of electrical activation within the heart is known to significantly distort the optically-recorded action potential (AP) upstroke, as well as affecting the magnitude of the measured response of ventricular tissue to strong electric shocks. Modelling approaches based on the photon diffusion equation have recently been instrumental in quantifying and helping to understand the origin of the resulting distortion. However, they are unable to faithfully represent regions of non-scattering media, such as small cavities within the myocardium which are filled with perfusate during experiments. Stochastic Monte Carlo (MC) approaches allow simulation and tracking of individual photon 'packets' as they propagate through tissue with differing scattering properties. Here, we present a novel application of the MC method of photon scattering simulation, applied for the first time to the simulation of cardiac optical mapping signals within unstructured, tetrahedral, finite element computational ventricular models. The method faithfully allows simulation of optical signals over highly-detailed, anatomically-complex MR-based models, including representations of fine-scale anatomy and intramural cavities. We show that optical action potential upstroke is prolonged close to large subepicardial vessels than further away from vessels, at times having a distinct 'humped' morphology. Furthermore, we uncover a novel mechanism by which photon scattering effects around vessels cavities interact with 'virtual-electrode' regions of strong de-/hyper-polarised tissue surrounding cavities during shocks, significantly reducing the apparent optically-measured epicardial polarisation. We therefore demonstrate the importance of this novel optical mapping simulation approach along with highly anatomically-detailed models to fully investigate electrophysiological phenomena driven by fine-scale structural heterogeneity. © 2014 Bishop and Plank.

Sommer G.,University of Graz | Regitnig P.,Medical University of Graz | Koltringer L.,Medical University of Graz | Holzapfel G.A.,University of Graz | Holzapfel G.A.,KTH Royal Institute of Technology
American Journal of Physiology - Heart and Circulatory Physiology | Year: 2010

Specimens of intact wall tubes of human common carotid arteries (CCA), internal carotid arteries (ICA) (n = 11, age 77.6 yr, SD 6.3), and related adventitia and media-intima tubes are mechanically examined. Cyclic, quasi-static extension-inflation tests at different axial stretches are performed on preconditioned tube specimens. Stress-free configurations show significant stress releases in the circumferential direction of the intact CCA and ICA walls and in the axial directions of the intact CCA walls and the CCA and ICA adventitias. All investigated tissues exhibit strong nonlinear, pseudoelastic mechanical behavior with small hysteresis. The "inversion" feature, where the pressure/axial stretch relationship becomes a vertical line, is found only for intact walls. Axial "inversion stretches" are 1.15 (SD 0.06) for CCA and 1.14 (SD 0.06) for ICA, and related external axial forces are 0.43 N (SD 0.15) and 0.30 N (SD 0.22), respectively. Significant negative correlations between age and axial inversion stretches for CCA (r = -0.67, P = 0.03) and ICA (r = -0.29, P = 0.04) are identified. Adventitias are very compliant at low pressures, but change into stiff tubes at high pressures. The burst pressure of the adventitia is beyond 250 kPa. A relatively low burst pressure of ∼60 kPa is found in the media-intima tubes, in which the pressure/circumferential stretch relationships are almost independent of the axial stretches. Stress analyses indicate a high degree of material anisotropy for all investigated tissues. High circumferential and axial stresses occur in the media-intima tubes at physiological conditions. The obtained data are intended to serve for an improvement of constitutive laws, determination of constitutive parameters, and enhancing our knowledge of the mechanical functions of arteries and their associated layers in specific pathophysiological and clinical problems, such as hypertension and angioplasty with stenting. Copyright © 2010 American Physiological Society.

Bishop M.J.,King's College London | Plank G.,Medical University of Graz | Plank G.,University of Oxford
Journal of Physiology | Year: 2012

Fine-scale anatomical structures in the heart may play an important role in sustaining cardiac arrhythmias. However, the extent of this role and how it may differ between species are not fully understood. In this study we used computational modelling to assess the impact of anatomy upon arrhythmia maintenance in the rabbit ventricles. Specifically, we quantified the dynamics of excitation wavefronts during episodes of simulated tachyarrhythmias and fibrillatory arrhythmias, defined as being respectively characterised by relatively low and high spatio-temporal disorganisation. Two computational models were used: a highly anatomically detailed MR-derived rabbit ventricular model (representing vasculature, endocardial structures) and a simplified equivalent model, constructed from the same MR-data but lacking such fine-scale anatomical features. During tachyarrhythmias, anatomically complex and simplified models showed very similar dynamics; however, during fibrillatory arrhythmias, as activation wavelength decreased, the presence of fine-scale anatomical details appeared to marginally increase disorganisation of wavefronts during arrhythmias in the complex model. Although a small amount of clustering of reentrant rotor centres (filaments) around endocardial structures was witnessed in follow-up analysis (which slightly increased during fibrillation as rotor size decreased), this was significantly less than previously reported in large animals. Importantly, no anchoring of reentrant rotors was visibly identifiable in arrhythmia movies. These differences between tachy- and fibrillatory arrhythmias suggest that the relative size of reentrant rotors with respect to anatomical obstacles governs the influence of fine-scale anatomy in the maintenance of ventricular arrhythmias in the rabbit. In conclusion, our simulations suggest that fine-scale anatomical features play little apparent role in the maintenance of tachyarrhythmias in the rabbit ventricles and, contrary to experimental reports in larger animals, appear to play only a minor role in the maintenance of fibrillatory arrhythmias. These findings also have important implications in optimising the level of detail required in anatomical computational meshes frequently used in arrhythmia investigations. © 2012 The Physiological Society.

Rosenfield K.,Massachusetts General Hospital | Jaff M.R.,Massachusetts General Hospital | White C.J.,Ochsner Medical Center | Rocha-Singh K.,Prairie Heart Institute At St Johns Hospital | And 11 more authors.
New England Journal of Medicine | Year: 2015

BACKGROUND The treatment of peripheral artery disease with percutaneous transluminal angioplasty is limited by the occurrence of vessel recoil and restenosis. Drug-coated angioplasty balloons deliver antiproliferative agents directly to the artery, potentially improving vessel patency by reducing restenosis. METHODS In this single-blind, randomized trial conducted at 54 sites, we assigned, in a 2:1 ratio, 476 patients with symptomatic intermittent claudication or ischemic pain while at rest and angiographically significant atherosclerotic lesions to angioplasty with a paclitaxel-coated balloon or to standard angioplasty. The primary efficacy end point was primary patency of the target lesion at 12 months (defined as freedom from binary restenosis or from the need for target-lesion revascularization). The primary safety end point was a composite of freedom from perioperative death from any cause and freedom at 12 months from limb-related death (i.e., death from a medical complication related to a limb), amputation, and reintervention. RESULTS The two groups were well matched at baseline; 42.9% of the patients had diabetes, and 34.7% were current smokers. At 12 months, the rate of primary patency among patients who had undergone angioplasty with the drug-coated balloon was superior to that among patients who had undergone conventional angioplasty (65.2% vs. 52.6%, P = 0.02). The proportion of patients free from primary safety events was 83.9% with the drug-coated balloon and 79.0% with standard angioplasty (P = 0.005 for noninferiority). There were no significant between-group differences in functional outcomes or in the rates of death, amputation, thrombosis, or reintervention. CONCLUSIONS Among patients with symptomatic femoropopliteal peripheral artery disease, percutaneous transluminal angioplasty with a paclitaxel-coated balloon resulted in a rate of primary patency at 12 months that was higher than the rate with angioplasty with a standard balloon. The drug-coated balloon was noninferior to the standard balloon with respect to safety. Copyright © 2015 Massachusetts Medical Society.

Ferrari R.,Azienda Ospedaliero Universitaria di Ferrara | Bohm M.,Universitatsklinikum des Saarlandes | Cleland J.G.F.,Imperial College London | Paulus W.J.S.,VU University Amsterdam | And 3 more authors.
European Journal of Heart Failure | Year: 2015

Many uncertainties surround the syndrome of heart failure with preserved ejection fraction (HFpEF), which was the topic reviewed in an Expert Meeting at the University of Ferrara. This concluded that the absence of clear diagnostic clinical criteria was the major barrier to progress. There was general agreement that symptoms or signs of heart failure, normal LVEF despite an elevated plasma concentration of natriuretic peptides, and signs of abnormal LV relaxation, LV filling, LV hypertrophy, or left atrial enlargement, or diastolic dysfunction supported the diagnosis. However, HFpEF, like all heart failure syndromes, is heterogeneous in aetiology and pathophysiology, rather than being a single disease. HFpEF may account for about half of all patients with heart failure. The classical risk factors for developing HFpEF include age and co-morbidities, notably hypertension, atrial fibrillation, and the metabolic syndrome. When complicated by increasing congestion requiring hospital admission, the prognosis is poor; 30% or more of patients will die within 1 year (nearly two-thirds die from cardiovascular causes). Patients with chronic stable symptoms have a much better prognosis. Despite many clinical trials, there is no solid evidence that any treatment alters the natural history of HFpEF. Several treatments have shown promising early results and are now being tested in substantial randomized clinical trials. Further basic research is required to better characterize the disease and accelerate progress. Our review highlights the many difficulties encountered in performing randomized clinical trials in HFpEF, often due to difficulties in characterizing HFpEF itself. © 2015 The Authors. European Journal of Heart Failure European Society of Cardiology.

Zeller T.,Universitats Herzzentrum Freiburg Bad Krozingen | Beschorner U.,coreLab Bad Krozingen GmbH | Pilger E.,Medical University of Graz | Bosiers M.,A.Z. Sint Blasius | And 6 more authors.
JACC: Cardiovascular Interventions | Year: 2015

Objectives The aim of BIOLUX P-II (BIOTRONIK'S-First in Man study of the Passeo-18 LUX drug releasing PTA Balloon Catheter vs. the uncoated Passeo-18 PTA balloon catheter in subjects requiring revascularization of infrapopliteal arteries) trial was to compare the safety and efficacy of a novel paclitaxel-coated drug-eluting balloon (DEB) versus an uncoated balloon (percutaneous transluminal angioplasty [PTA]) in de novo or native restenotic lesions of the infrapopliteal arteries in patients with claudication and critical limb ischemia. Background DEB have shown promising results in femoropopliteal lesions, but data for infrapopliteal lesions are scarce. Methods In this prospective, multicenter, randomized first-in-man study, 72 patients were randomized 1:1 to either a Passeo-18 Lux DEB (Biotronik AG, Buelach, Switzerland) (n = 36) or Passeo-18 PTA (n = 36). Follow-up assessments were scheduled at 1, 6, and 12 months, with angiographic assessment at 6 months. Adverse events were adjudicated by an independent clinical events committee, and angiographic parameters were assessed by an independent core laboratory. Results The primary safety endpoint (a composite of all-cause mortality, target extremity major amputation, target lesion thrombosis, and target vessel revascularization at 30 days) was 0% in the DEB group versus 8.3% in the PTA group (p = 0.239). The primary performance endpoint (patency loss at 6 months) was 17.1% in the DEB group versus 26.1% in the PTA group (p = 0.298), and major amputations of the target extremity occurred in 3.3% versus 5.6% of the patients at 12 months, respectively. Conclusions The Passeo-18 Lux DEB has been proven to be safe and effective in infrapopliteal lesions with comparable outcomes to PTA. © 2015 American College of Cardiology Foundation.

Place R.F.,University of California at San Francisco | Noonan E.J.,Center for Molecular Biology in Medicine | Noonan E.J.,Stanford University | Foldes-Papp Z.,Medical University of Graz | Li L.-C.,University of California at San Francisco
Current Pharmaceutical Biotechnology | Year: 2010

RNA interference (RNAi) is an evolutionary conserved mechanism by which small double-stranded RNA (dsRNA) - termed small interfering RNA (siRNA) - inhibit translation or degrade complementary mRNA sequences. Identifying features and enzymatic components of the RNAi pathway have led to the design of highly-effective siRNA molecules for laboratory and therapeutic application. RNA activation (RNAa) is a newly discovered mechanism of gene induction also triggered by dsRNAs termed small activating RNA (saRNA). It offers similar benefits as RNA interference (RNAi), while representing a new method of gene overexpression. In the present study, we identify features of RNAa and explore chemical modifications to saRNAs that improve the applicability of RNAa. We evaluate the rate of RNAa activity in order to define an optimal window of gene induction, while comparing the kinetic differences between RNAa and RNAi. We identify Ago2 as a conserved enzymatic component of both RNAa and RNAi implicating that saRNA may tolerate modification based on Ago2 function. As such, we define chemical modifications to saRNAs that manipulate RNAa activity, as well as exploit their effects to design saRNAs with enhanced medicinal properties. These findings reveal functional features of RNAa that may be utilized to augment saRNA function for mechanistic studies or the development of RNAa-based drugs. © 2010 Bentham Science Publishers Ltd.

Baumann G.,Medical University of Graz | Place R.F.,University of California at San Francisco | Foldes-Papp Z.,Medical University of Graz
Current Pharmaceutical Biotechnology | Year: 2010

In living cell or its nucleus, the motions of molecules are complicated due to the large crowding and expected heterogeneity of the intracellular environment. Randomness in cellular systems can be either spatial (anomalous) or temporal (heterogeneous). In order to separate both processes, we introduce anomalous random walks on fractals that represented crowded environments. We report the use of numerical simulation and experimental data of single-molecule detection by fluorescence fluctuation microscopy for detecting resolution limits of different mobile fractions in crowded environment of living cells. We simulate the time scale behavior of diffusion times τ D(τ) for one component, e.g. the fast mobile fraction, and a second component, e.g. the slow mobile fraction. The less the anomalous exponent α the higher the geometric crowding of the underlying structure of motion that is quantified by the ratio of the Hausdorff dimension and the walk exponent d f/d w and specific for the type of crowding generator used. The simulated diffusion time decreases for smaller values of α ≠ 1 but increases for a larger time scale τ at a given value of α ≠ 1. The effect of translational anomalous motion is substantially greater if α differs much from 1. An α value close to 1 contributes little to the time dependence of subdiffusive motions. Thus, quantitative determination of molecular weights from measured diffusion times and apparent diffusion coefficients, respectively, in temporal auto- and crosscorrelation analyses and from time-dependent fluorescence imaging data are difficult to interpret and biased in crowded environments of living cells and their cellular compartments; anomalous dynamics on different time scales τ must be coupled with the quantitative analysis of how experimental parameters change with predictions from simulated subdiffusive dynamics of molecular motions and mechanistic models. We first demonstrate that the crowding exponent α also determines the resolution of differences in diffusion times between two components in addition to photophyscial parameters well-known for normal motion in dilute solution. The resolution limit between two different kinds of single molecule species is also analyzed under translational anomalous motion with broken ergodicity. We apply our theoretical predictions of diffusion times and lower limits for the time resolution of two components to fluorescence images in human prostate cancer cells transfected with GFP-Ago2 and GFP-Ago1. In order to mimic heterogeneous behavior in crowded environments of living cells, we need to introduce so-called continuous time random walks (CTRW). CTRWs were originally performed on regular lattice. This purely stochastic molecule behavior leads to subdiffusive motion with broken ergodicity in our simulations. For the first time, we are able to quantitatively differentiate between anomalous motion without broken ergodicity and anomalous motion with broken ergodicity in time-dependent fluorescence microscopy data sets of living cells. Since the experimental conditions to measure a selfsame molecule over an extended period of time, at which biology is taken place, in living cells or even in dilute solution are very restrictive, we need to perform the time average over a subpopulation of different single molecules of the same kind. For time averages over subpopulations of single molecules, the temporal auto- and crosscorrelation functions are first found. Knowing the crowding parameter α for the cell type and cellular compartment type, respectively, the heterogeneous parameter γ can be obtained from the measurements in the presence of the interacting reaction partner, e.g. ligand, with the same α value. The product α · γ = γ̃ is not a simple fitting parameter in the temporal auto- and two-color crosscorrelation functions because it is related to the proper physical models of anomalous (spatial) and heterogeneous (temporal) randomness in cellular systems. We have already derived an analytical solution for γ̃ in the special case of γ = 3/2. In the case of two-color crosscorrelation or/and two-color fluorescence imaging (co-localization experiments), the second component is also a two-color species gr, for example a different molecular complex with an additional ligand. Here, we first show that plausible biological mechanisms from FCS/ FCCS and fluorescence imaging in living cells are highly questionable without proper quantitative physical models of subdiffusive motion and temporal randomness. At best, such quantitative FCS/ FCCS and fluorescence imaging data are difficult to interpret under crowding and heterogeneous conditions. It is challenging to translate proper physical models of anomalous (spatial) and heterogeneous (temporal) randomness in living cells and their cellular compartments like the nucleus into biological models of the cell biological process under study testable by single-molecule approaches. Otherwise, quantitative FCS/FCCS and fluorescence imaging measurements in living cells are not well described and cannot be interpreted in a meaningful way. © 2010 Bentham Science Publishers Ltd.

Marszalek M.,Sozialmedizinisches Zentrum Ost Donauspital | Marszalek M.,Medical University of Graz | Carini M.,University of Florence | Chlosta P.,Institute of Oncology | And 6 more authors.
European Urology | Year: 2012

Context: Little is known on the natural history of positive surgical margins (PSMs) in partial nephrectomy (PN). Accumulating data suggest that secondary nephrectomy might not be necessary in all patients with PSMs after PN. Objective: Provide an overview on incidence and risk factors for PSMs after partial nephrectomy and on the rate of local and distant disease recurrence related to PSMs. We also provide recommendations on how to avoid and how to treat PSMs after PN. Evidence acquisition: A nonsystematic literature research was based on Medline, Scopus, and Web of Science queries on these keywords: nephron-sparing surgery, partial nephrectomy/ies, and margin. Only human studies (original research) published in English were included. Evidence synthesis: PSMs are present in 0-7% of patients after open PN, in 0.7-4% after laparoscopic PN, and in 3.9-5.7% after robot-assisted PN. The thickness of healthy parenchyma surrounding the tumour is irrelevant as long as complete tumour removal is achieved. The coincidence of a highly malignant tumour and PSM increases the risk of local recurrence. Intermediate follow-up data indicate that the vast majority of patients with PSMs will not experience local or distant tumour recurrence. Frozen-section analysis for evaluation of resection margins during PN is of minor clinical significance, as the surgeon's gross assessment of macroscopically negative margins provides reliable results. Conclusions: PSMs in PN are rare. As indicated by intermediate follow-up data, the majority of patients with PSMs after PN remain without disease recurrence, and a surveillance strategy seems preferable to surgical reintervention. © 2011 European Association of Urology.

Schriefl A.J.,University of Graz | Zeindlinger G.,University of Graz | Pierce D.M.,University of Graz | Regitnig P.,Medical University of Graz | And 2 more authors.
Journal of the Royal Society Interface | Year: 2012

The established method of polarized microscopy in combination with a universal stage is used to determine the layer-specific distributed collagen fibre orientations in 11 human non-atherosclerotic thoracic and abdominal aortas and common iliac arteries (63 ± 15.3 years, mean ± s.d.). A dispersion model is used to quantify over 37 000 recorded fibre angles from tissue samples. The study resulted in distinct fibre families, fibre directions, dispersion and thickness data for each layer and all vessels investigated. Two fibre families were present for the intima, media and adventitia in the aortas, with often a third and sometimes a fourth family in the intima in the respective axial and circumferential directions. In all aortas, the two families were almost symmetrically arranged with respect to the cylinder axis, closer to the axial direction in the adventitia, closer to the circumferential direction in the media and in between in the intima. The same trend was found for the intima and adventitia of the common iliac arteries; however, there was only one preferred fibre alignment present in the media. In all locations and layers, the observed fibre orientations were always in the tangential plane of the walls, with no radial components and very small dispersion through the wall thickness. A wider range of in-plane fibre orientations was present in the intima than in the media and adventitia. The mean total wall thickness for the aortas and the common iliac artery was 1.39 and 1.05 mm, respectively. For the aortas, a slight thickening of the intima and a thinning of the media in increasingly distal regions were observed. A clear intimal thickening was present distal to the branching of the celiac arteries. All data, except for the media of the common iliac arteries, showed two prominent collagen fibre families for all layers so that two-fibre family models seem most appropriate. This journal is © 2011 The Royal Society.

Lazzeroni M.,Italian National Cancer Institute | Serrano D.,Italian National Cancer Institute | Pilz S.,VU University Amsterdam | Pilz S.,Medical University of Graz | Gandini S.,Italian National Cancer Institute
Anti-Cancer Agents in Medicinal Chemistry | Year: 2013

Data from experimental studies suggest that vitamin D receptor activation exerts anti-cancer effects on virtually all steps of carcinogenesis. Epidemiological data support an inverse association of vitamin D serum levels and vitamin D receptor polymorphisms with cancer incidence and mortality. Based on this promising rationale for use of vitamin D and its analogues in cancer prevention and treatment, several interventional studies have been initiated and partially published. Trials with vitamin D were mainly organized for the prevention of fracture in elderly people, usually in association with calcium supplements. Prevention studies with vitamin D have rarely been done in the context of vitamin D to evaluate a protective effect on cancer. Findings from prospective cohort studies on colorectal cancer risk and on mortality constitute pieces of evidence strong enough to consider that previous randomized controlled trials (RCTs) of vitamin D use and cancer may not have correctly addressed the question, and that new randomized trials should be organized. The reasons are due to several unsolved issues including selection of the effective dose, varying baseline levels of subjects before randomization, compliance with the intervention, contamination of the placebo group (i.e., intake of vitamin D supplements by subjects allocated to the placebo group) and unknown effective lag time between start of the intervention and disease onset. The present review summarizes the existing knowledge on vitamin D RCTs and cancer. In addition we also briefly describe the design of some ongoing trials on vitamin D supplementation and cancer. © 2013 Bentham Science Publishers.

Scioscia M.,Sacro Cuore Don Calabria General Hospital | Siwetz M.,Medical University of Graz | Fascilla F.,University of Bari | Huppertz B.,Medical University of Graz
Placenta | Year: 2012

Abnormalities in glucose metabolism linked to d-chiro-inostol phosphoglycans (IPGs) have been described in human placentas of preeclamptic women. In this study, a semi-quantitative approach to assess the histological assessment of IPGs revealed no significant differences between early and late onset preeclampsia and gestational age matched controls. However, there was a tendency towards higher values in early onset preeclampsia for villous stroma and placental vessels. Moreover, in control cases staining of plasma in placental vessels was present only in one part of vessels of mature intermediate villi while in preeclamptic specimens all placental vessels showed a similar staining. The tendencies of more staining in villous stroma associated with a differential staining of placental vessels only in preeclamptic specimens support a vectoral movement of d-chiro-inositol phosphoglycans from the fetus to the placenta. © 2012 Elsevier Ltd. All rights reserved.

Gugatschka M.,Medical University of Graz | Dehchamani D.,Medical University of Graz | Wascher T.C.,Hanuschkrankenhaus der WGKK | Friedrich G.,Medical University of Graz | Renner W.,Medical University of Graz
Experimental and Molecular Pathology | Year: 2011

Introduction: Genetic aberrations of DNA repair enzymes are known to be common events and to be associated with different cancer entities. Aim of the following study was to analyze the genetic association of single nucleotide polymorphisms (SNP) of the DNA repair genes with the risk of squamous cell carcinoma of the head and neck (HNSCC). Materials and methods: Genetic variants ERCC2 Lys751Gln (rs13181), ERCC2 Asp312Asn (rs1799793), XRCC1 Arg194Trp (rs1799782); XRCC1 Gln399Arg (rs25487), XRCC1 Arg280His (rs25489) and XRCC3 Thr241Met (rs861539) were analyzed in a primary study group comprising 169 patients with histologically confirmed HNSCC and 463 healthy control subjects. Polymorphisms associated with HNSCC were furthermore analyzed in an independent replication study including 125 HNSCC. Results: Only the ERCC2 751 Gln/Gln genotype was associated with HNSCC in the primary study (p= 0.033) and in the replication study (p= 0.023), resulting in an overall odds ratio of 0.54 (95% confidence interval 0.35-0.92; p= 0.006). Conclusion: Carriers of the homozygous ERCC2 751 Gln/Gln genotype may be at lower risk for HNSCC. © 2011 Elsevier Inc.

Roupret M.,University Paris - Sud | Babjuk M.,Charles University | Comperat E.,University Paris - Sud | Zigeuner R.,Medical University of Graz | And 8 more authors.
European Urology | Year: 2013

Context: The European Association of Urology (EAU) guideline group for upper tract urothelial carcinoma (UTUC) has prepared updated guidelines to aid clinicians in assessing the current evidence-based management of UTUC and to incorporate present recommendations into daily clinical practice. Objective: To provide a brief overview of the EAU guidelines on UTUC as an aid to clinicians in their daily clinical practice. Evidence acquisition: The recommendations provided in the current guidelines are based on a thorough review of available UTUC guidelines and articles identified using a systematic search of Medline. Data on urothelial malignancies and UTUCs in the literature were searched using Medline with the following keywords: urinary tract cancer; urothelial carcinomas; upper urinary tract, carcinoma; renal pelvis; ureter; bladder cancer; chemotherapy; nephroureterectomy; adjuvant treatment; instillation; neoadjuvant treatment; recurrence; risk factors; nomogram; and survival. References were weighted by a panel of experts. Evidence synthesis: There is a lack of data in the current literature to provide strong recommendations (ie, grade A) due to the rarity of the disease. A number of recent multicentre studies are now available, and there is a growing interest in UTUC in the recent literature. Overall, 135 references have been included here, but most of these studies are still retrospective analyses. The TNM 2009 classification is recommended. Recommendations are given for diagnosis as well as radical and conservative treatment (ie, imperative and elective cases); additionally, prognostic factors are discussed. Recommendations are also provided for patient follow-up after different therapeutic options. Conclusions: These guidelines contain information for the management of individual patients according to a current standardised approach. Physicians must take into account the specific clinical characteristics of each individual patient when determining the optimal treatment regimen including tumour location, grade, and stage; renal function; molecular marker status; and medical comorbidities. © 2013 European Association of Urology.

Baranyi A.,Medical University of Graz | Meinitzer A.,Clinical Institute of Medical and Chemical Laboratory Diagnostics | Stepan A.,Medical University of Graz | Putz-Bankuti C.,Medical University of Graz | And 4 more authors.
Psychotherapy and Psychosomatics | Year: 2013

Background: The aim of this prospective study was to gain a more comprehensive picture of the biopsychosocial effects of interferon (IFN) treatment of patients with chronic hepatitis C (HCV). The predictors of depressive development and changes in health-related quality of life, life satisfaction and cognitive ability were measured with the inclusion of the social context. Furthermore, the effects of IFN treatment on indoleamine 2,3-dioxygenase, the level of tryptophan supply in the brain, the development of neurotoxic kynurenine metabolites and the thyroid glands were investigated. Therefore, for the first time the conditions for the development of depressive episodes in HCV patients treated with IFN were examined over the entire period of treatment as well as 3 months later, applying a holistic biopsychosocial model. Method: Psychiatric and biological assessments were carried out at 6 different times: before, during (at 1, 3, 6 and 9 months) and after the end of IFN treatment. Results: During IFN treatment 22 (53.7%) of 41 patients fulfilled the criteria for a treatment-related depressive disorder at least once during treatment. Contributing factors are tryptophan depletion (tryptophan to competing amino acids quotient), increased neurotoxic challenge (kynurenine to kynurenic acid quotient), less social support, female gender, preexisting psychiatric vulnerability, means of transmission, low financial security, impaired sexual satisfaction, small circle of friends, impaired physical role, strong body pain, low general health and vitality, reduced social functioning, impaired mental health and impaired emotional role. Conclusions: The awareness of relevant risk factors of IFN treatment-induced depression is essential to develop preventative treatment strategies. © 2013 S. Karger AG, Basel.

Molina-Ruiz A.M.,Autonomous University of Madrid | Cerroni L.,Medical University of Graz | Kutzner H.,Dermatophatologische | Requena L.,Autonomous University of Madrid
American Journal of Dermatopathology | Year: 2014

The cutaneous deposition disorders are a group of unrelated conditions characterized by the accumulation of either endogenous or exogenous substances within the skin. These cutaneous deposits are substances that are not normal constituents of the skin and are laid down usually in the dermis, but also in the subcutis, in a variety of different circumstances. There are 5 broad categories of cutaneous deposits. The first group includes calcium salts, bone, and cartilage. The second category includes the hyaline deposits that may be seen in the dermis in several metabolic disorders, such as amyloidosis, gout, porphyria, and lipoid proteinosis. The third category includes various pigments, heavy metals, and complex drug pigments. The fourth category, cutaneous implants, includes substances that are inserted into the skin for cosmetic purposes. The fifth category includes miscellaneous substances, such as oxalate crystals and fiberglass. In this article, the authors review the clinicopathologic characteristics of cutaneous deposition diseases, classify the different types of cutaneous deposits, and identify all the histopathologic features that may assist in diagnosing the origin of a cutaneous deposit. © 2013 Lippincott Williams & Wilkins.

Conraads V.M.,University of Antwerp | Deaton C.,University of Manchester | Piotrowicz E.,Institute of Cardiology | Santaularia N.,Althaia | And 7 more authors.
European Journal of Heart Failure | Year: 2012

The practical management of heart failure remains a challenge. Not only are heart failure patients expected to adhere to a complicated pharmacological regimen, they are also asked to follow salt and fluid restriction, and to cope with various procedures and devices. Furthermore, physical training, whose benefits have been demonstrated, is highly recommended by the recent guidelines issued by the European Society of Cardiology, but it is still severely underutilized in this particular patient population. This position paper addresses the problem of non-adherence, currently recognized as a main obstacle to a wide implementation of physical training. Since the management of chronic heart failure and, even more, of training programmes is a multidisciplinary effort, the current manuscript intends to reach cardiologists, nurses, physiotherapists, as well as psychologists working in the field. © 2012 The Author.

Garvey W.T.,University of Alabama at Birmingham | Ryan D.H.,Pennington Biomedical Research Center | Henry R.,University of California at San Diego | Bohannon N.J.V.,Monteagle Medical Center | And 4 more authors.
Diabetes Care | Year: 2014

OBJECTIVE: To evaluate over 108 weeks the effect of phentermine and topiramate extended release (PHEN/TPM ER) treatment on progression to type 2 diabetes and/or cardiometabolic disease in subjects with prediabetes and/or metabolic syndrome (MetS) at baseline. RESEARCH DESIGN AND METHODS: Subanalysis of a phase 3, randomized, placebo-controlled, double-blind study of overweight/obese subjects (BMI ≥27 to ≤45 kg/m2) with two or more comorbidities. Subjects were randomized to placebo, PHEN 7.5 mg/TPM ER 46 mg (7.5/ 46), or PHEN 15 mg/TPM ER 92 mg (15/92) plus lifestyle modifications for 108 weeks. Percent weight loss in the intent-to-treat population using multiple imputation (ITT-MI), annualized incidence rate of progression to type 2 diabetes, and changes in glycemia, lipid parameters, blood pressure, and waist circumference were evaluated. RESULTS: At baseline, 475 subjects met the criteria for prediabetes and/or MetS. After 108 weeks, subjects with prediabetes and/or MetS in the placebo, 7.5/46, and 15/92 groups experienced mean percent weight loss of 2.5, 10.9, and 12.1%, respectively (ITT-MI; P < 0.0001 vs. placebo), associated with reductions of 70.5 and 78.7% in the annualized incidence rate of type 2 diabetes for those receiving 7.5/46 and 15/92, respectively (ITT, P< 0.05), versus placebo. The ability of PHEN/TPM ER to prevent diabetes was related to degree of weight lost and was accompanied by significant improvements in cardiometabolic parameters. PHEN/TPM ER was well tolerated by this subgroup over 2 years. CONCLUSIONS: PHEN/TPM ER plus lifestyle modification produced significant weight loss and markedly reduced progression to type 2 diabetes in overweight/obese patients with prediabetes and/or MetS, accompanied by improvements in multiple cardiometabolic disease risk factors. © 2014 by the American Diabetes Association.

Muschitz C.,Medical University of Vienna | Kocijan R.,Medical University of Vienna | Fahrleitner-Pammer A.,Medical University of Graz | Pavo I.,University of Szeged | And 4 more authors.
Journal of Bone and Mineral Research | Year: 2014

Nine month teriparatide (TPTD) monotherapy followed by co-administration of raloxifene (RAL) or alendronate (ALN) for another nine 9 months resulted in incremental bone mineral density (BMD) increase. The aim of this study was to investigate the effects of continued antiresorptive treatments for 12 months in the extension phase. Postmenopausal women (n=125) with severe osteoporosis on ongoing TPTD treatment for 9 months were randomized into three open-label groups for another 9 months: ALN (70 mg/week, n=41), RAL (60mg/d, n=37) in addition to TPTD or no additional medication (n=47) except Ca and vitamin D. After discontinuation of TPTD the respective antiresorptives were continued for a further 12 months, while patients in the TPTD monotherapy group received Ca and vitamin D. Amino-terminal propeptide of type I procollagen (P1NP) and cross-linked C-telopeptide (CTX), areal and volumetric BMD at the lumbar spine (LS) and hip were assessed. ALN resulted in continued BMD increase in LS (4.3±1.5%; mean±SD), femoral neck (4.2±1.6%) and total hip (4±1.6%; p<0.001 for all), while RAL was only effective at the LS (2.4±1.7%, p<0.001) but no changes at the femoral neck (0.4±1.4%) or total hip (-0.8±1.5%) were observed. Cortical bone only increased in the ALN group (femoral neck 6.7±2.7% and -1.3±2.5%; total hip 13.8±2.9% and -2.3±2.5% for ALN and RAL, p<0.001 for all; respectively). Analyzing the entire 30 months of therapy, the ALN group revealed the largest BMD increase in all regions. Our results suggest that the addition of ALN to ongoing TPTD and continuing ALN after TPTD was stopped may be beneficial for patients in terms of areal and volumetric BMD increase. Further research is warranted to determine the optimal timing of the initiation of the combination treatment, the respective antiresorptive medication and the potential benefit of this BMD increase regarding fracture prevention. © 2014 American Society for Bone and Mineral Research © 2014 American Society for Bone and Mineral Research.

Singh T.P.,Medical University of Graz | Singh T.P.,National Institute of Allergy and Infectious Diseases | Schon M.P.,University of Gottingen | Wallbrecht K.,University of Gottingen | And 3 more authors.
PLoS ONE | Year: 2013

It is thought that a Th1/Th17-weighted immune response plays a predominant role in the pathogenesis of psoriasis. Our findings now indicate a link between IL-9, a Th2 and Th9 cytokine, and Th17 pathway in psoriasis. In K5.hTGF-β1 transgenic mice, exhibiting a psoriasis-like phenotype, we found increased IL-9R and IL-9 expression in the skin and intradermal IL-9 injection induced Th17-related inflammation. IL-9 also promoted angiogenesis and VEGF and CD31 overexpression in mice in vivo and increased tube formation of human endothelial cells in vitro. Injecting anti-IL-9 antibody into K5.hTGF-β1 transgenic mice not only diminished inflammation (including skin infiltration by T cells, monocytes/macrophages, and mast cells) and angiogenesis but also delayed the psoriasis-like skin phenotype. Notably, injection of anti-psoriatic acting anti-IL-17 antibody reduced skin IL-9 mRNA and serum IL-9 protein levels in K5.hTGF-β1 transgenic mice and prevented IL-9-induced epidermal hyperplasia and inflammation of the skin of wild type mice. In addition, we observed that IL-9R expression in lesional skin from psoriasis patients was markedly higher than in healthy skin from control subjects. Moreover, IL-9 significantly enhanced IL-17A production by cultured human peripheral blood mononuclear cells or CD4+ T cells, especially in psoriasis patients. Thus, IL-9 may play a role in the development of psoriatic lesions through Th17-associated inflammation and angiogenesis. © 2013 Singh et al.

Lughezzani G.,Vita-Salute San Raffaele University | Burger M.,Friedrich - Alexander - University, Erlangen - Nuremberg | Margulis V.,University of Texas Southwestern Medical Center | Matin S.F.,University of Houston | And 5 more authors.
European Urology | Year: 2012

Context: The heterogeneity of upper tract urothelial carcinoma (UTUC) biology and prognosis, as well as the presence of different treatment options, makes the clinical decision-making process extremely challenging. Objective: Provide an overview of the currently available prognostic factors for UTUC, focusing on clinical and pathologic characteristics, as well as on molecular markers. Evidence acquisition: A systematic literature search was conducted using the PubMed, Scopus, and Embase databases to identify original articles, review articles, and editorials regarding prognostic factors in patients with UTUC. Keywords included urothelial carcinoma, renal pelvis, ureter, upper urinary tract urothelial carcinoma, upper urinary tract transitional cell carcinoma, prognosis, prognostic factors, markers, and survival. Articles published between 2000 and 2011 were reviewed and selected with the consensus of all the authors. Evidence synthesis: Prognostic factors can be divided into four different categories: preoperative/clinical factors, intraoperative/ surgical factors, postoperative/pathologic factors, and molecular markers. Because of the rarity of the disease, only a small amount of level 1 evidence information from prospective randomized trials is available. Conversely, several single-institutional and multi-institutional studies have been published providing level 3 evidence information on various prognostic factors. Tumor stage and grade represent the best-established predictors of prognosis in patients with UTUC, but controversies still exist regarding the prognostic impact of tumor location and tumor necrosis. Several promising biomarkers have also been evaluated, but further studies evaluating their prognostic role are still needed. Finally, few prognostic models have been developed to provide clinicians with accurate estimates of the outcome of interest. Conclusions: In the past few years, several prognostic factors have been identified to help clinicians dealing with patients with UTUC in the decision-making process. However, well-designed multi-institutional studies are still needed to provide stronger evidence and to promote the use of these prognostic factors in clinical practice. © 2012 European Association of Urology.

Agency: Cordis | Branch: FP7 | Program: CP-IP | Phase: HEALTH.2012.2.1.1-2 | Award Amount: 17.67M | Year: 2013

As more people survive into old age, the prevalence of heart failure (HF), one of the most common and debilitating diseases in older people, will rise still further. Delaying or preventing HF will have great benefit to those at personal risk, their families, society and the economy. HOMAGE aims to provide a biomarker (BM) approach that will a) help identify i. patients at high risk of developing HF before the onset of symptoms and ii. subsets of patients who are more likely to respond to specifically targeted therapies (personalized medicine). In available cohorts, we will identify the most promising omics-based BM profiles for the pre-symptomatic diagnosis and future prediction of HF in patients at risk. The predictive value of the BMs for other co-morbidities commonly associated with HF and ageing will also be investigated. Furthermore, in a prospective trial, we will investigate the potential for targeting preventive therapy at patients with the greatest likelihood of response and the lowest risk of adverse effects. Our selection of innovative omics-based BMs is based on knowledge of biological pathways of the disease, which may facilitate identification of Biotargets for future therapies. On the economic side, HOMAGE will act as an economic catalyst for European SMEs in the field of cardiovascular and ageing BMs, estimated to peak annual turnovers of up to 800 M.

Agency: Cordis | Branch: FP7 | Program: CP-IP | Phase: KBBE-2009-2-2-03 | Award Amount: 7.82M | Year: 2010

The food and health relationship focuses on maintenance of optimal health, both in terms of physiology and new European legislation. Yet, most accepted biomarkers quantify (intermediate) disease endpoints or damage. This has led to major problems in demonstrating health benefits and establishing health claims, and blocks competitive economic and health developments in the food sector. BIOCLAIMS develops new biomarkers by exploiting the new concept of health biomarkers through quantification of the robustness of the homeostatic mechanisms involved in maintaining optimal health, based on the assumption that the ability to maintain homeostasis in a continuously challenged environment and changing physiology is key for healthy ageing. Mechanisms involved will be investigated during a series of food interventions in animal models and humans using predisposed conditions. Human models of presumed impaired robustness in maintaining metabolic and vascular health will be employed to study the responses of established and novel biomarkers to the challenging of homeostasis and to selected food interventions. Both advanced analytical methodology including nutrigenomics tools (transcriptomics, metabolomics, fatty acid composition, adipokine profile, macromolecule damage) and whole body physiological assessments will be exploited to derive a series of new biomarkers. Gender differences will be addressed. BIOCLAIMS thus delivers a series of robust biomarkers predictive of a healthy metabolic phenotype during ageing, based on stressors of homeostasis, These biomarkers will be fully characterized and evaluated for practical application in human nutrition, and compared to traditional ones. The consortium consists of 11 teams, balanced in gender and geographical distribution, with track records in animal physiology, human studies in the relevant health areas, nutrigenomics and new analytical approaches, and scientific assessment of health claims in the EU.

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2011.2.4.2-2 | Award Amount: 8.11M | Year: 2011

EU-MASCARA is a collaborative project that aims to improve diagnosis of cardiovascular diseases and prediction of cardiovascular risk by analysing a panel of biomarkers. EU-MASCARA aims to examine genetic, proteomic and metabolomic markers together with markers of inflammation, oxidative stress and cardiac remodelling to study their incremental diagnostic and predictive value over and above existing diagnostic and predictive algorithms. For this purpose a large number of cohorts from different European regions, both patient and population cohorts, that have been accurately assessed for cardiovascular phenotypes are readily available to the consortium. Access to clinical samples and to standardised cardiovascular phenotypes will be granted by a strong clinical platform as one of the key work packages of EU-MASCARA. Both cross-sectional and prospective analyses will be performed that will result in the development of improved risk prediction scores. The consortium is heavily supported by contributions of SMEs in key areas of the proposed research: biomarker testing, data handling and analysis, assay development and project management. EU-MASCARA is further characterised by a strong integrative approach both within and across work packages, with results from one task informing strategies of research in other tasks. With a dedicated bioinformatics and health economic platform the most robust biomarkers will be selected and analysed for their benefit in clinical practice. EU-MASCARA will rigorously validate biomarkers that have been proposed to be associated with cardiovascular disease and risk across different disease entities and also in independent general population samples. The most robust biomarkers will be implemented in novel biochip based assays for clinical use.

Silbernagel G.,University of Tübingen | Genser B.,University of Heidelberg | Genser B.,Federal University of Bahia | Nestel P.,Baker IDI Heart and Diabetes Institute | And 3 more authors.
Current Opinion in Lipidology | Year: 2013

PURPOSE OF REVIEW: Plant sterols as ingredients to functional foods are recommended for lowering LDL cholesterol. However, there is an ongoing discussion whether the use of plant sterols is safe. RECENT FINDINGS: Genetic analyses showed that common variants of the ATP binding cassette transporter G8 (ABCG8) and ABO genes are associated with elevated circulating plant sterols and higher risk for cardiovascular disease. However, these data do not prove a causal role for plant sterols in atherosclerosis because the risk alleles in ABCG8 and ABO are also related to elevated total and LDL cholesterol levels. The ABO locus exhibits still further pleiotropy. Moreover, analyses in the general population indicated that moderately elevated circulating plant sterols are not correlated with present or future vascular disease. In agreement, novel studies using food frequency questionnaires, studies in experimental animals, and dietary intervention studies support that ingestion of plant sterols may be beneficial to cardiovascular health. SUMMARY: Taken together, current evidence supports the recommendations for the use of plant sterols as LDL cholesterol-lowering agents. Nevertheless, a prospective, randomized, controlled, double-blinded, intervention trial conclusively showing that plant sterol supplementation will prevent hard cardiovascular endpoints is not available to date. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2012.2.1.2-1 | Award Amount: 3.88M | Year: 2012

Therapeutic antibodies are the largest and fastest growing class of pharmaceutical biotechnology products, with annual sales above 30 billion US$. In some cases, antibody products have revolutionized the management of patients, e.g. TNF-blocking antibodies in Arthritis or Rituxan in lymphoma. However, for most antibody therapies, only a subset of patients benefit from treatment. Thus, there is an urgent need to develop more potent therapeutic antibodies and to understand the molecular basis for the differential responses of patients to treatment. This consortium consists of European centres of excellence being pioneers in the field of therapeutic antibody development and (pre-) clinical studies and will tackle both of these challenges: Innovative immunocytokines L19-IL2 and F8-IL10 are developed by Philogen for the treatment of metastatic melanoma and rheumatoid arthritis respectively at multiple clinical centres including Graz and Tbingen. Building on the strong background in proteomics biomarker discovery of ETH Zurich and Philochem, an innovative methodology (HLA-peptidome analysis) will be utilized for gaining information on the immune response in animal models and patients which receive antibody treatments. This method is based on the observation that HLA molecules in complex with peptides can be detected in the patient blood and that hundreds of HLA-associated peptides can be sequenced by mass spectrometry. The technology will be used for the profiling of responses following antibody treatment for patients with cancer and rheumatoid arthritis, as well as animal models of transplant rejection. This systems biology approach has the potential to revolutionize patient stratification in very short time. Finally, patient selection strategies will be investigated using the clinical-grade immunocytokine (F8-IL10) as an example, monitoring antibody uptake at the site of disease by immuno-PET imaging methodologies at VUMC Amsterdam in collaboration with Philogen.

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH-2009-2.4.3-1 | Award Amount: 3.86M | Year: 2010

Europe is facing a rapidly growing threat from Type 2 diabetes mellitus (T2D), which is undoubtedly associated with an unhealthy diet and a more sedentary lifestyle. Evidence is accumulating that gestational diabetes mellitus (GDM) may be playing a role in this process. Thus it provides a significant opportunity for preventing future T2D. Not only is GDM prevalence on the rise, but intrauterine exposure to hyperglycaemia predisposes the offspring to diabetes and obesity. Another putative contributing factor is a low vitamin D status, which is also increasing in prevalence and may have causal links with both obesity and decreased glucose tolerance. The main aims of this project are: 1) to establish the current status of the prevalence of GDM in Europe and facilitate the adoption of a single diagnostic approach and 2) to deliver the best strategy that prevents GDM. The latter was deemed as not fully feasible within the scope of this call and our decision was to test the most relevant approaches (diet, exercise, vitamin D, alone or in combination) against surrogate variables of GDM (fasting blood glucose, insulin sensitivity, pregnancy weight gain) to come up with the best intervention for entry into a definitive GDM prevention trial. Deliverables include the sample size and modus operandi for such a trial. Value will be added to the project by 1) Assessing variables modifying the uptake of preventive interventions, 2) Exploring health costs of GDM and potential savings of preventive approaches, 3) Improving pathophysiological understanding by assessing intervention effect on several parameters in mother and foetus and 4) Facilitating future research through a well defined cohort of mother-offspring pairs and comprehensive biobanking.

Agency: Cordis | Branch: H2020 | Program: RIA | Phase: FETOPEN-1-2014 | Award Amount: 2.46M | Year: 2015

The ageing society and demographic change is one of the major challenges which Europe is facing now, and even more so in the future. Mastering this challenge requires radically new diagnostic and therapeutic treatments as key factors in achieving the healthy well-being of European citizens. Molecular imaging (MI) plays a pivotal role in diagnosis, understanding of disease and in the development of effective treatments. CONQUER will explore a fundamentally new contrast mechanism with the potential to push magnetic resonance imaging (MRI) far beyond its limits towards a powerful MI modality. This will be achieved by exploiting the cross relaxation between 1H and large quadrupolar nuclei (QN) for contrast agent (CA) design. The main objective is to synthesize bio-compatible QN compounds and nano-particles (NPs), high efficiency and manifold degrees of freedom in the design of smart properties, such as the ability to switch the contrast on and off by changing the magnetic field or chemical binding (e.g. targeting). The NPs will be tailored based on quantum-mechanical simulations. Sensitivity and contrast switching will be demonstrated with MRI in cell cultures. This highly interdisciplinary project combines expertise in quantum physics, chemical and biomedical engineering, material characterisation as well as nanotoxicology. Today, European scientists and companies are already leading global players in CA development. CONQUER will significantly fertilise this field and lay the scientific foundations for a new technology by providing theoretical groundwork, synthesis guidelines, imaging instrumentation and toxicological references. These results will be actively transferred to academia and industry as well in order to strengthen European competitiveness. The combination of a so far unexploited quantum-mechanical phenomenon and cutting-edge imaging technologies has the potential to create MI solutions with significant impact.

Nenoff P.,Laboratory for Medical Microbiology | Kruger C.,Laboratory for Medical Microbiology | Ginter-Hanselmayer G.,Medical University of Graz | Tietz H.-J.,Institute of Fungal Diseases and Microbiology
JDDG - Journal of the German Society of Dermatology | Year: 2014

Dermatomycoses are caused most commonly by dermatophytes. The anthropophilic dermatophyte Trichophyton rubrum is still the most frequent causative agent worldwide. Keratinolytic enzymes, e.g. hydrolases and keratinases, are important virulence factors of T. rubrum. Recently, the cysteine dioxygenase was found as new virulence factor. Predisposing host factors play a similarly important role for the development of dermatophytosis of the skin and nails. Chronic venous insufficiency, diabetes mellitus, disorders of cellular immunity, and genetic predisposition should be considered as risk factors for onychomycosis. A new alarming trend is the increasing number of cases of onychomycosis-mostly due to T. rubrum-in infancy. In Germany, tinea capitis is mostly caused by zoophilic dermatophytes, in particular Microsporum canis. New zoophilic fungi, primarily Trichophyton species of Arthroderma benhamiae, should be taken into differential diagnostic considerations of tinea capitis, tinea faciei, and tinea corporis. Source of infection are small household pets, particularly rodents, like guinea pigs. Anthropophilic dermatophytes may be introduced by families which immigrate from Africa or Asia to Europe. The anthropophilic dermatophytes T. violaceum, T. tonsurans (infections occurring in fighting sports clubs as "tinea gladiatorum capitis et corporis") and M. audouinii are causing outbreaks of small epidemics of tinea corporis and tinea capitis in kindergartens and schools. Superficial infections of the skin and mucous membranes due to yeasts are caused by Candida species. Also common are infections due to the lipophilic yeast fungus Malassezia. Today, within the genus Malassezia more than 10 different species are known. Malassezia globosa seems to play the crucial role in pityriasis versicolor. Molds (also designated non-dermatophyte molds, NDM) are increasingly found as causative agents in onychomycosis. Besides Scopulariopsis brevicaulis, several species of Fusarium and Aspergillus are found. © 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

Weisbecker H.,University of Graz | Viertler C.,Medical University of Graz | Pierce D.M.,University of Graz | Holzapfel G.A.,University of Graz | Holzapfel G.A.,KTH Royal Institute of Technology
Journal of Biomechanics | Year: 2013

In a previous study we were able to accurately fit experimental data on arterial tissues at supra-physiological loads using a material model that accounts for softening/damage only in the portion of the model associated with the collagen fibers (Weisbecker et al., 2012). Naturally, this result leads to the hypothesis that the softening behavior is related only to the collagen fibers, and not to the matrix material. In this study we test this hypothesis by conducting uniaxial extension tests on elastase and collagenase treated tissues and on untreated control specimens from the media of human thoracic aortas. We relate structural changes in the tissue after enzyme treatment to changes in the corresponding mechanical behavior. Collagenase treated tissue does not exhibit any softening behavior under quasi-static cyclic loading, a result supporting our hypothesis. Conversely, elastase treated tissue exhibits continuous softening under the same loading conditions, indicating that the integrity of the tissue is destroyed upon removal of the elastin. Finally, we fit isotropic and anisotropic constitutive models to the mechanical response of the collagenase treated arterial tissue, while our anisotropic model better approximates the response of collagenase treated arterial tissues, we show that an isotropic matrix model is sufficient to accurately reproduce the mechanical response of untreated control specimens, consistent with current practice in the literature. © 2013 Elsevier Ltd.

Batla A.,University College London | Erro R.,University College London | Stamelou M.,University College London | Stamelou M.,National and Kapodistrian University of Athens | And 5 more authors.
Movement Disorders | Year: 2014

Background: We previously reported on a cohort of dystonic tremor and patients with scans without evidence of dopaminergic deficit (SWEDDs). We aim to report the long-term clinical and imaging follow-up of these patients. Patients and Methods: Patients with at least 5-year follow-up were included. These patients had an asymmetric arm tremor, a previous diagnosis of Parkinson's disease (PD), and a subsequent normal DaTscan. The imaging and clinical follow-up was done on the clinical basis. Results: Sixteen patients were included. The mean gap between the first and subsequent scans was 5.4 years. Two patients (12.5%) had reduced nigrostriatal uptake on follow-up DaTscan, whereas 14 continued to have normal dopaminergic imaging. Conclusion: This is the longest follow up of patients with asymmetric rest tremor and normal DaT scans (SWEDDs) reported to date. We show here that only a minority of them show reduced striatonigral uptake over long term follow up. © 2014 International Parkinson and Movement Disorder Society.

News Article | December 21, 2016

Tumor suppressors stop healthy cells from becoming cancerous. Researchers from Charité - Universitätsmedizin Berlin, the Medical University of Graz and the German Institute of Human Nutrition in Potsdam-Rehbruecke have found that p53, one of the most important tumor suppressors, accumulates in liver after food withdrawal. They also show that p53 in liver plays a crucial role in the body's metabolic adaptation to starvation. These findings may provide the foundation for the development of new treatment options for patients with metabolic or oncologic disorders. Results of this study have been published in The FASEB Journal*. Previously described as the 'guardian of the genome' and voted 'Molecule of the Year' in 1993, p53 is one of the most important proteins regulating cell growth and a major focus for oncology research. It is a protein that has the ability to interrupt the cell cycle and block the division of diseased cells. In order to better understand its physiological regulation, the researchers around Prof. Dr. Michael Schupp from Charité's Institute of Pharmacology studied the regulation and function of p53 in normal, healthy cells. After withholding food from mice for several hours, the researchers were able to show that p53 protein accumulates in the liver. In order to determine which type of liver cells cause this accumulation, the researchers repeated the experiment using cultured hepatocytes. They found that the starvation-induced accumulation of p53 was indeed detectable in hepatocytes, irrespective of whether these cells were of mouse or human origin. "Our data also suggest that the accumulation of p53 is mediated by a cellular energy sensor, and that it is crucial for the metabolic changes associated with starvation," explains Prof. Michael Schupp. The researchers were able to show that mice with an acute inactivation of the p53 gene in liver had difficulties in adapting their metabolisms to starvation. "Food intake seems crucial in determining the protein levels of p53 in liver, and p53 also plays an important role in normal liver metabolism," says Prof. Schupp. The researchers are planning to study whether their observations are limited to liver cells, or whether this p53 accumulation also occurs in other tissues and organs. Prof. Schupp concludes: "It would be interesting to conduct further experiments to test whether the starvation-induced accumulation of p53 has an effect on the development of specific forms of cancer, or whether certain ways of timing meals might affect p53 protein levels in such a way as to promote cancer development." Prokesch A, Graef FA, Madl T, Kahlhofer J, Heidenreich S, Schumann A, Moyschewitz E, Pristoynik P, Blaschitz A, Knauer M, Muenzner M, Bogner-Strauss JG, Dohr G, Schulz TJ, Schupp M. Liver p53 is stabilized upon starvation and required for amino acid catabolism and gluconeogenesis. FASEB J. 2016 Nov 3. doi: 10.1096/fj.201600845R. pii: fj.201600845R. [Epub ahead of print] PubMed PMID: 27811061.

News Article | April 11, 2016

Several studies have recognized a link between obesity and cancer. Richard Lehner, professor of Pediatrics and investigator at the University of Alberta's Faculty of Medicine & Dentistry, has taken his research further to understand how tumour cells grow through scavenging very low-density lipoproteins (VLDL) and low-density lipoproteins (LDL), commonly known as the "bad cholesterol", and what mechanisms can be used to reduce the malignant cells' growth. The innovative study, an effort of over 2 years by Lehner's group in collaboration with Gerald Hoefler and his team (Medical University of Graz, Austria), was published in scientific journal Cell Reports. The data gathered from their experiments suggest a feed-forward loop, in which tumours not only use lipids as "building blocks" to grow, but they can regulate their host's lipid metabolism to increase production of these lipids. The "bad cholesterol" binds to LDL receptors in the liver, the organ in charge of degrading it and excreting it from the organism as bile. "Cancer cells need lipids to grow. They can make their own lipids or get more from the host because these cells grow so fast," explains Lehner. "The tumour signals to the liver: 'I need more cholesterol for growth' and the liver is reprogrammed to secrete those lipids." One of the key factors for this process are proteins we all have that, in larger quantities, may cause a decrease in the amount of LDL receptors to excrete the cholesterol. The tumour affects these proteins to reduce clearance of cholesterol from the blood, leaving the LDL for cancer to feed off of it. These findings led Lehner and Hoefler to an interesting hypothesis: minimizing the liver's production of LDL would deprive a tumour from its constant supply and therefore reduce its possibility of growth. Their experiments in pre-clinical models proved to be successful, confirming lower tumour development with the regulation of the proteins that affect production of VLDL (precursors of LDL) and uptake of LDL by receptors from the liver. This research received the support of grants from the Canadian Institutes of Health Research (CIHR) and Austrian Science Fund (FWF) and its DK Programme. It was also possible through the Faculty of Medicine & Dentistry's Lipid Analysis Core Facility, the Women and Children Health Research Institute (WCHRI) and the Canada Foundation for Innovation (CFI). The next step for Lehner and his team will be to test existing medications that would help in limiting the production of cholesterol on patients undergoing cancer treatment -- adding them to their current therapies. "There are medications approved that we can test", says Lehner. "They were not developed for cancer, they were manufactured for people with hypercholesterolemia [chronic condition where patients have very high level of cholesterol in their blood], but it will be interesting for us to test them with cancer patients and see if there is improvement." Lehner intends to expand the support received and develop these tests locally, including technology and facilities from the institutes and clinics related to the University of Alberta. "The collaboration with Austria was to set the concept of the investigation," he explains. "We have a great group here, great cancer researchers. We are in good hands to continue." Should these potential clinical trials prove to be effective, we could be facing an improved way to help cancer patients: eliminating the tumour, while preventing it from growing at the same time.

Roupret M.,Institut Universitaire de France | Babjuk M.,Charles University | Comperat E.,Institut Universitaire de France | Zigeuner R.,Medical University of Graz | And 10 more authors.
European Urology | Year: 2015

Context The European Association of Urology (EAU) guidelines panel on upper urinary tract urothelial cell carcinoma (UTUC) has prepared updated guidelines to aid clinicians in the current evidence-based management of UTUC and to incorporate recommendations into clinical practice. Objective To provide a brief overview of the EAU guidelines on UTUC as an aid to clinicians. Evidence acquisition The recommendations provided in the current guidelines are based on a thorough review of available UTUC guidelines and articles identified following a systematic search of Medline. Data on urothelial malignancies and UTUC were searched using these keywords: urinary tract cancer; urothelial carcinomas; upper urinary tract, carcinoma; renal pelvis; ureter; bladder cancer; chemotherapy; nephroureterectomy; adjuvant treatment; instillation; neoadjuvant treatment; recurrence; risk factors; and survival. References were weighted by a panel of experts. Evidence synthesis Due to the rarity of UTUC, there are insufficient data to provide strong recommendations (ie, grade A). However, the results of recent multicentre studies are now available, and there is a growing interest in UTUC. The 2009 TNM classification is recommended. Recommendations are given for diagnosis and risk stratification as well as radical and conservative treatment, and prognostic factors are discussed. A single postoperative dose of intravesical mitomycin after nephroureterectomy reduces the risk of bladder tumour recurrence. Recommendations are also provided for patient follow-up after different therapeutic strategies. Conclusions These guidelines contain information on the management of individual patients according to a current standardised approach. Urologists should take into account the specific clinical characteristics of each patient when determining the optimal treatment regimen, based on the proposed risk stratification of these tumours. Patient summary Urothelial carcinoma of the upper urinary tract is rare, but because 60% of these tumours are invasive at diagnosis, an appropriate diagnosis is most important. A number of known risk factors exist. © 2015 European Association of Urology.

Langkammer C.,Medical University of Graz | Liu T.,New York Medical College | Khalil M.,Medical University of Graz | Enzinger C.,Medical University of Graz | And 5 more authors.
Radiology | Year: 2013

Purpose: To apply quantitative susceptibility mapping (QSM) in the basal ganglia of patients with multiple sclerosis (MS) and relate the findings to R2 mapping with regard to the sensitivity for clinical and morphologic measures of disease severity. Materials and Methods: The local ethics committee approved this study, and all subjects gave written informed consent. Sixty-eight patients (26 with clinically isolated syndrome, 42 with relapsing-remitting MS) and 23 control subjects underwent 3-T magnetic resonance (MR) imaging. Susceptibility and R2 maps were reconstructed from the same three-dimensional multiecho spoiled gradient-echo sequence. Mean susceptibilities and R2 rates were measured in the basal ganglia and were compared between different phenotypes of the disease (clinically isolated syndrome, MS) and the control subjects by using analysis of variance, and regressing analysis was used to identify independent predictors. Results: Compared with control subjects, patients with MS and clinically isolated syndrome had increased (more paramagnetic) magnetic susceptibilities in the basal ganglia. R2 mapping proved less sensitive than QSM regarding group differences. The strongest predictor of magnetic susceptibility was age. Susceptibilities were higher with increasing neurologic deficits (r = 0.34, P < .01) and lower with normalized volumes of gray matter (r = 20.35, P < .005) and the cortex (r = 20.35, P < .005). Conclusion: QSM provides superior sensitivity over R2 mapping in the detection of MS-related tissue changes in the basal ganglia. With QSM but not with R2 mapping, changes were already observed in patients with clinically isolated syndrome, which suggests that QSM can serve as a sensitive measure at the earliest stage of the disease. © RSNA, 2013.

Moissl-Eichinger C.,Medical University of Graz | Cockell C.,University of Edinburgh | Rettberg P.,German Aerospace Center
FEMS Microbiology Reviews | Year: 2016

One of the biggest challenges of science is the determination of whether extraterrestrial life exists. Although potential habitable areas might be available for complex life, it is more likely that microbial life could exist in space. Many extremotolerant and extremophilic microbes have been found to be able to withstand numerous, combined environmental factors, such as high or low temperatures and pressures, high-salt conditions, high doses of radiation, desiccation or nutrient limitations. They may even survive the transit from one planet to another. Terrestrial Mars-analogue sites are one focus of researchers, in order to understand the microbial diversity in preparation for upcoming space missions aimed at the detection of life. However, such missions could also pose a risk with respect to contamination of the extraterrestrial environment by accidentally transferred terrestrial microorganisms. Closer to the Earth, the International Space Station is the most enclosed habitat, where humans work and live-and with them numerous microorganisms. It is still unknown how microbes adapt to this environment, possibly even creating a risk for the crew. Information on the microbiology of the ISS will have an impact on the planning and implementation of long-term human spaceflights in order to ensure a safe, stable and balanced microbiome on board. © FEMS 2016. All rights reserved.

Holzinger A.,Medical University of Graz | Bruschi M.,Medical University of Graz | Eder W.,Wolfgang Eder Unternehmensentwicklung
Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics) | Year: 2013

Emotions are important mental and physiological states influencing perception and cognition and have been a topic of interest in Human-Computer Interaction (HCI) for some time. Popular examples include stress detection or affective computing. The use of emotional effects for various applications in decision support systems is of increasing interest. Emotional and affective states represent very personal data and could be used for burn-out prevention. In this paper we report on first results and experiences of our EMOMES project, where the goal was to design and develop an end-user centered mobile software for interactive visualization of physiological data. Our solution was a star-plot visualization, which has been tested with data from N=50 managers (aged 25-55) taken during a burn-out prevention seminar. The results demonstrate that the leading psychologist could obtain insight into the data appropriately, thereby providing support in the prevention of stress and burnout syndromes. © 2013 IFIP International Federation for Information Processing.

Dahaba A.A.,Medical University of Graz | Liu D.W.,Peking Union Medical College | Metzler H.,Medical University of Graz
Minerva Anestesiologica | Year: 2010

Diagnosis of ictal discharges during epileptic activity should be based on raw electroencephalography (EEG). The apparatus necessary for such a diagnosis would typically require time to properly set up and operate. The bispectral index (BIS), an EEG-derived parameter that is easy to establish and easy to use, has been shown to correlate with numerous EEG conditions and may represent a useful tool. Acute encephalitis with refractory, repetitive, partial seizures (AERRPS) is an epileptic syndrome first described by Sakuma in Japan in 2001. We assessed the utility of using BIS monitoring as a diagnostic tool and as a monitor of anticonvulsive therapy in a 14-year-old patient admitted to the intensive care unit with AERRPS. After BIS monitor montage, BIS, electromyography (EMG) and raw EEG data were continuously recorded. Epileptic seizures lasting 1-2 min were repeated every 3-4 min. Using paired t-test analysis, mean ±SD BIS and EMG peak values at the start of epileptic seizures (94.5±3.6, 55.8±2.5 dB) were significantly higher than values measured at the end of seizures (55.1±12.5, 34.5±2.8 dB), respectively. Real-time EEG revealed bursts of epileptiform discharges replaced by slow δand θwaves with ictal remissions. During induced pharmacologic barbiturate/diazepam coma, BIS decreased to near isoelectricity (11.9±2.5) with a steady increase in suppression ratio (65.5±9.7). The characteristic BIS profile of repetitive 1-2 min high EEG/EMG activity could serve as an indicator of a global increase in cerebral activity with seizures. Our report suggests that BIS, an easy-to-use device, might be helpful in monitoring clinical trends after EEG confirmation of diagnosis as well as in successfully depicting the efficacy of therapy.

Morbach H.,University of Würzburg | Hedrich C.M.,Beth Israel Deaconess Medical Center | Beer M.,University of Würzburg | Beer M.,Medical University of Graz | Girschick H.J.,Childrens Hospital
Clinical Immunology | Year: 2013

Autoinflammatory bone disorders are characterized by chronic non-infectious osteomyelitis and inflammation-induced bone resorption and result from aberrant activation of the innate immune system. Sporadic chronic non-bacterial osteomyelitis (CNO) is the most common disease subtype. The clinical picture is highly variable and the exact underlying pathophysiology remains to be determined. Recently, novel insights in the pathophysiology of sterile bone inflammation have been gathered by analyzing patients with rare, monogenic inflammatory diseases. In this overview CNO and Majeed syndrome, cherubism, hypophosphatasia and primary hypertrophic osteoarthropathy will be discussed. For the latter four disorders, a genetic cause affecting bone metabolism and leading to chronic bone inflammation has been described. The exact pathophysiology of CNO remains to be determined. Insights from monogenic autoinflammatory bone diseases and the identification of distinct inflammatory pathways may help to understand the pathogenesis of bone inflammation and inflammation-induced bone resorption in more common diseases. © 2013 Elsevier Inc.

Langner C.,Medical University of Graz | Aust D.,TU Dresden | Ensari A.,Ankara University | Villanacci V.,Institute of Pathology | And 4 more authors.
Histopathology | Year: 2015

Microscopic colitis has emerged as a major cause of chronic watery non-bloody diarrhoea, particularly in elderly females. The term is used as an umbrella term to categorize a subgroup of colitides with distinct clinicopathological phenotypes and no significant endoscopic abnormalities. Lymphocytic colitis is defined by an increased number of surface intraepithelial lymphocytes, and collagenous colitis by a thickened collagen band underneath the surface epithelium. There is increased inflammation in the lamina propria, but only little or no crypt architectural distortion. Incomplete and variant forms showing less characteristic features have been reported under different names. The differential diagnosis mainly includes resolving infectious colitis and changes related to the intake of drugs such as non-steroidal anti-inflammatory drugs. Substantial clinical and histological overlap between lymphocytic and collagenous colitis has been described, raising the suspicion that the conditions are two histological manifestations of the same entity, possibly representing different manifestations during the disease course or different stages of disease development. In this review, we provide a practical approach for pathologists, with a focus on diagnostic criteria and differential diagnosis, and discuss recent insights into the pathogenesis of disease and the relationship with classic chronic inflammatory bowel disease, i.e. Crohn's disease and ulcerative colitis. © 2014 John Wiley & Sons Ltd.

Reiter U.,Medical University of Graz | Reiter G.,Siemens AG | Dorr K.,Feldbach Regional Hospital | Greiser A.,Siemens AG | And 2 more authors.
Radiology | Year: 2014

To introduce blood normalization for myocardial T1 values at magnetic resonance (MR) imaging and to evaluate regional differences between systolic and diastolic myocardial T1 values in healthy subjects. Materials and Methods: This prospective study ( identification number, NCT01728597) was approved by the institutional review board, and volunteer informed consent was obtained. Forty healthy subjects (20 women; age range, 20- 35 years) underwent electrocardiographically gated 1.5-T MR imaging. A modified Look-Locker inversion recovery sequence was used to acquire myocardial T1 maps in systole and diastole. Regional T1 values were evaluated in 16 myocardial segments; blood T1 was derived from the blood pool in the center of the left ventricular cavity. Linear regression slopes between myocardial and blood T1 values were used to normalize myocardial T1 to the mean blood T1 of the study population. Mean T1 values were compared by using the t test, with P < .05 considered to indicate a significant difference. Results: Mean myocardial T1 (984 msec ± 28 [standard deviation] in diastole, 959 msec ± 21 in systole) and all segmental T1 values between diastole and systole differed significantly (P < .001). Blood T1 correlated well with segmental myocardial T1 (R = 0.73 for diastole, R = 0.72 for systole). After normalization to blood T1, significant sex differences in myocardial T1 disappeared and variances in mean myocardial T1 decreased. Blood-normalized diastolic and systolic myocardial T1 values correlated strongly with each other on segmental (r = 0.72) and global (r = 0.89) levels. Subregional myocardial T1 distribution characteristics in diastole were similar to those in systole. Conclusion: In normal myocardium, diastolic and systolic myocardial T1 values differ significantly but correlate strongly. Blood normalization eliminates sex differences in myocardial T1 values and reduces their variability. © RSNA, 2014.

Ljubojevic S.,Medical University of Graz | Walther S.,Medical University of Graz | Asgarzoei M.,Medical University of Graz | Sedej S.,Medical University of Graz | And 3 more authors.
Biophysical Journal | Year: 2011

Quantification of subcellularly resolved Ca 2+ signals in cardiomyocytes is essential for understanding Ca 2+ fluxes in excitation-contraction and excitation-transcription coupling. The properties of fluorescent indicators in intracellular compartments may differ, thus affecting the translation of Ca 2+-dependent fluorescence changes into [Ca 2+] changes. Therefore, we determined the in situ characteristics of a frequently used Ca 2+ indicator, Fluo-4, and a ratiometric Ca 2+ indicator, Asante Calcium Red, and evaluated their use for reporting and quantifying cytoplasmic and nucleoplasmic Ca 2+ signals in isolated cardiomyocytes. Ca 2+ calibration curves revealed significant differences in the apparent Ca 2+ dissociation constants of Fluo-4 and Asante Calcium Red between cytoplasm and nucleoplasm. These parameters were used for transformation of fluorescence into nucleoplasmic and cytoplasmic [Ca 2+]. Resting and diastolic [Ca 2+] were always higher in the nucleoplasm. Systolic [Ca 2+] was usually higher in the cytoplasm, but some cells (15%) exhibited higher systolic [Ca 2+] in the nucleoplasm. Ca 2+ store depletion or blockade of Ca 2+ leak pathways eliminated the resting [Ca 2+] gradient between nucleoplasm and cytoplasm, whereas inhibition of inositol 1,4,5-trisphosphate receptors by 2-APB reversed it. The results suggest the presence of significant nucleoplasmic-to-cytoplasmic [Ca 2+] gradients in resting myocytes and during the cardiac cycle. Nucleoplasmic [Ca 2+] in cardiomyocytes may be regulated via two mechanisms: diffusion from the cytoplasm and active Ca 2+ release via inositol 1,4,5-trisphosphate receptors from perinuclear Ca 2+ stores. © 2011 by the Biophysical Society.

Ludwig H.,Center for Oncology | Kasparu H.,Hospital Elisabethinen | Leitgeb C.,Center for Oncology | Rauch E.,Center for Oncology | And 7 more authors.
Blood | Year: 2014

Bendamustine with bortezomib and dexamethasone was evaluated in 79 patients with relapsed/refractory multiple myeloma. Median age was 64 years, and patients had a median of 2 prior treatment lines (range, 1 to 6 lines). Bendamustine 70 mg/m2 days 1 and 4; bortezomib 1.3 mg/m2 intravenously days 1, 4, 8, and 11; and dexamethasone 20 mg days 1, 4, 8, and 11 once every 28 days was given for up to 8 cycles. Primary end point was overall response rate (ORR). Secondary end points were progression-free survival (PFS), overall survival, time to response, and toxicity. ORR was 60.8%, and when minor responses were included, 75.9%. Median time to response was 31 days. ORR rate was similar in patients previously exposed to bortezomib, lenalidomide, and bortezomib plus lenalidomide. PFS was 9.7 and OS was 25.6 months. Multivariate analysis showed high lactate dehydrogenase, ≥3 prior treatment lines, and low platelet counts correlating with short survival. Grade 3/4 thrombocytopenia was noted in 38%, and grade 3/4/5 infections were noted in 23%. Grade ≤2 polyneuropathy increased from 19% at baseline to 52% at cycle 8 and grade 4, from 0% to 7%. Bendamustine-bortezomib-dexamethasone is active and well tolerated in patients with relapsed/refractory myeloma. This trial was registered in the EudraCT database as No. 2008-006421-13. © 2014 by The American Society of Hematology.

Simonneau G.,Assistance Publique Hopitaux de Paris | Gatzoulis M.A.,Imperial College London | Adatia I.,University of Alberta | Celermajer D.,University of Sydney | And 9 more authors.
Journal of the American College of Cardiology | Year: 2013

In 1998, a clinical classification of pulmonary hypertension (PH) was established, categorizing PH into groups which share similar pathological and hemodynamic characteristics and therapeutic approaches. During the 5th World Symposium held in Nice, France, in 2013, the consensus was reached to maintain the general scheme of previous clinical classifications. However, modifications and updates especially for Group 1 patients (pulmonary arterial hypertension [PAH]) were proposed. The main change was to withdraw persistent pulmonary hypertension of the newborn (PPHN) from Group 1 because this entity carries more differences than similarities with other PAH subgroups. In the current classification, PPHN is now designated number 1. Pulmonary hypertension associated with chronic hemolytic anemia has been moved from Group 1 PAH to Group 5, unclear/multifactorial mechanism. In addition, it was decided to add specific items related to pediatric pulmonary hypertension in order to create a comprehensive, common classification for both adults and children. Therefore, congenital or acquired left-heart inflow/outflow obstructive lesions and congenital cardiomyopathies have been added to Group 2, and segmental pulmonary hypertension has been added to Group 5. Last, there were no changes for Groups 2, 3, and 4. © 2013 by the American College of Cardiology Foundation. Published by Elsevier Inc.

Murali R.,Sloan Kettering Cancer Center | Wiesner T.,Sloan Kettering Cancer Center | Wiesner T.,Medical University of Graz | Scolyer R.A.,Royal Prince Alfred Hospital | And 2 more authors.
Pathology | Year: 2013

BAP1 (BRCA1-Associated Protein 1) was initially identified as a protein that binds to BRCA1. BAP1 is a tumour suppressor that is believed to mediate its effects through chromatin modulation, transcriptional regulation, and possibly via the ubiquitin-proteasome system and the DNA damage response pathway. Germline mutations of BAP1 confer increased susceptibility for the development of several tumours, including uvealmelanoma, epithelioid atypical Spitz tumours, cutaneous melanoma, and mesothelioma. However, the complete tumour spectrum associated with germline BAP1 mutations is not yet known. Somatic BAP1 mutations are seen in cutaneous melanocytic tumours (epithelioid atypical Spitz tumours and melanoma), uveal melanoma, mesothelioma, clear cell renal cell carcinoma, and other tumours. Here, we reviewthe current state of knowledge about the functional roles of BAP1, and summarise data on tumours associated with BAP1 mutations. Awareness of these tumours will help pathologists and clinicians to identify patients with a high likelihood of harbouring germline or somatic BAP1 mutations. We recommend that pathologists consider testing for BAP1 mutations in epithelioid atypical Spitz tumours and uveal melanomas, or when other BAP1-associated tumours occur in individual patients. Tumour tissues may be screened for BAP1mutations/loss/inactivation by immunohistochemistry (IHC) (demonstrated by loss of nuclear staining in tumour cells). Confirmatory sequencing may be considered in tumours that exhibit BAP1 loss by IHC and in those with equivocal IHC results. If a BAP1 mutation is confirmed in a tumour, the patient's treating physician should be informed of the possibility of a BAP1 germline mutation, so they can consider whether genetic counselling and further testing of the patient and investigation of their family is appropriate. Recognition and evaluation of larger numbers of BAP1-associated tumours will also be necessary to facilitate identification of additional distinct clinico-pathological characteristics or other genotype-phenotype correlations that may have prognostic and management implications. © 2013 Royal College of Pathologists of Australasia.

Kempf W.,Kempf und Pfaltz Histologische Diagnostik | Kempf W.,University of Zürich | Kazakov D.V.,Charles University | Palmedo G.,Dermatopathologie Bodensee | And 4 more authors.
American Journal of Surgical Pathology | Year: 2012

Pityriasis lichenoides comprises a clinicopathologic spectrum of cutaneous inflammatory disorders, with the 2 most common variants being pityriasis lichenoides et varioliformis acuta (PLEVA) and pityriasis lichenoides chronica. The aim of the study was to describe 13 cases of a unique PLEVA variant characterized in the conspicuous CD30 + component and thus mimicking lymphomatoid papulosis (LyP), a condition currently classified in the spectrum of CD30 + lymphoproliferative disorders. The cohort included 10 female and 3 male patients whose ages at diagnosis ranged from 7 to 89 years (mean 41 y; median 39 y). The clinical manifestation was that of PLEVA, with small erythematous macules quickly evolving into necrotic papules. No waxing and waning was seen on follow-up in any of the cases. Histopathologically, typical features of PLEVA were present, but an unusual finding was occurrence of a considerable number of CD30 + small lymphocytes as detected immunohistochemically. Over half of the cases also displayed a large number of CD8 + cells and showed coexpression of CD8 and CD30 in the intraepidermal and dermal component of the infiltrate. Of the 11 cases of PLEVA studied for T-cell receptor gene rearrangement, 6 evidenced a monoclonal T-cell population, and 5 were polyclonal. Parvovirus B19 (PVB19) DNA was identified in 4 of 10 cases investigated, and positive serology was observed for PVB19 in 2 patients, altogether suggesting that PVB19 is pathogenetically linked to PLEVA at least in a subset of cases. The presence of CD30 + lymphocytes and CD8 lymphocytes would be consistent with an inflammatory antiviral response, as CD30, even atypically appearing lymphoid cells have been identified in some viral skin diseases. The main significance of the PLEVA variant is, however, its potential confusion with LyP or some cytotoxic lymphomas. Admittedly, the CD30 PLEVA variant described herein and LyP show considerable overlap if one takes into account all known variations of the 2 conditions recognized in recent years, thus suggesting that LyP and PLEVA may be much more biologically closely related entities than currently thought or can even occur on a clinicopathologic spectrum. © 2012 by Lippincott Williams & Wilkins.

Ritz E.,Nierenzentrum | Tomaschitz A.,Medical University of Graz
Nephrology Dialysis Transplantation | Year: 2014

Beyond the classical effect of aldosterone on sodium reabsorption in the distal nephron, the spectrum of aldosterone-induced effects on the kidney (and the cardiovascular system) continues to expand at a rapid pace. Blockade of this system has become an attractive target for intervention. Major contributions have been reported in the past 2-3 years. By necessity this brief summary addresses only some of the emerging issues of nephrological relevance. In this fast moving field, we try to give a concise discussion of papers with potential nephrological relevance in the past 2-3 years. © 2013 The Author.

Pfeiffer R.M.,U.S. National Cancer Institute | Riedl R.,Medical University of Graz
Statistics in Medicine | Year: 2015

We assess the asymptotic bias of estimates of exposure effects conditional on covariates when summary scores of confounders, instead of the confounders themselves, are used to analyze observational data. First, we study regression models for cohort data that are adjusted for summary scores. Second, we derive the asymptotic bias for case-control studies when cases and controls are matched on a summary score, and then analyzed either using conditional logistic regression or by unconditional logistic regression adjusted for the summary score. Two scores, the propensity score (PS) and the disease risk score (DRS) are studied in detail. For cohort analysis, when regression models are adjusted for the PS, the estimated conditional treatment effect is unbiased only for linear models, or at the null for non-linear models. Adjustment of cohort data for DRS yields unbiased estimates only for linear regression; all other estimates of exposure effects are biased. Matching cases and controls on DRS and analyzing them using conditional logistic regression yields unbiased estimates of exposure effect, whereas adjusting for the DRS in unconditional logistic regression yields biased estimates, even under the null hypothesis of no association. Matching cases and controls on the PS yield unbiased estimates only under the null for both conditional and unconditional logistic regression, adjusted for the PS. We study the bias for various confounding scenarios and compare our asymptotic results with those from simulations with limited sample sizes. To create realistic correlations among multiple confounders, we also based simulations on a real dataset. © 2015 John Wiley & Sons, Ltd.

Munch A.,Linköping University | Langner C.,Medical University of Graz
Clinical Gastroenterology and Hepatology | Year: 2015

Microscopic colitis is a chronic inflammatory bowel disease characterized by chronic nonbloody diarrhea and specific histopathology features. Active disease, defined as 3 or more stools or 1 or more watery stools per day, significantly reduces quality of life. Epidemiologic studies have found the incidence and prevalence of microscopic colitis to be comparable with those of Crohn's disease and ulcerative colitis. Nevertheless, microscopic colitis is still under-recognized in clinical practice-most health care workers know little about its etiology and pathophysiology. Furthermore, there are many challenges to the diagnosis and treatment of patients. We review the epidemiologic and clinical features of this disorder and discuss its pathogenesis. We also outline the criteria for histopathologic evaluation of microscopic colitis, recently published by the European Consensus on Inflammatory Bowel Disease, and discuss a treatment algorithm created by the European Microscopic Colitis Group. Treatment options for patients with budesonide-refractory disease are discussed. © 2015 AGA Institute.

Lee J.M.,Baylor College of Medicine | Wagner M.,Baylor College of Medicine | Wagner M.,Medical University of Graz | Xiao R.,Baylor College of Medicine | And 5 more authors.
Nature | Year: 2014

Autophagy is an evolutionarily conserved catabolic process that recycles nutrients upon starvation and maintains cellular energy homeostasis. Its acute regulation by nutrient-sensing signalling pathways is well described, but its longer-term transcriptional regulation is not. The nuclear receptors peroxisome proliferator-activated receptor-α (PPAR α) and farnesoid X receptor (FXR) are activated in the fasted and fed liver, respectively. Here we show that both PPARα and FXR regulate hepatic autophagy in mice. Pharmacological activation of PPAR α reverses the normal suppression of autophagy in the fed state, inducing autophagic lipid degradation, or lipophagy. This response is lost in PPAR α knockout (Ppara -/-, also known as Nr1c1 -/-') mice, which are partially defective in the induction of autophagy by fasting. Pharmacological activation of the bile acid receptor FXR strongly suppresses the induction of autophagy in the fasting state, and this response is absent in FXR knockout (Fxr -/-, also known as Nr1h4 -/-) mice, which show a partial defect in suppression of hepatic autophagy in the fed state. PPAR α and FXR compete for binding to shared sites in autophagic gene promoters, with opposite transcriptional outputs. These results reveal complementary, interlocking mechanisms for regulation of autophagy by nutrient status. © 2014 Macmillan Publishers Limited.

Haybaeck J.,Medical University of Graz | Zeller N.,Albert Ludwigs University of Freiburg | Heikenwalder M.,Helmholtz Center Munich
Swiss Medical Weekly | Year: 2011

In recent years, enormous progress has been made in identifying microRNAs (miRNAs) as important regulators of gene expression and their association with or control of various liver diseases such as fibrosis, hepatitis and hepatocellular carcinoma (HCC). Indeed, many genes encoding miRNAs as well as their targets have been described and their direct or indirect link to the respective liver diseases has been investigated in various experimental systems as well as in human tissue. Here we discuss current knowledge of miRNAs and their involvement in liver diseases, elaborating in particular on the contribution of miRNAs to hepatitis, fibrosis and HCC formation. We also debate possible prognostic, predictive and therapeutic values of respective miRNAs in liver diseases. The discovery of liver disease related miRNAs has constituted a major breakthrough in liver research and will most likely be of high relevance for future therapeutic strategies, especially when dealing with hepatitis, fibrosis and HCC.

Pichler K.,Medical University of Graz | Loreto C.,University of Catania | Leonardi R.,University of Catania | Reuber T.,Albert Ludwigs University of Freiburg | And 2 more authors.
Histology and Histopathology | Year: 2013

The aim of this study was to investigate bone tissue and plasma levels of RANKL and OPG in rats with prednisolone-induced osteoporosis and to evaluate the outcomes of physical activity on the skeletal system by treadmill and vibration platform training. Osteoporosis is a disease characterised by low bone mass and structural deterioration of bone tissue leading to bone fragility. Vibration exercise is a new and effective measure to prevent muscular atrophy and osteoporosis. The animals were divided into 5 groups. 1: control rats; 2: rats with osteoporosis receiving prednisolone; 3: rats receiving prednisolone and treadmill training; 4: rats receiving prednisolone and vibration stimulation training; 5: rats receiving prednisolone, treadmill and vibration stimulation training. For bone evaluations we used whole-body scans, histology and histomorphometric analysis. RANKL and OPG expression was evaluated by immunohistochemistry and biochemical analysis. After treatment, our data demonstrated that RANKL expression was significantly increased in groups 2 and 3 and decreased in groups 4 and 5. Conversely, OPG expression was significantly decreased in groups 2 and 3 and increased in groups 4 and 5. In conclusion, our findings suggest that mechanical stimulation inhibits the activity of RANKL. This finding provides new insights into the occurrence and progression of osteoporosis.

Agency: Cordis | Branch: FP7 | Program: CP-IP | Phase: HEALTH.2010.2.4.2-3 | Award Amount: 15.68M | Year: 2010

The initiation and perpetuation of atrial fibrillation (AF) can be regarded as a complication of a progressive transformation of the structure and functional properties of the atria. This transformation is the result of complex and multiple changes at the molecular, cellular and organ levels which interact to form the basis for proarrhythmic mechanisms in AF. Numerous individual and environmental factors are probably involved in this profound transformation process in the atria. Therefore, we believe that progress in the diagnostics, prevention and treatment of AF requires highly integrative research from the molecule to bedside and from specific signaling pathways and electrophysiological mechanisms to population based studies. A consortium was formed providing this variety of expertises and has identified central research objectives for improvements in AF prevention and therapy. In 5 work packages focusing on basic research, new biomarkers for AF and therapeutic targets will be identified. We will study mechanisms of conduction disturbances in the atria, explore new ion channel targets for treatment of AF, identify specific alterations in the atria depending on the underlying heart disease, and evaluate beneficial effects of organ-protective compounds. Within two clinically oriented work packages the clinical application of these findings will be tested. The predictive value of diagnostic tools like serum biomarkers, 3D reconstruction of atrial conduction patterns based on high resolution body surface ECGs, and echocardiographic markers will be studied in large scale population studies. The new therapeutic targets will be explored in smaller prove-of-principle clinical trials (substrate oriented ablation, new pharmacological targets, and local gene delivery).

Agency: Cordis | Branch: FP7 | Program: CP-CSA-Infra | Phase: INFRA-2012-1.1.9. | Award Amount: 10.48M | Year: 2013

In recent years, biomedical research has crossed international borders in large, collaborative studies showing the value of multidisciplinarity and scale advantage. This has yielded valuable insights and some led to new and better medicines and treatments for diseases. However, disease-focused studies provide less insight in the real disease onset, the relative disease burden in the population, and the actual comparability of selected patients. Large prospective cohort (LPC) studies following up initially healthy participants for years or decades are considered more reliable and different diseases can be studied. LPC studies require large numbers of subjects which are costly but particularly benefited from the advent of high throughput techniques providing opportunities for powerful study designs. This project unites the large study sets of the European Biobanking and Biomolecular Research Infrastructure (BBMRI) and the International Agency for Research on Cancer (IARC), thus achieving a worldwide unique scale of integration. Specifically, we aim to:1)Evaluate/improve the harmonization of individual data on health, lifestyle and other exposures;2)Develop/implement harmonized definitions of diseases;3)Improve biobanking and research technologies and develop innovative solutions facilitating high-quality, fair access to samples and data;4)Provide free transnational access by users, through study proposals selected by an open, pan-European call;5)In the framework of these studies, generate and provide access to whole genome sequences, transcriptome, proteome, metabolome and methylome data;6)Build new public-private partnerships involving large-scale prospective cohorts, and strengthening existing ones, allowing transparent industrial access to academic expertise;7) Build a network transferring the expertise of established European large-scale biobanks to new biobank initiatives under development in other countries.

Zeller T.,Universitats Herzzentrum Freiburg Bad Krozingen | Baumgartner I.,University of Bern | Scheinert D.,Park Hospital Leipzig | Brodmann M.,Medical University of Graz | And 8 more authors.
Journal of the American College of Cardiology | Year: 2014

Background Drug-eluting balloons (DEB) may reduce infrapopliteal restenosis and reintervention rates versus percutaneous transluminal angioplasty (PTA) and improve wound healing/limb preservation.Objectives The goal of this clinical trial was to assess the efficacy and safety of IN.PACT Amphirion drug-eluting balloons (IA-DEB) compared to PTA for infrapopliteal arterial revascularization in patients with critical limb ischemia (CLI).Methods Within a prospective, multicenter, randomized, controlled trial with independent clinical event adjudication and angiographic and wound core laboratories 358 CLI patients were randomized 2:1 to IA-DEB or PTA. The 2 coprimary efficacy endpoints through 12 months were clinically driven target lesion revascularization (CD-TLR) and late lumen loss (LLL). The primary safety endpoint through 6 months was a composite of all-cause mortality, major amputation, and CD-TLR.Results Clinical characteristics were similar between the 2 groups. Significant baseline differences between the IA-DEB and PTA arms included mean lesion length (10.2 cm vs. 12.9 cm; p = 0.002), impaired inflow (40.7% vs. 28.8%; p = 0.035), and previous target limb revascularization (32.2% vs. 21.8%; p = 0.047). Primary efficacy results of IA-DEB versus PTA were CD-TLR of 9.2% versus 13.1% (p = 0.291) and LLL of 0.61 ± 0.78 mm versus 0.62 ± 0.78 mm (p = 0.950). Primary safety endpoints were 17.7% versus 15.8% (p = 0.021) and met the noninferiority hypothesis. A safety signal driven by major amputations through 12 months was observed in the IA-DEB arm versus the PTA arm (8.8% vs. 3.6%; p = 0.080).Conclusions In patients with CLI, IA-DEB had comparable efficacy to PTA. While primary safety was met, there was a trend towards an increased major amputation rate through 12 months compared to PTA. (Study of IN.PACT Amphirion™ Drug Eluting Balloon vs. Standard PTA for the Treatment of Below the Knee Critical Limb Ischemia [INPACT-DEEP]; NCT00941733). © 2014 by the American College of Cardiology Foundation.

Agency: Cordis | Branch: FP7 | Program: CSA-SA | Phase: HEALTH.2013.4.1-2 | Award Amount: 559.84K | Year: 2013

This proposal aims at collecting and analysing facts and figures in order to assess the current legislation on the therapeutic use of somatic cells, and to bridge it with the research infrastructure capacity building. Although EU has adopted 3 Directives on Tissues and cells between 2004 and 2006 to harmonise the procurement, storage and use of cells for therapeutic use in Europe, countries have implemented these directives in very different ways. Furthermore, research has been partially covered by the initial regulation, calling into question the match between regulation and practices that will develop in the near future, in particular with the emergence of European research infrastructures. Finally many changes have occurred in the scientific, legal and institutional environment of cell use, leading to a necessary update of this regulation with regards to its implementation in national legislation and its impact on research practice and innovation. Two domains are at stake: research (infrastructures) and medical practice/public health measures (cells). The therapeutic use of cells is regulated by EU law whereas its research counterpart is mainly depending on national laws and regulations. This gap calls for a coordinated action in order to optimize the translational process, since the full pipeline is not coherently taken into account in current legislations. To achieve these objectives, our project relies on a coherent consortium of experts in the fields of cells therapies, cells banks and translational biomedicine, having strong expertise in law and/ or in governance issues. After 36 months the project will deliver evidence about the contemporary practices around cells and will design a picture of the market and its distribution between the public and private sector. The project will thus help the Commission in the regulatory choices covering the use of human cells for therapeutic purposes and to foster the innovation potential of related research activities.

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH-2007-2.4.1-3 | Award Amount: 4.03M | Year: 2008

GENINCA will address two tumor entities, for which we have good access to pre-malignant lesions and in which genomic instability is a common feature: colorectal and liver cancer. Colorectal cancer amounts to 13.2% of all incident cases of cancer, the second most common form of cancer, surpassed only by lung cancer (13.3%). Liver cancer accounts for about 2% of total cancers, however, the most common liver cancer, i.e. hepatocellular carcinoma (HCC), is among the most lethal form of cancer, and its incidence in Europe has been steadily rising over the last few decades. GENINCA represents a collaborative study of 8 academic and 3 industrial partners from 5 European countries. GENINCA will focus on exploring pre-cancerous and cancer lesions of the two aforementioned tumor entities and their respective microenvironment. As the recent identification of human colon-cancer initiating cells by one of our academic consortium members paves the way for completely new strategies for studying mechanisms of tumorigenesis, a particular focus of this grant proposal will be the detailed characterization of these cancer initiating stem cells. At present, it is still a matter of debate which genomic changes are already present in precursor lesions and whether these lesions already show genetic instability. We will therefore address the occurrence of genomic instability and explore their underlying mechanisms especially in pre-cancerous and early cancer lesions. This will be greatly facilitated by in vivo endomicroscopy approaches, sophisticated animal models and large-scale genomic and proteomic analyses. Furthermore, we will include an in-depth analysis of the corresponding microenvironment. As this represents a translational research effort, we expect to identify markers for novel therapeutic and/or preventative strategies, as well as to facilitate tumor diagnosis, prognosis, and monitoring.

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2013.2.4.2-1 | Award Amount: 8.33M | Year: 2014

Asymptomatic vascular damage accumulates for years before patients are identified and subjected to therapeutic measures. The limited knowledge on early vascular disease pathophysiology is reflected in the lack of therapeutic options. SysVasc aims to overcome this limitation by mounting a comprehensive systems medicine approach to elucidate pathological mechanisms, which will yield molecular targets for therapeutic intervention. The consortium is based on established multidisciplinary European research networks, including specialists in pre-clinical and clinical research, omics technologies, and systems biology from research intensive SMEs and academia; partners synergistically provide access to an extensive number of selected population-based cohorts and associated datasets, cutting edge modeling and simulation methods, and established cardiovascular disease (CVD) animal models and patient cohorts. The coordinated application of these tools and know-how will identify pathophysiological mechanisms and key molecules responsible for onset and progression of CVD and validate their potential to serve as molecular targets for therapeutic intervention. To this end, the consortium will also use unique resources to evaluate molecular homology between the available model systems and human disease, which will yield reliable essential preclinical research tools to explore proof of concepts for therapeutic intervention studies and ultimately translate relevant results into novel therapeutic approaches. Collectively, SysVasc will identify and validate novel biology-driven key molecular targets for CVD treatment. Major scientific, societal and economic impact is expected including, but not limited to, providing a valuable resource to further CVD research, and enhance competitiveness of participating SMEs and European health industry in general by translating knowledge into innovative services in therapeutic target and drug research.

Medical University of Graz and Karlsruhe Institute of Technology | Date: 2010-12-10

The invention relates to a neural prosthesis, a neural prosthesis for use in the treatment of severed nerves and to a method for producing a neural prosthesis. Said neural prosthesis comprises a coupling element receptacle and at least one coupling element having a first and a second coupling section, wherein the coupling element is fixed by the coupling element receptacle, and wherein the first coupling section can be arranged on a first nerve region and the second coupling section on a second nerve region so that both nerve regions can be coupled by means of the neural prosthesis.

Hyb & Seq Single Molecule Chemistry Sequences Oncogenes from FFPE Samples with High Accuracy and Simple Workflow Free of Library, Enzymes and Amplification 3D Biology Enables Simultaneous Detection of Somatic DNA Mutations and Expressed Fusion Transcripts plus Expression Profiling of Proteins from Lung-Tumor FFPE Samples Digital Spatial Profiling of RNA and Protein Expression in Tumor Microenvironment from FFPE Tissue Sections HOLLYWOOD, Fla., Feb. 16, 2017 (GLOBE NEWSWIRE) -- NanoString Technologies, Inc. (NASDAQ:NSTG), a provider of life science tools for translational research and molecular diagnostic products, today highlighted advancements of a series of innovative technologies designed to open up new possibilities for biologic research and diagnostics of the future at the Advances in Genome Biology and Technology (AGBT) conference in Hollywood, Florida.  With the novel library-free Hyb & Seq™ sequencing chemistry, the ability to spatially map both gene and protein expression using Digital Spatial Profiling technology, and 3D Biology™ assays enabling the simultaneous measurement of DNA mutations, RNA and protein expression, NanoString’s optical barcoding technology provides an unparalleled platform to comprehensively characterize the biology of a sample.  These technologies were showcased in two oral presentations and four posters at the AGBT 2017 meeting, in what is the largest display of new technology advancements in company history. “The capabilities highlighted this week are the product of an unprecedented period of innovation at NanoString, and illustrate how we are harnessing the full potential of our optical barcoding technology,” said Brad Gray, president and CEO of NanoString Technologies. “We’re proud of the tremendous progress that our R&D team has made on these programs over the past year, and we look forward to translating these innovations into a powerful suite of research and diagnostic products over the next several years.” Hyb & Seq The Hyb & Seq chemistry is designed to enable a workflow that is simpler and faster than current sequencing methods due to the absence of library preparation, enzymes and amplification.  Hyb & Seq’s simple workflow and compatibility with a variety of sample types would make it ideally suited for targeted clinical sequencing. This chemistry is also unique in providing both short and long read capability simultaneously, as well as the ability to sequence both DNA and RNA in parallel. In proof-of-concept experiments using well defined reference standard reagents, Hyb & Seq chemistry demonstrated a low intrinsic error rate, and the ability to provide high consensus accuracy at low coverage by non-destructively sequencing the same native molecule multiple times. “Hyb & Seq is a brand-new sequencing chemistry, based entirely on hybridization.  It offers high accuracy, flexibility, and simplicity that potentially enable a wide range of clinical applications where rapid sample-to-answer capability is advantageous,” stated Joe Beechem, Ph.D., senior vice president of R&D for NanoString. “While we are still early in the development of this platform, we have moved from proof-of-concept to targeted sequencing on difficult FFPE samples in only 12 months, demonstrating the potential commercial viability of this novel chemistry.” Hyb & Seq chemistry was described in one oral presentation by Dr. Beechem and three posters, highlighting the unique attributes of the platform: Hyb & Seq technology’s simplicity, flexibility, and accuracy offers an ideal sample-to-answer solution for the sequencing lab.  Hyb & Seq technology is currently for research use only and is not for use in diagnostic procedures.  The company is currently evaluating alternatives for the further development of the Hyb & Seq instrument, including corporate and academic partnerships. 3D Biology enables a unique application of the company's proprietary optical barcoding technology for measurement of DNA, RNA, and protein simultaneously in a single experiment. 3D Biology applications enable researchers to make entirely new observations about cancer biology while maximizing the data generated from precious samples.  3D Biology assays are currently commercially available under NanoString’s Vantage 3D™ line of products. 3D Biology results were presented by Julia Kargl, PhD of Medical University of Graz in a plenary session titled 3D Biology™ View of Cancer: Simultaneous Detection of Somatic DNA Mutations and Expressed Fusion Transcripts Plus Expression Profiling of Phosphor and Total Signaling Proteins From Lung-Tumor FFPE Samples.  In this study, a cohort of over 40 lung cancer patient samples were assayed simultaneously with an SNV panel targeting over 100 solid tumor somatic mutations, a lung cancer fusion gene panel targeting ALK, RET, ROS1 and NTRK1 transcripts, and a protein panel measuring over 25 targets, including key members of the EGFR, PI3K, and MAPK signaling pathways.  Combined with separately collected 770-plex RNA profiling of key cancer pathways and 770-plex immune gene expression analysis, this multidimensional dataset points the way to a new generation of molecular biomarker-based signatures of disease. 3D Biology assays are for research use only and are not for use in diagnostic procedures. NanoString's Digital Spatial Profiling (DSP) technology enables the precise quantification of protein and gene expression spatially for regions of interest across the landscape of a heterogeneous FFPE tumor slice. Regions of interest can be any shape and size, down to a single cell level. Combining both multiplexed nucleic acid and protein on the same platform gives researchers the ability to spatially measure RNA when suitable antibodies do not exist. The platform includes imaging and fluidic components to capture spatial context, and current nCounter® instruments provide the quantification. DSP technology was described in a poster titled Spatially resolved, multiplexed digital characterization of RNA and protein expression in FFPE tissue sections: Application to high-plex profiling of tumor microenvironments. NanoString is currently accepting applications to a Technology Access Program for its DSP technology at  A DSP instrument system is under development and is expected to be commercially available in late 2018. The DSP instrument is intended for research use only and is not intended for use in diagnostic procedures. #705: ShortStack™ Technology: Accurate, reference-guided assembly of Hyb & Seq ™ reads for targeted sequencing to resolve short nucleotide variants and InDels - Erin Piazza, Ph.D., Bioinformatics Scientist About NanoString Technologies, Inc. NanoString Technologies provides life science tools for translational research and molecular diagnostic products. The company's nCounter Analysis System has been employed in life sciences research since it was first introduced in 2008 and has been cited in more than 1,450 peer-reviewed publications. The nCounter Analysis System offers a cost-effective way to easily profile the expression of hundreds of genes, proteins, miRNAs, or copy number variations, simultaneously with high sensitivity and precision, facilitating a wide variety of basic research and translational medicine applications, including biomarker discovery and validation. The company's technology is also being used in diagnostics. The Prosigna® Breast Cancer Prognostic Gene Signature Assay together with the nCounter Dx Analysis System is FDA 510(k) cleared for use as a prognostic indicator for distant recurrence of breast cancer. In addition, the company is collaborating with multiple biopharmaceutical companies in the development of companion diagnostic tests for various cancer therapies, helping to realize the promise of precision oncology. For more information, please visit Forward-Looking Statements  This news release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934 and the Private Securities Litigation Reform Act of 1995. These forward-looking statements include statements regarding the expected performance of the company’s Hyb & Seq chemistry and its potential superiority to existing sequencing methods, the company’s Hyb & Seq chemistry’s potential role as the basis for development of a DNA-sequencing instrument for clinical applications, the commercial potential of the company’s Hyb & Seq chemistry and the anticipated timing for the commercial release of the DSP instrument. Such statements are based on current assumptions that involve risks and uncertainties that could cause actual outcomes and results to differ materially. 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Stacher E.,Medical University of Graz | Stacher E.,Ludwig Boltzmann Research Institute | Stacher E.,Program in Translational Lung Research | Graham B.B.,Program in Translational Lung Research | And 9 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2012

Rationale: The impact of modern treatments of pulmonary arterial hypertension (PAH) on pulmonary vascular pathology remains unknown. Objectives: To assess the spectrum of pulmonary vascular remodeling in the modern era of PAH medication. Methods: Assessment ofpulmonary vascular remodeling and inflammation in 62 PAH and 28 control explanted lungs systematically sampled. Measurements and Main Results: Intima and intima plus media fractional thicknesses of pulmonary arteries were increased in the PAH group versus the control lungs and correlated with pulmonary hemodynamic measurements. Despite a high variability of morphological measurements within a given PAH lung and among all PAH lungs, distinct pathological subphenotypes were detected in cohorts of PAH lungs. These included a subset of lungs lacking intima or, most prominently, media remodeling, which had similar numbers of profiles of plexiform lesions as those in lungs with more pronounced remodeling. Marked perivascular inflammation was present in a high number of PAH lungs and correlated with intima plus media remodeling. The number of profiles of plexiform lesions was significantly lower in lungs of male patients and those never treated with prostacyclin or its analogs. Conclusions: Our results indicate that multiple features of pulmonary vascular remodeling are present in patients treated with modern PAH therapies. Perivascular inflammation may have an important role in the processes of vascular remodeling, all of which may ultimately lead to increased pulmonary artery pressure. Moreover, our study provides a framework to interpret and design translational studies in PAH. Copyright © 2012 by the American Thoracic Society.

Krieger H.-U.,German Research Center for Artificial Intelligence | Schulz S.,Medical University of Graz
Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics) | Year: 2016

Medical natural language statements uttered by physicians are usually graded, i.e., are associated with a degree of uncertainty about the validity of a medical assessment. This uncertainty is often expressed through specific verbs, adverbs, or adjectives in natural language. In this paper, we look into a representation of such graded statements by presenting a simple non-normal modal logic which comes with a set of modal operators, directly associated with the words indicating the uncertainty and interpreted through confidence intervals in the model theory. We complement the model theory by a set of RDFS-/OWL 2 RL-like entailment (if-then) rules, acting on the syntactic representation of modalized statements. Our interest in such a formalization is related to the use of OWL as the de facto standard in (medical) ontologies today and its weakness to represent and reason about assertional knowledge that is uncertain or that changes over time. The approach is not restricted to medical statements, but is applicable to other graded statements as well. © Springer-Verlag Berlin Heidelberg 2016.

Langkammer C.,Medical University of Graz | Langkammer C.,Ludwig Boltzmann Institute for Clinical Forensic Imaging | Krebs N.,Ludwig Boltzmann Institute for Clinical Forensic Imaging | Goessler W.,University of Graz | And 5 more authors.
Radiology | Year: 2010

Purpose: To investigate the relationship between transverse relaxation rates R2 and R2*, the most frequently used surrogate markers for iron in brain tissue, and chemically determined iron concentrations. Materials and Methods: This study was approved by the local ethics committee, and informed consent was obtained from each individual's next of kin. Quantitative magnetic resonance (MR) imaging was performed at 3.0 T in seven human postmortem brains in situ (age range at death, 38-81 years). Following brain extraction, iron concentrations were determined with inductively coupled plasma mass spectrometry in prespecified gray and white matter regions and correlated with R2 and R2* by using linear regression analysis. Hemispheric differences were tested with paired t tests. Results: The highest iron concentrations were found in the globus pallidus (mean ± standard deviation, 205 mg/kg wet mass ± 32), followed by the putamen (mean, 153 mg/kg wet mass ± 29), caudate nucleus (mean, 92 mg/kg wet mass ± 15), thalamus (mean, 49 mg/kg wet mass ± 11), and white matter regions. When all tissue samples were considered, transverse relaxation rates showed a strong linear correlation with iron concentration throughout the brain(r2 = 0.67 for R2, r 2 = 0.90 for R2*; P < .001). In white matter structures, only R2* showed a linear correlation with iron concentration. Chemical analysis revealed significantly higher iron concentrations in the left hemisphere than in the right hemisphere, a finding that was not reflected in the relaxation rates. Conclusion: Because of their strong linear correlation with iron concentration, both R2 and R2* can be used to measure iron deposition in the brain. Because R2* is more sensitive than R2 to variations in brain iron concentration and can detect differences in white matter, it is the preferred parameter for the assessment of iron concentration in vivo. © RSNA, 2010.

Popper H.H.,Medical University of Graz | Ryska A.,Charles University | Timar J.,Semmelweis University | Olszewski W.,Cancer Center
Translational Lung Cancer Research | Year: 2014

The clinical expectations how pathologists should submit lung cancer diagnosis have changed dramatically. Until mid 90-ties a clear separation between small cell lung carcinoma (SCLC) and nonsmall cell lung carcinoma (NSCLC) was mostly sufficient. With the invention of antiangiogenic treatment a differentiation between squamous and non-squamous NSCLC was requested. When epidermal growth factor receptor (EGFR) mutation was detected in patients with pulmonary adenocarcinomas and subsequent specific treatment with tyrosine kinase inhibitors (TKIs) was invented, sub-classification of NSCLC and molecular analysis of the tumor tissue for mutations was asked for. Pathologists no longer submit just a diagnosis, but instead are involved in a multidisciplinary team for lung cancer patient management. After EGFR several other driver genes such as echinoderm microtubule associated protein like 4-AL-Kinase 1 (EML4-ALK1), c-ros oncogene 1 , receptor tyrosine kinase (ROS1), discoidin domain receptor tyrosine kinase 2 (DDR2), fibroblast growth factor receptor 1 (FGFR1) were discovered, and more to come. Due to new developments in bronchology (EUS, EBUS) the amount of tissue submitted for diagnosis and molecular analysis is decreasing, however, the genes to be analyzed are increasing. Many of these driver gene aberrations are inversions or translocations and thus require FISH analysis. Each of these analyses requires a certain amount of tumor cells or one to two tissue sections from an already limited amount of tissues or cells. In this respect new genetic test systems have been introduced such as next generation sequencing, which enables not only to detect multiple mutations in different genes, but also amplifications and fusion genes. As soon as these methods have been validated for routine molecular analysis this will enable the analysis of multiple genetic changes simultaneously. In this review we will focus on genetic aberrations in NSCLC, resistance to new target therapies, and also to methodological requirements for a meaningful evaluation of lung cancer tissue and cells. © Translational lung cancer research. All rights reserved.

Popper H.H.,Medical University of Graz | Timar J.,Semmelweis University | Ryska A.,Charles University | Olszewski W.,Cancer Center
Translational Lung Cancer Research | Year: 2014

From the aspect of the contemporary pathologic diagnostics of lung cancer, it is a key issue of the tissue obtained since small biopsies and cytology still play a major role. In the non-small cell lung cancer era, cytology considered equal to biopsy. However, in recent years it is unable to provide quality diagnosis and must be replaced by biopsy. Various molecular techniques can handle various different tissue samples which must be considered during molecular pathology diagnosis. Besides, tumor cell-normal cell ratio in the obtained tissue as well as the absolute tumor cell number have great significance whose information must be provided in the primary lung cancer diagnosis. Last but not least, for continuous sustainable molecular diagnostics of lung cancer rational algorythms, affordable technology and appropriate reimbursement are equally necessary. © Translational lung cancer research. All rights reserved.

Petrovic A.,Ludwig Boltzmann Institute for Clinical Forensic Imaging | Petrovic A.,University of Graz | Scheurer E.,Ludwig Boltzmann Institute for Clinical Forensic Imaging | Scheurer E.,Medical University of Graz | Stollberger R.,University of Graz
Magnetic Resonance in Medicine | Year: 2015

Purpose: T2 quantification with multiecho sequences is typically impaired by the contribution of stimulated echoes to the echo decay due to B1+ inhomogeneity and slice profile effects. In this work, a compact signal model based on the generating functions approach, which accounts for both sources of error, is presented. Methods: The generating functions (GF) approach is used to obtain a closed solution to the evolution of the transverse magnetization in an echo train, however, not in the time domain, but in the transformed z-domain. The approach is generalized by the incorporation of flip angle distribution across the refocusing slice profiles. The approach is tested by fitting the model to simulated data as well as to phantom and in vivo measurements, followed by a comparison with the common monoexponential fitting approach. Results: The fitting simulations indicate that T2 errors of up to 30% can be commonplace in a clinical setting using the monoexponential method. Conversely, the GF approach produced accurate results. Phantom and in vivo experiments showed a good agreement of the GF values with spectroscopic measurements and single-echo spin-echo sequences. Conclusion: A correction for stimulated echoes is necessary to compute comparable T2 values. The presented approach provides a solution to this issue. © 2014 Wiley Periodicals, Inc.

Pludowski P.,Childrens Memorial Health Institute | Holick M.F.,Vitamin D | Pilz S.,Medical University of Graz | Pilz S.,VU University Amsterdam | And 8 more authors.
Autoimmunity Reviews | Year: 2013

Background: Optimal vitamin D intake and its status are important not only for bone and calcium-phosphate metabolism, but also for overall health and well-being. Vitamin D deficiency and insufficiency as a global health problem are likely to be a risk for wide spectrum of acute and chronic illnesses. Methods: A review of randomized controlled trials, meta-analyses, and other evidence of vitamin D action on various health outcomes. Results: Adequate vitamin D status seems to be protective against musculoskeletal disorders (muscle weakness, falls, fractures), infectious diseases, autoimmune diseases, cardiovascular disease, type 1 and type 2 diabetes mellitus, several types of cancer, neurocognitive dysfunction and mental illness, and other diseases, as well as infertility and adverse pregnancy and birth outcomes. Vitamin D deficiency/insufficiency is associated with all-cause mortality. Conclusions: Adequate vitamin D supplementation and sensible sunlight exposure to reach optimal vitamin D status are among the front line factors of prophylaxis for the spectrum of disorders. Supplementation guidance and population strategies for the eradication of vitamin D deficiency must be included in the priorities of physicians, medical professionals and healthcare policy-makers. © 2013 Elsevier B.V.

Brezinschek H.-P.,Medical University of Graz | Rainer F.,Hospital Barmherzige Brueder | Brickmann K.,Medical University of Graz | Graninger W.B.,Medical University of Graz
Arthritis Research and Therapy | Year: 2012

Introduction: The prediction of therapeutic response to rituximab in rheumatoid arthritis is desirable. We evaluated whether analysis of B lymphocyte subsets by flow cytometry would be useful to identify non-responders to rituximab ahead of time.Methods: Fifty-two patients with active rheumatoid arthritis despite therapy with TNF-inhibitors were included in the national rituximab registry. DAS28 was determined before and 24 weeks after rituximab application. B cell subsets were analyzed by high-sensitive flow cytometry before and 2 weeks after rituximab administration. Complete depletion of B cells was defined as CD19-values below 0.0001 x10 9cells/liter.Results: At 6 months 19 patients had a good (37%), 23 a moderate (44%) and 10 (19%) had no EULAR-response. The extent of B lymphocyte depletion in peripheral blood did not predict the success of rituximab therapy. Incomplete depletion was found at almost the same frequency in EULAR responders and non-responders. In comparison to healthy controls, non-responders had elevated baseline CD95 +pre-switch B cells, whereas responders had a lower frequency of plasmablasts.Conclusions: The baseline enumeration of B lymphocyte subsets is still of limited clinical value for the prediction of response to anti-CD20 therapy. However, differences at the level of CD95+ pre switch B cells or plasmablasts were noticed with regard to treatment response. The criterion of complete depletion of peripheral B cells after rituximab administration did not predict the success of this therapy in rheumatoid arthritis. © 2012 Brezinschek et al.; licensee BioMed Central Ltd.

Pichler G.,Research Unit for Cerebral Development and Oximetry | Binder C.,Research Unit for Cerebral Development and Oximetry | Avian A.,Medical University of Graz | Beckenbach E.,Research Unit for Cerebral Development and Oximetry | And 4 more authors.
Journal of Pediatrics | Year: 2013

Objective To define reference ranges for regional cerebral tissue oxygen saturation (crSO2) and regional cerebral fractional tissue oxygen extraction (cFTOE) during the first 15 minutes after birth in neonates requiring no medical support. Study design The crSO2 was measured using near infrared spectroscopy (Invos 5100 cerebral/somatic oximeter monitor; Somanetics Corp, Troy, Michigan) during the first 15 minutes after birth for term and preterm neonates. The near infrared spectroscopy sensor was placed on the left forehead. Peripheral oxygen saturation and heart rate were continuously measured by pulse oximetry, and cFTOE was calculated. Neonates were excluded if they required any medical support. Results A total of 381 neonates were included: 82 term neonates after vaginal delivery, 272 term neonates after cesarean delivery, and 27 preterm neonates after cesarean delivery. In all neonates, median (10th-90th percentiles) crSO2 was 41% (23-64) at 2 minutes, 68% (45-85) at 5 minutes, 79% (65-90) at 10 minutes, and 77% (63-89) at 15 minutes of age. In all neonates, median (10th-90th percentiles) cFTOE was 33% (11-70) at 2 minutes, 21% (6-45) at 5 minutes, 15% (5-31) at 10 minutes, and 18% (7-34) at 15 minutes of age. Conclusion We report reference ranges of crSO2 and cFTOE in neonates requiring no medical support during transition immediately after birth. The use of cerebral oxygenation monitoring and use of these reference ranges in neonates during transition may help to guide oxygen delivery and avoid cerebral hypo-oxygenation and hyperoxygenation. © 2013 Mosby Inc. All rights reserved.

Zhou L.,University of Alabama at Birmingham | Solhjoo S.,Johns Hopkins University | Millare B.,Johns Hopkins University | Plank G.,Medical University of Graz | And 4 more authors.
Circulation: Arrhythmia and Electrophysiology | Year: 2014

Background-Sudden cardiac death often involves arrhythmias triggered by metabolic stress. Loss of mitochondrial function is thought to contribute to the arrhythmogenic substrate, but how mitochondria contribute to uncoordinated electrical activity is poorly understood. It has been proposed that the formation of metabolic current sinks, caused by the nonuniform collapse of mitochondrial inner membrane potential (Δψm), contributes to re-entrant arrhythmias because Δψm depolarization is tightly coupled to the activation of sarcolemmal ATP-sensitive K+ channels, hastening action potential repolarization and shortening the refractory period. Methods and Results-Here, we use computational and experimental methods to investigate how Δψm instability can induce re-entrant arrhythmias. We develop the first tissue-level model of cardiac electrical propagation incorporating cellular electrophysiology, excitation-contraction coupling, mitochondrial energetics, and reactive oxygen species balance. Simulations show that re-entry and fibrillation can be initiated by regional Δψm loss because of the disparity of refractory periods inside and outside the metabolic sink. Computational results are compared with the effects of a metabolic sink generated experimentally by local perfusion of a mitochondrial uncoupler in a monolayer of cardiac myocytes. Conclusions-The results demonstrate that regional mitochondrial depolarization triggered by oxidative stress activates sarcolemmal ATP-sensitive K+ currents to form a metabolic sink. Consequent shortening of the action potential inside, but not outside, the sink increases the propensity for re-entry. Δψ m recovery during pacing can lead to novel mechanisms of ectopic activation. The findings highlight the importance of mitochondria as potential therapeutic targets for sudden death associated with cardiovascular disease. © 2013 American Heart Association, Inc.

Nikolaidis M.G.,Aristotle University of Thessaloniki | Kerksick C.M.,University of New Mexico | Lamprecht M.,Medical University of Graz | McAnulty S.R.,Appalachian State University
Oxidative Medicine and Cellular Longevity | Year: 2012

The detrimental outcomes associated with unregulated and excessive production of free radicals remains a physiological concern that has implications to health, medicine and performance. Available evidence suggests that physiological adaptations to exercise training can enhance the body's ability to quench free radicals and circumstantial evidence exists to suggest that key vitamins and nutrients may provide additional support to mitigate the untoward effects associated with increased free radical production. However, controversy has risen regarding the potential outcomes associated with vitamins C and E, two popular antioxidant nutrients. Recent evidence has been put forth suggesting that exogenous administration of these antioxidants may be harmful to performance making interpretations regarding the efficacy of antioxidants challenging. The available studies that employed both animal and human models provided conflicting outcomes regarding the efficacy of vitamin C and E supplementation, at least partly due to methodological differences in assessing oxidative stress and training adaptations. Based on the contradictory evidence regarding the effects of higher intakes of vitamin C and/or E on exercise performance and redox homeostasis, a permanent intake of non-physiological dosages of vitamin C and/or E cannot be recommended to healthy, exercising individuals. © 2012 Michalis G. Nikolaidis et al.

Roupret M.,Pitie Salpetrire Hospital | Roupret M.,University Pierre and Marie Curie | Zigeuner R.,Medical University of Graz | Palou J.,Fundacio Puigvert | And 6 more authors.
European Urology | Year: 2011

Context: The European Association of Urology (EAU) Guideline Group for urothelial cell carcinoma of the upper urinary tract (UUT-UCC) has prepared new guidelines to aid clinicians in assessing the current evidence-based management of UUT-UCC and to incorporate present recommendations into daily clinical practice. Objective: This paper provides a brief overview of the EAU guidelines on UUT-UCC as an aid to clinicians in their daily practice. Evidence acquisition: The recommendations provided in the current guidelines are based on a thorough review of available UUT-UCC guidelines and papers identified using a systematic search of Medline. Data on urothelial malignancies and UUT-UCCs in the literature were searched using Medline with the following keywords: urinary tract cancer, urothelial carcinomas, upper urinary tract, carcinoma, transitional cell, renal pelvis, ureter, bladder cancer, chemotherapy, nephroureterectomy, adjuvant treatment, neoadjuvant treatment, recurrence, risk factors, and survival. A panel of experts weighted the references. Evidence synthesis: There is a lack of data in the current literature to provide strong recommendations due to the rarity of the disease. A number of recent multicentre studies are now available, whereas earlier publications were based only on limited populations. However, most of these studies have been retrospective analyses. The TNM classification 2009 is recommended. Recommendations are given for diagnosis as well as for radical and conservative treatment; prognostic factors are also discussed. Recommendations are provided for patient follow-up after different therapeutic options. Conclusions: These guidelines contain information for the diagnosis and treatment of individual patients according to a current standardised approach. When determining the optimal treatment regimen, physicians must take into account each individual patient's specific clinical characteristics with regard to renal function including medical comorbidities; tumour location, grade and stage; and molecular marker status. © 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Malli N.,Universitatsplatz 4 | Ehammer T.,Universitatsplatz 4 | Yen K.,Universitatsplatz 4 | Yen K.,University of Heidelberg | And 2 more authors.
International Journal of Legal Medicine | Year: 2013

The purpose of this prospective study was to evaluate the rate of detection and correct classification of traumatic soft tissue injuries of the head using clinical multislice computed tomography (MSCT) compared with an external forensic examination. Thirty-one patients with soft tissue injuries after head trauma and clinically indicated cerebral MSCT scan underwent an external forensic examination with documentation of the morphological appearance and the exact localization of scalp and facial injuries. MSCT data were evaluated by a radiologist blinded to the results of the external examination using axial images as well as multiplanar reconstruction tools. The results of the radiological and forensic report were compared and analyzed. The main finding was that clinical MSCT data of the head detected 55 % of all external lesions and diagnosed the correct morphological type of lesion in 30 %. All lacerations and 44 % of the hematomas were correctly identified in the radiological report, whereas the diagnosis of swellings and abrasions was difficult. MSCT showed a high specificity for all types of soft tissue lesions. Additionally, a substantial number of internal lesions such as fractures or intracerebral bleedings were revealed which were not detected in the external examination. The results demonstrate that the forensic-radiologic evaluation of clinical MSCT data has a good diagnostic performance and is a valuable method to retrospectively supplement external forensic examination in living crime victims. It also might - to a certain extent - be used as the only source in cases where no forensic external examination has taken place within due time. © 2012 Springer-Verlag.

Min L.,CAS Shanghai Institutes for Biological Sciences | Ji Y.,Fudan University | Bakiri L.,Spanish National Cancer Research Center | Qiu Z.,CAS Shanghai Institutes for Biological Sciences | And 9 more authors.
Nature Cell Biology | Year: 2012

Understanding stage-dependent oncogenic mechanisms is critical to develop not only targeted therapies, but also diagnostic markers and preventive strategies. The mechanisms acting during cancer initiation remain elusive, largely owing to a lack of suitable animal models and limited availability of human precancerous lesions. Here we show using genetic mouse models specific for liver cancer initiation, that survival of initiated cancer cells is controlled by c-Jun, independently of p53, through suppressing c-Fos-mediated apoptosis. Mechanistically, c-Fos induces SIRT6 transcription, which represses survivin by reducing histone H3K9 acetylation and NF-κB activation. Importantly, increasing the level of SIRT6 or targeting the anti-apoptotic activity of survivin at the initiation stage markedly impairs cancer development. Moreover, in human dysplastic liver nodules, but not in malignant tumours, a specific expression pattern with increased c-Jun-survivin and attenuated c-Fos-SIRT6 levels was identified. These results reveal a regulatory network connecting stress response and histone modification in liver tumour initiation, which could be targeted to prevent liver tumorigenesis. © 2012 Macmillan Publishers Limited.

Neumann H.,Friedrich - Alexander - University, Erlangen - Nuremberg | Vieth M.,Klinikum Bayreuth GmbH | Langner C.,Medical University of Graz | Neurath M.F.,Friedrich - Alexander - University, Erlangen - Nuremberg | Mudter J.,Friedrich - Alexander - University, Erlangen - Nuremberg
World Journal of Gastroenterology | Year: 2011

The risk of developing neoplasia leading to colorectal cancer is significantly increased in ulcerative colitis (UC) and most likely in Crohn's disease. Several endoscopic surveillance strategies have been implemented to identify these lesions. The main issue is that colitis-associated neoplasms often occurs in flat mucosa, often being detected on taking random biopsies rather than by identification of these lesions via endoscopic imaging. The standard diagnostic procedure in long lasting UC is to take four biopsies every 10 cm. Image enhancement methods, such as chromoendoscopy and virtual histology using endomicroscopy, have greatly improved neoplasia detection rates and may contribute to reduced random biopsies by taking targeted "smart" biopsies. Chromoendoscopy may effectively be performed by experienced endoscopists for routine screening of UC patients. By contrast, endomicroscopy is often only available in selected specialized endoscopic centers. Importantly, advanced endoscopic imaging has the potential to increase the detection rate of neoplasia whereas the interplay between endoscopic experience and interpretation of histological biopsy evaluation allows the physician to make a proper diagnosis and to find the appropriate therapeutic approach. Colitis-associated intraepithelial neoplasms may occur in flat mucosa of endoscopically normal appearance or may arise as dysplasia-associated lesion or mass (DALM), which may be indistinguishable from sporadic adenomas in healthy or non-colitis mucosa [adenoma-like mass (ALM)]. The aim of this review was to summarize endoscopic and histological characteristics of DALM and ALM in the context of therapeutic procedures. © 2011 Baishideng Publishing Group Co. All rights reserved.

Tomaschitz A.,Medical University of Graz | Pilz S.,Medical University of Graz | Ritz E.,University of Heidelberg | Obermayer-Pietsch B.,Medical University of Graz | Pieber T.R.,Medical University of Graz
Nature Reviews Endocrinology | Year: 2010

In the setting of primary aldosteronism, elevated aldosterone levels are associated with increased blood pressure. Aldosterone concentrations within the normal range, however, can also alter blood pressure. Furthermore, the aldosterone-to-renin ratio, an indicator of aldosterone excess, is associated with hypertension, even in patients without excessive absolute aldosterone levels. In this Review we assess the data on the role of aldosterone in the development and maintenance of hypertension. We provide an overview of the complex crosstalk between genetic and environmental factors, and about aldosterone-mediated arterial hypertension and target organ damage. The discussion is organized according to major targets of aldosterone action: the collecting duct in the kidney, the vasculature and the central nervous system. The antihypertensive efficacy of mineralocorticoid-receptor blockers, even in patients with aldosterone values in the normal range, supports the evidence that aldosterone plays a part in blood pressure elevation in the absence of primary aldosteronism. © 2010 Macmillan Publishers Limited. All rights reserved.

Campe G.V.,Medical University of Graz | Moschopulos M.,Kantonsspital Aarau | Hefti M.,Neurochirurgisches Zentrum
Acta Neurochirurgica | Year: 2012

Background Frameless stereotactic biopsies are replacing frame-based stereotaxy as a diagnostic approach to brain lesions. In order to avoid a sampling bias or negative histology, multiple specimens are often taken. This in turn increases the risk of hemorrhagic complications. Objective We present the use of 5-aminolevulinic acid (5- ALA)-induced protoporphyrin IX fluorescence in frameless stereotaxy to improve the procedure duration and yield, and thereby reduce the risk of complications. Methods Patients with suspected high-grade brain tumors are given 5-ALA 4 h prior to stereotactic biopsy. The biopsy needle is guided to the target using frameless stereotaxy based either on preoperative images or combined with intraoperative MRI sequences. The specimen is illuminated with blue light to look for fluorescence. In case of a positive fluorescence within the tissue sample, no frozen sections are obtained, and no further specimens are taken. Results The samples of 13 patients revealed a positive fluorescence and were histologically confirmed as malignant or high-grade brain neoplasms. four cases were fluorescence-negative, requiring frozen section confirmation and/or multiple samples. In theses cases histology was either nonspecific gliotic changes or low-grade tumors. There were no complications related to the additional use of 5-ALA. Conclusion 5-ALA fluorescence in stereotactic biopsies can increase the safety and accuracy of these procedures by reducing sampling errors and eliminating the need for multiple samples and/or frozen section verification, creating a more accurate, faster and safer procedure for cases of suspected malignant or high-grade brain tumors situated in deep or eloquent areas. © Springer-Verlag 2012.

Babjuk M.,Charles University | Burger M.,University of Würzburg | Zigeuner R.,Medical University of Graz | Shariat S.F.,Medical University of Vienna | And 8 more authors.
European Urology | Year: 2013

Context The first European Association of Urology (EAU) guidelines on bladder cancer were published in 2002 [1]. Since then, the guidelines have been continuously updated. Objective To present the 2013 EAU guidelines on non-muscle-invasive bladder cancer (NMIBC). Evidence acquisition Literature published between 2010 and 2012 on the diagnosis and treatment of NMIBC was systematically reviewed. Previous guidelines were updated, and the levels of evidence and grades of recommendation were assigned. Evidence synthesis Tumours staged as Ta, T1, or carcinoma in situ (CIS) are grouped as NMIBC. Diagnosis depends on cystoscopy and histologic evaluation of the tissue obtained by transurethral resection (TUR) in papillary tumours or by multiple bladder biopsies in CIS. In papillary lesions, a complete TUR is essential for the patient's prognosis. Where the initial resection is incomplete, where there is no muscle in the specimen, or where a high-grade or T1 tumour is detected, a second TUR should be performed within 2-6 wk. The risks of both recurrence and progression may be estimated for individual patients using the EORTC scoring system and risk tables. The stratification of patients into low-, intermediate-, and high-risk groups is pivotal to recommending adjuvant treatment. For patients with a low-risk tumour, one immediate instillation of chemotherapy is recommended. Patients with an intermediate-risk tumour should receive one immediate instillation of chemotherapy followed by 1 yr of full-dose bacillus Calmette-Guérin (BCG) intravesical immunotherapy or by further instillations of chemotherapy for a maximum of 1 yr. In patients with high-risk tumours, full-dose intravesical BCG for 1-3 yr is indicated. In patients at highest risk of tumour progression, immediate radical cystectomy should be considered. Cystectomy is recommended in BCG-refractory tumours. The long version of the guidelines is available from the EAU Web site: Conclusions These abridged EAU guidelines present updated information on the diagnosis and treatment of NMIBC for incorporation into clinical practice. Patient summary The EAU Panel on Non-muscle Invasive Bladder Cancer released an updated version of their guidelines. Current clinical studies support patient selection into different risk groups; low, intermediate and high risk. These risk groups indicate the likelihood of the development of a new (recurrent) cancer after initial treatment (endoscopic resection) or progression to more aggressive (muscle-invasive) bladder cancer and are most important for the decision to provide chemo- or immunotherapy (bladder installations). Surgical removal of the bladder (radical cystectomy) should only be considered in patients who have failed chemo- or immunotherapy, or who are in the highest risk group for progression. © 2013 European Association of Urology.

Sun M.,University of Montréal | Shariat S.F.,Cornell University | Cheng C.,Singapore General Hospital | Ficarra V.,University of Padua | And 5 more authors.
European Urology | Year: 2011

Context: The natural history of renal cell carcinoma (RCC) is highly unpredictable. Small renal masses may be accompanied by metastatic disease. Conversely, patients with locally advanced disease may enjoy long-term disease-free survival. Objective: To review the status of prognostic factors in RCC. Evidence acquisition: A literature review was performed using the PubMed, MEDLINE, and Cochrane databases for articles published as of February 15, 2010. Electronic articles published ahead of print were also considered. Search was limited to the English language. Search was conducted using the following keywords: renal cell carcinoma, molecular, tissue, markers, blood, urine, progression, prognosis, risk factor, and survival. Studies were selected according to the relevance of the study, the number of patients included, originality, actuality, and clinical applicability of the results. Evidence synthesis: Four areas of prediction were examined: (1) new RCC diagnostics, (2) RCC grade and stage at diagnosis, (3) disease progression, and (4) disease-specific mortality. All identified reports represented either case series or controlled studies. Although a large number of markers were identified, only a few were validated. Several prognostic factors were integrated in predictive or prognostic models. Conclusions: Several prognostic factors can help discriminate between favourable and unfavourable RCC phenotypes. Of those, several clinical, pathologic, and biologic markers have been tested and validated, and they are used in predictive and prognostic models. Nonetheless, the search continues, especially for informative markers predicting the response to targeted therapies.

Dornbusch H.J.,Medical University of Graz | Groll A.,University Childrens Hospital | Walsh T.J.,Cornell University
Clinical Microbiology and Infection | Year: 2010

Early recognition and rapid initiation of effective treatment is a prerequisite for successful management of children with invasive fungal infections. The increasing diversity of fungal pathogens in high-risk patients, the differences in the antifungal spectra of available agents and the increasing rates of resistance call for identification of the infecting isolate at the species level and for information on drug resistance, in order to provide state-of-the-art patient care. Microscopy and culture of appropriate specimens remain the reference standard for mycological diagnosis, despite difficulties in obtaining appropriate and/or sufficient specimens, long durations of culture and false-negative results. Modern imaging studies and detection of circulating fungal cell wall components and DNA in blood and other body fluids or in affected tissues may improve the laboratory diagnosis of invasive mycoses. © 2010 The Authors Clinical Microbiology and Infection © 2010 European Society of Clinical Microbiology and Infectious Diseases.

Lallas A.,Arcispedale Santa Maria Nuova Instituto Of Ricerca E Cura A Carattere Scientifico Irccs | Kyrgidis A.,Aristotle University of Thessaloniki | Ferrara G.,Gaetano Rummo General Hospital | Kittler H.,Medical University of Vienna | And 8 more authors.
The Lancet Oncology | Year: 2014

Sentinel lymph node biopsy has been proposed as a diagnostic method for estimation of the malignant potential of atypical Spitz tumours. However, although cell deposits are commonly detected in the sentinel lymph nodes of patients with atypical Spitz tumours, their prognosis is substantially better than that of patients with melanoma and positive sentinel lymph node biopsies. We did a systematic review of published reports to assess the role of sentinel lymph node biopsy as a prognostic method in the management of atypical Spitz tumours. The results of our analysis did not show any prognostic benefit of sentinel lymph node biopsy; having a positive sentinel lymph node does not seem to predict a poorer outcome for patients with atypical Spitz tumours. These findings indicate that, especially in the paediatric population, it might be prudent initially to use complete excision with clear margins and careful clinical follow-up in patients with atypical Spitz tumours. © 2014 Elsevier Ltd.

Peter S.,DSM Nutritional Products Ltd. | Pilz S.,Medical University of Graz | Eggersdorfer M.,DSM Nutritional Products Ltd. | Weber P.,DSM Nutritional Products Ltd.
International Journal for Vitamin and Nutrition Research | Year: 2013

The main function of vitamin E is to protect against scavenging of reactive oxygen species; it is the primary protective agent against lipid peroxidation. Overt vitamin E deficiency is present only in patients with severe malnutrition and certain chronic diseases. The latest Recommended Dietary Allowance for vitamin E is based on the correlation between hydrogen peroxide-induced erythrocyte lysis and plasma α-tocopherol concentrations (Institute of Medicine, United States), or the prevention of lipid peroxidation (National Nutrition Societies of Germany, Austria and Switzerland, D-ACH). According to the current recommendations, the reference plasma concentration for vitamin E is 12 - 46 μmol/L (daily intake of 15 - 30 mg α-tocopherol equivalents). Epidemiological studies suggest a beneficial effect of vitamin E on cardiovascular health at a plasma concentration of 30 μmol/L (a daily intake of ∼ 50 IU). Vitamin E is also an important micronutrient for maintaining the immune system, especially in the elderly. A workshop was organized with the main objective to propose a concept for developing markers of status, functionality, and health in the field of nutritional research, in order to define desirable vitamin E requirements in healthy individuals. © 2013 Hans Huber Publishers.

Senker W.,General Hospital Amstetten | Meznik C.,General Hospital Amstetten | Avian A.,Medical University of Graz | Berghold A.,Medical University of Graz
European Spine Journal | Year: 2011

The medical profession is increasingly confronted with the epidemic phenomenon of obesity. Its impact on spine surgery is not quite clear. Published data concerning the use of minimally invasive surgery (MIS) in the spine among obese patients is scarce. The purpose of the present retrospective study was to evaluate perioperative as well as postoperative complication rates in MIS fusion of the lumbar spine in obese, overweight and normal patients classified according to their body mass index. Lumbar MIS fusion was performed by means of TLIF procedures and/or posterolateral fusion alone. A laminotomy was performed in patients with spinal stenosis. Of 72 patients, 39 underwent additional laminotomy for spinal stenosis. No differences were registered in respect of the numbers of fused segments or cages. Any harmful event occurring peri- or postoperatively was noted and included in the statistical analysis. No infection at the site of surgery or severe wound healing disorder was encountered. We registered no difference in blood loss, drainage, or the length of the hospital stay between the three BMI groups. We also observed no difference in complication rates between the three groups. This study confirms the low soft tissue damage of minimal access surgery techniques, which is an important type of surgery in obese patients. The smaller approach helps to minimize infections and wound healing disorders. Moreover, deeper regions of wounds are clearly visualized with the aid of tubular retractors. © The Author(s) 2011.

Ghofrani H.-A.,Justus Liebig University | Morrell N.W.,Addenbrookes and Papworth Hospitals | Hoeper M.M.,Medizinische Hochschule | Olschewski H.,Medical University of Graz | And 7 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2010

Rationale: Pulmonary arterial hypertension (PAH) is a progressive condition with a poor prognosis. Platelet-derived growth factor receptor (PDGFR) signaling plays an important role in its pathobiology. Objectives: To assess safety, tolerability, and efficacy of the PDGFR inhibitor imatinib in patients with PAH. Methods: Patients with PAH in functional classes II-IV were enrolled in a 24-week randomized, double-blind, placebo-controlled pilot study. Patients received imatinib (an inhibitor of PDGFR activity) 200 mg orally once daily (or placebo), which was increased to 400 mg if the initial dose was well tolerated. The primary endpoints were safety and change from baseline in the 6-minute-walk distance (6MWD). Secondary endpoints included hemodynamics and functional classification. Measurements and Main Results: Fifty-nine patients enrolled (imatinib [n = 28]; placebo [n = 31]); 42 completed the study. Dropouts were equally matched between the two groups. In the intention-to-treat (ITT) population there was no significant change in the 6MWD (mean ± SD) in the imatinib versus placebo group (+22 ± 63 versus -1.0 ± 53 m). There was a significant decrease in pulmonary vascular resistance (imatinib -300 ± 347 versus placebo -78 ± 269 dynes·s·cm -5, P < 0.01) and increase in cardiac output (imatinib +0.6 ± 1.2 versus placebo -0.1 ± 0.9 L/min, P = 0.02). Serious adverse events occurredin 11 imatinib recipients (39%) and 7 placebo recipients (23%). Three deaths occurred in each group. Post hoc subgroup analyses suggest that patients with greater hemodynamic impairment may respond better than patients with less impairment. Conclusions: These data from a Phase II study are consistent with imatinib being well tolerated in patients with PAH, and provide proof of concept for further studies evaluating its safety, tolerability, and efficacy in PAH. Clinical trial registered with (NCT00477269).

Feigl B.,Queensland University of Technology | Feigl B.,University of Queensland | Mattes D.,Medical University of Graz | Thomas R.,University of Queensland | Zele A.J.,Queensland University of Technology
Investigative Ophthalmology and Visual Science | Year: 2011

Purpose. To determine whether glaucoma alters intrinsically photosensitive retinal ganglion cell (ipRGC) function. Methods. Forty-one patients (25 with glaucoma and 16 healthy age-matched control participants) were tested. Intrinsically photosensitive retinal ganglion cell function was directly measured by the sustained, postillumination pupil response (PIPR). Forty-one eyes of 41 participants were tested with 7°, 10-second, short-wavelength (488 nm; bluish) and long-wavelength (610 nm; reddish) stimuli (14.2 log photons · cm -2 · s -1) presented to the right eye in Maxwellian view, and the consensual pupil response of the left eye was measured by infrared pupillometry. The difference between PIPR amplitude (percentage baseline pupil diameter), net PIPR (percentage change) and kinetics (time in mm · s -1 to the PIPR plateau) for the blue and red stimuli in patients with early and advanced (moderate/severe) glaucoma was compared to that in age-matched control participants. Results. The blue PIPR was significantly smaller between normal participants and patients with advanced glaucoma, as well as between those with early and those with advanced glaucoma (P < 0.05). The kinetics of the red and blue PIPRs were not significantly different between any groups. Normal age-matched participants and patients with early-stage glaucoma were not significantly different on any parameter, and neither was the normal and glaucoma group (advanced and early combined). Conclusions. Persons with moderate and severe glaucoma have a dysfunctional ipRGC-mediated PIPR. Intrinsically photosensitive retinal ganglion cell function measured directly with the PIPR may become a clinical indicator of progressive changes in glaucoma. © 2011 The Association for Research in Vision and Ophthalmology, Inc.

Ortega M.,University of Texas Health Science Center at San Antonio | Bhatnagar H.,University of Texas Health Science Center at San Antonio | Lin A.-P.,University of Texas Health Science Center at San Antonio | Wang L.,University of Texas Health Science Center at San Antonio | And 4 more authors.
Leukemia | Year: 2015

Growing evidence suggests that microRNAs (miRNAs) facilitate the cross-talk between transcriptional modules and signal transduction pathways. MYC and NOTCH1 contribute to the pathogenesis of lymphoid malignancies. NOTCH induces MYC, connecting two signaling programs that enhance oncogenicity. Here we show that this relationship is bidirectional and that MYC, via a miRNA intermediary, modulates NOTCH. MicroRNA-30a (miR-30a), a member of a family of miRNAs that are transcriptionally suppressed by MYC, directly binds to and inhibits NOTCH1 and NOTCH2 expression. Using a murine model and genetically modified human cell lines, we confirmed that miR-30a influences NOTCH expression in a MYC-dependent fashion. In turn, through genetic modulation, we demonstrated that intracellular NOTCH1 and NOTCH2, by inducing MYC, suppressed miR-30a. Conversely, pharmacological inhibition of NOTCH decreased MYC expression and ultimately de-repressed miR-30a. Examination of genetic models of gain and loss of miR-30a in diffuse large B-cell lymphoma (DLBCL) and T-acute lymphoblastic leukemia (T-ALL) cells suggested a tumor-suppressive role for this miRNA. Finally, the activity of the miR-30a-NOTCH-MYC loop was validated in primary DLBCL and T-ALL samples. These data define the presence of a miRNA-mediated regulatory circuitry that may modulate the oncogenic signals originating from NOTCH and MYC. © 2015 Macmillan Publishers Limited.

Wagner W.,RWTH Aachen | Bork S.,University of Heidelberg | Lepperdinger G.,Institute for Biomedical Aging Research | Joussen S.,RWTH Aachen | And 3 more authors.
Aging | Year: 2010

Mesenchymal stromal cells (MSC) are currently tested in a large number of clinical trials and raise high hope inregenerative medicine. These cells have to be expanded in vitro before transplantation and several studies demonstratedthat long-term culture evokes continuous changes in MSC: proliferation rate decays, the cell size increases, differentiationpotential is affected, chromosomal instabilities may arise and molecular changes are acquired. Long-term culture of cellpreparations might also have therapeutic consequences, although this has hardly been addressed in ongoing trials so far. Reliable therapeutic regimens necessitate quality control of cellular products. This research perspective summarizesavailable methods to track cellular aging of MSC. We have demonstrated that gene expression changes [1] and epigeneticmodifications [2] are continuously acquired during replicative senescence. Molecular analysis of a suitable panel of genesmight provide a robust tool to assess efficiency and safety of long-term expansion. © Wagner et al.

Lerchbaum E.,Medical University of Graz | Lerchbaum E.,University of Heidelberg | Rabe T.,University of Heidelberg
Current Opinion in Obstetrics and Gynecology | Year: 2014

Purpose of review: Apart from the well known effects of vitamin D on maintaining calcium homeostasis and promoting bone mineralization, there is some evidence suggesting that vitamin D also modulates human reproductive processes. We will review the most interesting and relevant studies on vitamin D and female fertility published over the past year. Recent findings: In the past year, several observational studies reported a better in-vitro fertilization outcome in women with sufficient vitamin D levels (≥ 30 ng/ml), which was mainly attributed to vitamin D effects on the endometrium. One randomized controlled trial found an increased endometrial thickness in women with polycystic ovary syndrome (PCOS) receiving vitamin D during intrauterine insemination cycles. Further, vitamin D supplementation had a beneficial effect on serum lipids in PCOS women. Vitamin D treatment improved endometriosis in a rat model and increased vitamin D intake was related to a decreased risk of incident endometriosis. Vitamin D was also favorably associated with primary dysmenorrhea, uterine leiomyoma, and ovarian reserve in late reproductive aged women. Summary: In women undergoing in-vitro fertilization, a sufficient vitamin D level (≥ 30 ng/ml) should be obtained. Vitamin D supplementation might improve metabolic parameters in women with PCOS. A high vitamin D intake might be protective against endometriosis. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH-2009-2.4.5-1 | Award Amount: 7.81M | Year: 2010

Non-alcoholic fatty liver disease (NAFLD) has become one of the top concerns for the practising hepatogastroenterologist due to the obesity epidemic and its potential to progress to advanced liver disease which significantly impacts on overall and liver-related mortality. The aim of the FLIP (Fatty Liver: Inhibition of Progression) project is to understand and prevent the progression of liver disease in NAFLD. FLIP is a consortium of basic scientists and practising clinical hepatologists with an established track record and focus on research into the underlying mechanisms and management of patients with NAFLD. Therefore FLIP provides a unique opportunity to assemble the largest European cohort of patients with histologically diagnosed NAFLD with clinical and epidemiological data and with biobanks of DNA, frozen liver tissue and serum. These will be used in a wide range of collaborative inter-disciplinary research projects aimed at addressing key unanswered questions related to the mechanisms and consequences of liver injury in NAFLD and the development of novel preventive and therapeutic strategies. The main outcomes of FLIP will be new insights in the progression of liver disease in NAFLD in terms of initiating mechanisms and patients at risk, innovative diagnostic methods particularly adapted for large-scale screening and prognostic evaluation, improved implementation of lifestyle changes, collaboration with leading biotechnological or pharmaceutical companies in order to translate to the market diagnostic tests or newly identified molecular targets for pharmacological therapy. By disseminating the projects results, FLIP will further help the European Community to suggest guidelines on the management of this emerging liver disease. The long-term goal is to lay the foundations for the future of NAFLD research in Europe by creating a Collaborative Research Network on NAFLD that will continue the work initiated by the FLIP consortium.

Agency: Cordis | Branch: FP7 | Program: CP | Phase: ICT-2013.5.2 | Award Amount: 5.89M | Year: 2013

CARDIOPROOF is a proof-of-concept project that consolidates the outcomes of previous VPH projects and checks the applicability and effectiveness of available predictive modelling and simulation tools, validating them in interrelated clinical trials conducted in three European centres of excellence in cardiac treatment (from Germany, Italy and the UK). CARDIOPROOF focuses on patients with aortic valve disease and aortic coarctation, which, if left untreated, can ensue irreversible heart failure. As a result treatment becomes mandatory, but optimum timing and the best type of treatment still remain difficult to determine. With more than 50.000 interventions per year within the EU, the diseases addressed by CARDIOPROOF have a significant socio-economic impact. Present clinical guidelines are highly complex and rely mostly on imaging diagnostics and clinical parameters, without benefiting, as yet, from patient-specific disease modelling based prediction. CARDIOPROOF goes beyond the current state of the art by conducting validation trials aimed at covering and comparing the complete spectrum of cardiovascular treatment, predicting the evolution of the disease and the immediate and mid-term outcome of treatment. Operational clustering is going to provide a seamless clinical solution that applies different modeling methods to realize the potential of personalised medicine taking into account user-friendliness as a key component of clinical usability. CARDIOPROOFs goal is to provide first-hand data on comparative cost-effectiveness and clinical efficacy of the most advanced VPH approaches compared to conventional diagnostics and treatment algorithms, thus accelerating the deployment of VPH methods in clinical environments, and bring to maturity holistic patient-specific computer-based predictive models and simulations.

Agency: Cordis | Branch: H2020 | Program: MSCA-ITN-EJD | Phase: MSCA-ITN-2014-EJD | Award Amount: 3.88M | Year: 2015

Many natural and artificial systems are often composed of oscillatory elements which, besides evolving according to their own non-trivial internal dynamics, mutually interact. As a result, many temporal and spatial scales are typically present, often accompanied by the spontaneous emergence of collective properties. Altogether, such features make the task of understanding the resulting evolution a challenging interdisciplinary problem. Zero-knowledge methods do generally require too large amount of data to allow drawing meaningful conclusions. In order to overcome this limitation, it is necessary to add skilful hypotheses about the structure of the underlying model and, thereby, on the relevant variables. This task is often tackled in an ad hoc way and the approach is based rather on personal preferences than on objective elements. The goal of this project is to fill the gap, by developing a general and coherent set of tools for the system identification and control, as well as to improve our ability to make predictions. The task will be pursued by combining top-down with bottom-up approaches which will be used to identify the most appropriate variables. Such analysis will be integrated by performing suitable case studies and mutually validating the various techniques to test the correctness of the underlying assumptions (both in the context of theoretical models as well as in experimental time series, such as physiological and neural data). A user-friendly software package will be ultimately developed to make the methods accessible to a broad set of potential users, including those with minimal theoretical competences. Furthermore, we will train a new generation of scientists able to implement a broad range of interdisciplinary approaches to the multivariate time signals that may be generated by the evolution of complex systems.

Agency: Cordis | Branch: FP7 | Program: MC-ITN | Phase: FP7-PEOPLE-2011-ITN | Award Amount: 3.13M | Year: 2011

Cost reduction and improvement of the quality of life is a major issue in health care. This challenge can be tackled by intelligent biomaterials and smart implants which are resorbed by the body upon remodelling of the tissue: What is possible for polymer materials should also be realized for biodegradable metallic materials. MagnIM will train 12 ESRs to contribute to this demanding aims by the development of new aluminium free Magnesium implant materials with tailored properties specific for a bone related application especially in children and for sport medicine. To reach this goal carefully selected materials and processing routes will be combined with comprehensive research to elucidate the correlation between microstructure and corrosion processes. This will be monitored in vitro and in vivo. The ultimate goal will be a prototype implant design which is based on the achievements of this network. To do this, the specific combination of the MagnIM research team is necessary. MagnIM brings together world leading scientists from various research fields: Material scientists and engineers who develop new alloys with tailored properties for biomedical applications and medical scientists and biologists researching on macro- and microscopically changes in bones and bone cells with in vitro and in vivo methods. MagnIM collectively covers basically all aspects, instrumental techniques and approaches necessary to tackle successfully the challenge to understand, and ultimately control, interactions at the material bone interface. The full achievements of this research are gained because the consortium covers the full value chain from fundamental engineering research towards implant production including relevant industry partners and clinics.

Langkammer C.,Harvard University | Langkammer C.,Medical University of Graz | Bredies K.,University of Graz | Poser B.A.,Maastricht University | And 8 more authors.
NeuroImage | Year: 2015

Quantitative susceptibility mapping (QSM) allows new insights into tissue composition and organization by assessing its magnetic property. Previous QSM studies have already demonstrated that magnetic susceptibility is highly sensitive to myelin density and fiber orientation as well as to para- and diamagnetic trace elements. Image resolution in QSM with current approaches is limited by the long acquisition time of 3D scans and the need for high signal to noise ratio (SNR) to solve the dipole inversion problem.We here propose a new total-generalized-variation (TGV) based method for QSM reconstruction, which incorporates individual steps of phase unwrapping, background field removal and dipole inversion in a single iteration, thus yielding a robust solution to the reconstruction problem. This approach has beneficial characteristics for low SNR data, allowing for phase data to be rapidly acquired with a 3D echo planar imaging (EPI) sequence. The proposed method was evaluated with a numerical phantom and in vivo at 3 and 7. T.Compared to total variation (TV), TGV-QSM enforced higher order smoothness which yielded solutions closer to the ground truth and prevented stair-casing artifacts. The acquisition time for images with 1. mm isotropic resolution and whole brain coverage was 10. s on a clinical 3. Tesla scanner.In conclusion, 3D EPI acquisition combined with single-step TGV reconstruction yields reliable QSM images of the entire brain with 1. mm isotropic resolution in seconds. The short acquisition time combined with the robust reconstruction may enable new QSM applications in less compliant populations, clinical susceptibility tensor imaging, and functional resting state examinations. © 2015 Elsevier Inc.

Blevins T.,Texas Diabetes and Endocrinology | Pieber T.R.,Medical University of Graz | Colon Vega G.,American Telemedicine Center | Zhang S.,Eli Lilly and Company | And 3 more authors.
Diabetes, Obesity and Metabolism | Year: 2016

Aims: To evaluate the efficacy and safety of basal insulin peglispro (BIL) with those of insulin glargine, both in combination with prandial insulin lispro, in patients with type 2 diabetes (T2D). Methods: In this phase III, multicentre, double-blind, 26-week study, we randomized patients with T2D [glycated haemoglobin (HbA1c) ≥7 and <12%, on ≥1 insulin injections daily) to BIL (n = 691) or glargine (n = 678), in combination with lispro. Results: At week 26, the primary objective of non-inferiority of BIL versus glargine for HbA1c reduction was achieved (least squares mean difference −0.21%; 95% confidence interval −0.31 to −0.11%), with statistical superiority of BIL with multiplicity adjustment (p < 0.001). HbA1c at baseline was 8.4% versus 8.5% for BIL versus glargine and at 26 weeks it was 6.8% versus 7.0%. At 26 weeks, more patients reached HbA1c <7% with BIL than with glargine (63.3% vs 53.3%; p < 0.001), the nocturnal hypoglycaemia rate (≤3.9 mmol/l) was lower with BIL (0.51 vs 0.92 events/30 days; p < 0.001), but the daytime hypoglycaemia rate was higher with BIL (5.47 vs 4.53 events/30 days; p < 0.001). The total hypoglycaemia relative rate was 1.10 (p = 0.053). At 26 weeks, patients in the BIL group had lower fasting serum glucose levels, higher basal insulin dosing, with no statistically significant difference in prandial or total insulin dosing, reduced glucose variability and less weight gain (1.3 kg vs 2.2 kg) compared with the glargine group. The BIL group had higher mean triglyceride and aminotransferase levels. Conclusions: In patients with T2D, BIL with insulin lispro provided greater improvement in glycaemic control with less nocturnal hypoglycaemia, lower glucose variability and less weight gain compared with glargine. The daytime hypoglycaemia rate and mean triglyceride and aminotransferase levels were higher with BIL. © 2016 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Wang N.,Ghent University | De Bock M.,Ghent University | Antoons G.,Medical University of Graz | Gadicherla A.K.,Ghent University | And 6 more authors.
Basic Research in Cardiology | Year: 2012

Connexin mimetic peptides (CxMPs), such as Gap26 and Gap27, are known as inhibitors of gap junction channels but evidence is accruing that these peptides also inhibit unapposed/non-junctional hemichannels (HCs) residing in the plasma membrane. We used voltage clamp studies to investigate the effect of Gap26/27 at the single channel level. Such an approach allows unequivocal identification of HC currents by their single channel conductance that is typically ~220 pS for Cx43. In HeLa cells stably transfected with Cx43 (HeLa-Cx43), Gap26/27 peptides inhibited Cx43 HC unitary currents over minutes and increased the voltage threshold for HC opening. By contrast, an elevation of intracellular calcium ([Ca 2+] i) to 200-500 nM potentiated the unitary HC current activity and lowered the voltage threshold for HC opening. Interestingly, Gap26/27 inhibited the Ca 2+-potentiated HC currents and prevented lowering of the voltage threshold for HC opening. Experiments on isolated pig ventricular cardiomyocytes, which display strong endogenous Cx43 expression, demonstrated voltage-activated unitary currents with biophysical properties of Cx43 HCs that were inhibited by small interfering RNA targeting Cx43. As observed in HeLa-Cx43 cells, HC current activity in ventricular cardiomyocytes was potentiated by [Ca 2+] i elevation to 500 nM and was inhibited by Gap26/27. Our results indicate that under pathological conditions, when [Ca 2+] i is elevated, Cx43 HC opening is promoted in cardiomyocytes and CxMPs counteract this effect. © 2012 Springer-Verlag Berlin Heidelberg.

Kau T.,Institute of Diagnostic and Interventional Radiology | Taschwer M.,Institute of Diagnostic and Interventional Radiology | Deutschmann H.,Medical University of Graz | Schonfelder M.,Klinikum Klagenfurt | And 2 more authors.
European Radiology | Year: 2013

Objectives: Susceptibility weighted imaging (SWI) may have the potential to depict the perivenous extent of white matter lesions (WMLs) in multiple sclerosis (MS). We aimed to assess the discriminatory value of the "central vein sign" (CVS). Methods: In a 3-T magnetic resonance imaging (MRI) study, 28 WMLs in 14 patients with at least one circumscribed lesion >5 mm and not more than eight non-confluent lesions >3 mm were prospectively included. Only WMLs in FLAIR images with a maximum diameter of >5 mm were correlated to their SWI equivalent for CVS evaluation. Results: Five patients fulfilled the revised McDonald criteria for MS and nine patients were given alternative diagnoses. Nineteen MS-WMLs and nine non-MS-WMLs >5 mm were detected. Consensus reading found a central vein in 16 out of 19 MS-WMLs (84 %) and in one out of nine non-MS-WMLs (11 %), respectively. The CVS proved to be a highly significant discriminator (P < 0.001) between MS-WMLs and non-MS-WMLs with a sensitivity, specificity, positive and negative predictive value and accuracy of 84 %, 89 %, 94 %, 73 % and 86 %, respectively. Inter-rater agreement was good (κ = 0.77). Conclusions: Even though the CVS is not exclusively found in MS-WMLs, SWI may be a useful adjunct in patients with possible MS. © 2013 European Society of Radiology.

Grasser G.,Medical University of Graz | Van Dyck D.,Ghent University | Van Dyck D.,Research Foundation Flanders | Titze S.,University of Graz | Stronegger W.,Medical University of Graz
International Journal of Public Health | Year: 2013

Objectives: The aim of this study was to investigate which GIS-based measures of walkability (density, land-use mix, connectivity and walkability indexes) in urban and suburban neighbourhoods are used in research and which of them are consistently associated with walking and cycling for transport, overall active transportation and weight-related measures in adults. Methods: A systematic review of English publications using PubMed, Science Direct, Active Living Research Literature Database, the Transportation Research Information Service and reference lists was conducted. The search terms utilised were synonyms for GIS in combination with synonyms for the outcomes. Results: Thirty-four publications based on 19 different studies were eligible. Walkability measures such as gross population density, intersection density and walkability indexes most consistently correlated with measures of physical activity for transport. Results on weight-related measures were inconsistent. Conclusions: More research is needed to determine whether walkability is an appropriate measure for predicting weight-related measures and overall active transportation. As most of the consistent correlates, gross population density, intersection density and the walkability indexes have the potential to be used in planning and monitoring. © 2012 Swiss School of Public Health.

Kottner J.,Charité - Medical University of Berlin | Blume-Peytavi U.,Charité - Medical University of Berlin | Lohrmann C.,Medical University of Graz | Halfens R.,Maastricht University
International journal of nursing studies | Year: 2014

BACKGROUND: Incontinent patients are at risk for incontinence-associated dermatitis. Prolonged exposures of the skin to urine and/or stool are causal factors but the exact aetiology and pathophysiology are not fully understood.OBJECTIVES: The aim of the current investigation was to identify person and health-related variables most strongly associated with incontinence-associated dermatitis development.DESIGN: Secondary data analysis of a multicentre-prevalence study in 2012.SETTINGS: Hospitals, nursing homes, home care in Austria and the Netherlands.PARTICIPANTS: Nursing home residents, hospital patients, home care clients who completed an incontinence assessment and who were incontinent (n = 3713). Mean age 81.2 (SD 11.2) years.METHODS: Demographic, functional and physiological parameters were compared between subjects with incontinence-associated dermatitis and without. A logistic regression model predicting incontinence-associated dermatitis was build.RESULTS: Subjects with incontinence-associated dermatitis were statistically significantly more often male, had more often diabetes mellitus, had a higher BMI, were less often affected by urinary but more often by faecal incontinence and showed higher degrees of functional and psychical impairments. Being faecal incontinent (OR 1.70; 95% CI 1.14-2.55), having diabetes mellitus (OR 1.46; 95% CI 1.03-2.06) and having "friction and shear" problems (OR 0.65; 95% CI 0.51-0.81) according to the Braden scale item were the strongest covariates for the presence of incontinence-associated dermatitis.CONCLUSIONS: It is recommended to target special preventive skin care interventions especially to persons who are faecal incontinent and who have moist perineal skin, who have higher BMIs, who are diabetics, and who need increased assistance in moving. Copyright © 2014 Elsevier Ltd. All rights reserved.

Schiffner S.,University of Regensburg | Chen S.,Rutgers University | Becker J.C.,Medical University of Graz | Bosserhoff A.-K.,University of Regensburg
Experimental Dermatology | Year: 2012

Murine model systems are critically required tools for the investigation of unknown mechanisms of melanoma development and metastasis and for developing more efficient therapies. The Tg(Grm1)EPv melanoma mouse model is characterized by spontaneous development of pigmented cutaneous melanomas at hairless skin regions, with a short latency and 100% penetrance. Local metastasis was described in initial analyses; however, melanoma cells were not observed in distant organs. Here, we demonstrate that the established Tg(Grm1)EPv melanoma mouse model exhibits more extensive metastasis into distant organs than previously described. Disseminated cells undergo phenotypic changes, as we observed high numbers of non-pigmented Grm1-expressing melanoma cells within distant organs. As such changes during metastasis are common in human melanoma, our findings demonstrate that this mouse model represents an even more useful tool to study unknown mechanisms of metastasis in human melanoma than previously assumed. © 2012 John Wiley & Sons A/S.

Guyot J.-P.,University of Geneva | Sigrist A.,University of Geneva | Pelizzone M.,University of Geneva | Feigl G.C.,Medical University of Graz | Kos M.I.,University of Geneva
Annals of Otology, Rhinology and Laryngology | Year: 2011

Objectives: Recently, we demonstrated that it was possible to elicit vertical eye movements in response to electrical stimulation of the posterior ampullary nerve. In order to develop a vestibular implant, a second site of stimulation is required to encode the horizontal movements. Methods: Three patients with disabling Meniere's disease were included in the study. Before a labyrinthectomy via a standard transcanal approach was performed, their lateral and anterior ampullary nerves were surgically exposed under local anesthesia through a procedure we recently developed. The attic was opened, the incus and malleus head were removed, and a small well was drilled above the horizontal portion of the facial nerve canal to place an electrode. This electrode was used to deliver balanced biphasic trains of electrical pulses. Results: The electrical stimuli elicited mainly horizontal nystagmus without simultaneous stimulation of the facial nerve. Conclusions: It is possible to stimulate electrically the lateral and superior ampullary nerves without simultaneous stimulation of the facial nerve. Because the nerves run close to each other, electrical stimulation provoked eye movements that were not purely horizontal, but also had some vertical components. Nevertheless, this site can be used to encode horizontal movements, because central adaptation may correct unnatural afferent vestibular cues delivered by a prosthetic sensor. The range of stimulus intensities that produced a response was broad enough for us to envision the possibility of encoding eye movements of various speeds. © 2011 Annals Publishing Company. All rights reserved.

Sadoghi P.,Medical University of Graz | Liebensteiner M.,Innsbruck Medical University | Agreiter M.,Innsbruck Medical University | Leithner A.,Medical University of Graz | And 2 more authors.
Journal of Arthroplasty | Year: 2013

The authors performed a complication-based analysis of total knee (TKA), total hip (THA), and total ankle arthroplasty (TAA) using worldwide arthroplasty registers. We extracted data with respect to reason for revision surgery and pooled causes. The most common causes for revisions in THA were aseptic loosening (55.2%), dislocation (11.8 %), septic loosening (7.5%), periprosthetic fractures (6%), and others. The most common causes in TKA were aseptic loosening (29.8%), septic loosening (14.8%), pain (9.5%), wear (8.2%), and others. The most common causes in TAA were aseptic loosening (38%), technical errors (15%), pain (12%), septic loosening (9.8%), and others. Revisions in TKA and THA differ with respect to type of complication. However, in case of TAA, higher rates of technically related complications are reported. © 2013 Elsevier Inc.

Pichler G.,Albert Schweitzer Hospital Graz | Fazekas F.,Medical University of Graz
Resuscitation | Year: 2016

Background: The "Unresponsive wakefulness syndrome" (UWS) or previously termed vegetative state is a possible consequence of severe brain damage where individuals just open their eyes but show no conscious behavioural reaction. While head trauma has previously been considered the prevailing cause, clinical experience suggests shows that cardiopulmonary arrest plays an increasingly important role. We therefore attempted to study this hypothesis in a well-defined region of Austria. Methods: Prospective population-based cohort study to calculate the incidence and aetiologies of the UWS. All facilities in the state of Styria (n = 38), which are involved in the medical care of patients with brain damage, participated. Among the adult population of Styria (n = 1010,164) we identified all individuals who developed UWS over a one year period. The diagnosis was based on a formal neurologic evaluation at least 4 weeks after the brain damage and had to be in line with the criteria of the "Multi-society Task Force on Persistent Vegetative State". Results: We identified 19 individual with UWS which correspond to an annual incidence of 1.88/100,000 people. Male gender predominated (78.9%) and the mean age was 57.8 years (age range 18-78 years). The most frequent cause of UWS was cerebral hypoxia in the wake of cardiopulmonary resuscitation (63%), cerebral bleeding (21%) and brain trauma (16%). Conclusions: Cardiopulmonary resuscitation has become the major cause of UWS which leads to an increasing incidence with age. These aspects may become even more prominent with the ageing of our population and need to be considered in the organisation of care. © 2016 Elsevier Ireland Ltd.

Unterrainer H.-F.,Center for Integrative Addiction Research Gruner Kreis Society | Unterrainer H.-F.,Medical University of Graz | Lewis A.J.,Deakin University
Psychiatry Research | Year: 2014

It has been asserted that schizotypy has a negative relationship with subjective well-being. By employing a multidimensional measure of spiritual well being with 400 British College students we report a more complex relationship. The Multidimensional Inventory for Religious/Spiritual Well-Being and Schizotypal Personality Questionnaire-Brief Version were used and analysis made use of Canonical Correlational Analysis. Results suggested that two distinct relationships emerged between schizotypy and spirituality. First, a positive association between cognitive/perceptual features of schizotypy and spiritual connectedness emerged. Second a more global negative relationship between feelings of spiritual isolation and despair was found for all aspects of schizotypy. These findings challenge the previous literature based on one-dimensional subjective well being measures which have found only a negative relationship. However, the positive association between connectedness and cognitive-perceptual aspects of schizotypy raises import questions about the possible benefit of certain types of schizotypal experience. © 2014 Elsevier Ireland Ltd.

Pabinger C.,EAR European Arthroplasty Register Scientific Office | Pabinger C.,Medical University of Graz | Geissler A.,Care Technology Systems
Osteoarthritis and Cartilage | Year: 2014

Background: Hip arthroplasty and revision surgery is growing exponentially in OECD countries, but rates vary between countries. Methods: We extracted economic data and utilization rates data about hip arthroplasty done in OECD countries between 1990 and 2011. Absolute number of implantations and compound annual growth rates were computed per 100,000 population and for patients aged 65 years old and over and for patients aged 64 years and younger. Results: In the majority of OECD countries, there has been a significant increase in the utilization of total hip arthroplasty in the last 10 years, but rates vary to a great extent: In the United States, Switzerland, and Germany the utilization rate exceeds 200/100,000 population whereas in Spain and Mexico rates are 102 and 8, respectively. There is a strong correlation between gross domestic product (GDP) and health care expenditures per capita with utilization rate. Utilization rates in all age groups have continued to rise up to present day. A seven fold higher growth rate was seen in patients aged 64 years and younger as compared to older patients. Conclusion: We observed a 38-fold variation in the utilization of hip arthroplasty among OECD countries, correlating with GDP and health care expenditures. Over recent years, there has been an increase in the utilization rate in most countries. This was particularly evident in the younger patients. Due to increasing life expectancy and the disproportionally high use of arthroplasty in younger patients we expect an exponential increase of revision rate in the future. © 2014 Osteoarthritis Research Society International.

Holzinger A.,Medical University of Graz | Simonic K.-M.,Medical University of Graz | Yildirim P.,Okan University
Proceedings - International Computer Software and Applications Conference | Year: 2012

The MEDLINE database (Medical Literature Analysis and Retrieval System Online) contains an enormously increasing volume of biomedical articles. There is urgent need for techniques which enable the discovery, the extraction, the integration and the use of hidden knowledge in those articles. Text mining aims at developing technologies to help cope with the interpretation of these large volumes of publications. Co-occurrence analysis is a technique applied in text mining and the methodologies and statistical models are used to evaluate the significance of the relationship between entities such as disease names, drug names, and keywords in titles, abstracts or even entire publications. In this paper we present a method and an evaluation on knowledge discovery of disease-disease relationships for rheumatic diseases. This has huge medical relevance, since rheumatic diseases affect hundreds of millions of people worldwide and lead to substantial loss of functioning and mobility. In this study, we interviewed medical experts and searched the ACR (American College of Rheumatology) web site in order to select the most observed rheumatic diseases to explore disease-disease relationships. We used a web based text-mining tool to find disease names and their co-occurrence frequencies in MEDLINE articles for each disease. After finding disease names and frequencies, we normalized the names by interviewing medical experts and by utilizing biomedical resources. Frequencies are normally a good indicator of the relevance of a concept but they tend to overestimate the importance of common concepts. We also used Pointwise Mutual Information (PMI) measure to discover the strength of a relationship. PMI provides an indication of how more often the query and concept co-occur than expected by change. After finding PMI values for each disease, we ranked these values and frequencies together. The results reveal hidden knowledge in articles regarding rheumatic diseases indexed by MEDLINE, thereby exposing relationships that can provide important additional information for medical experts and researchers for medical decision-making. © 2012 IEEE.

Konrad K.,University of Duisburg - Essen | Thon A.,Hannover Medical School | Fritsch M.,Medical University of Vienna | Frohlich-Reiterer E.,Medical University of Graz | And 3 more authors.
Diabetes Care | Year: 2013

OBJECTIVE-The prevalence of cystic fibrosis-related diabetes (CFRD) has increased with improved life expectancy of patients. Clinical and care characteristics were compared with type 1 diabetes mellitus (T1DM) in a multicenter analysis of pediatric data. RESEARCH DESIGN AND METHODS-Auxological and treatment data from 47,227 patients aged younger than 21 years with CFRD or T1DM in the German/Austrian Diabetes Prospective Documentation Initiative registry were analyzed by multivariable mixed regression modeling. RESULTS-Diabetes onset (mean [interquartile range]) occurred later in individuals with CFRD (14.5 [11.8-16.3] years) than in individuals with T1DM (8.5 [4.9-11.8] years), with female preponderance in CFRD (59.1% vs. 47.5%; P < 0.01). CFRD patients had lower BMI standard deviation scores (20.85 [21.59 to 20.12] vs. +0.52 [20.10 to +1.16]; P < 0.01) and lower HbA1c (6.87% vs. 7.97%; P < 0.01). Self-monitoring of blood glucose was more frequent in patients with T1DM(4.5 vs. 3.5; P<0.01); 72%of CFRD patients received insulin. In insulintreated patients, insulin dosage adjusted for age, sex, and diabetes duration differed significantly (T1DM: 0.79 IE per kilogram of body weight; CFRD: 0.83 IE per kilogram of body weight). Use of short-acting and long-acting insulin analogs was significantlymore frequent in T1DM(47%vs. 39% and 37% vs. 28%; both P < 0.05). Metabolic control in CFRD patients without insulin was better compared with CFRD on insulin (HbA1c: 6.00 vs. 7.12; P <0.01), but duration of disease was significantly shorter (0.8 years [0.1-2.4] compared with 2.4 years [0.6-4.6]). There was no significant difference for BMI standard deviations scores between CFRD patients with or without insulin treatment. CONCLUSIONS-Pediatric patients with CFRD show clear auxological and metabolic differences from those with T1DM, with different treatment choices. © 2013 by the American Diabetes Association.

Becker J.C.,Medical University of Graz | Zur Hausen A.,Maastricht University
Journal of Investigative Dermatology | Year: 2014

Adult skin stem cells do not protect their genome by asymmetric chromosome segregation; thus, they are prone to accumulating oncogenic mutations.

Van Ballegooijen A.J.,VU University Amsterdam | Reinders I.,VU University Amsterdam | Visser M.,VU University Amsterdam | Dekker J.M.,VU University Amsterdam | And 5 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2013

Context: Higher PTH concentrations have been associated with fatal cardiovascular diseases (CVDs), but data in the general population are scarce. Objective: We investigated whether higher PTH concentrations are prospectively associated with all-cause and CVD mortality. Design, Setting, Participants: This study used data from the Hoorn Study, a prospective population-based cohort with baseline measurements between 2000 and 2001. We included 633 participants, mean age 70.1 ± 6.6 years, 51% female. Serum intact PTH was measured using a 2-site immunoassay. Main Outcome Measures: Outcomes were all-cause and CVD mortality based on clinical files and coded according to the International Classification of Diseases, ninth revision. We used Kaplan-Meier plots to estimate survival curves and Cox regression to estimate hazard ratios (HRs) using season-specific PTH quartiles. Results: During a median follow-up of 7.8 years, 112 participants died, of which 26 deaths (23%) were cardiovascular. Survival curves by PTH quartiles differed for all-cause mortality (log-rank P = .054) and CVD mortality (log-rank P = .022). In a multivariate model, the highest PTH quartile was associated with all-cause mortality; HR = 1.98 (1.08, 3.64). Kidney function slightly attenuated the PTH risk association, but risk persisted; HR = 1.93 (1.04, 3.58). The results for CVD mortality showed a similar pattern, although the association was significant only in a threshold model (quartile 4 vs quartile 1-3); HR = 2.56 (1.11, 5.94). Conclusions: Among a general older population, higher PTH concentrations were associated with higher all-cause mortality risk, mostly explained by fatal CVD events. We suggest to evaluate whether individuals with high PTH concentrations benefit from therapeutic approaches targeted to decrease PTH concentrations. Copyright © 2013 by The Endocrine Society.

Cochand-Priollet B.,Anatomie et Cytologie Pathologiques | Schmitt F.C.,University of Porto | Totsch M.,Medical University of Graz | Vielh P.,Institute Gustave Roussy
Acta Cytologica | Year: 2011

Objectives: A 2007 conference held at the National Cancer Institute, Bethesda, Md., USA, proposed a new terminology for classifying the results of thyroid fine-needle aspiration (FNA)-The Bethesda System for Reporting Thyroid Cytology (TBSRTC). The need to standardize thyroid FNA terminology was emphasized during the 35th European Congress of Cytology in 2009. An interobserver review study to assess the new terminology for analyzing the results of thyroid FNA was organized by the scientific committee of the European Federation of Cytology Societies. Study Design: Four experts in thyroid FNA examined and classified 116 FNAs according to the 6 levels of TBSRTC which are: nondiagnostic (ND); benign; atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS); follicular neoplasm/suspicious for a follicular neoplasm (FN/SFN), with those of Hürthle cell type reported as follicular neoplasm, Hürthle cell type/suspicious for a follicular neoplasm, Hürthle cell type (FNHCT/SFNHCT); suspicious (SUS), and malignant. Results: The total consensus was 62.1%; the cytopathologists disagreed on 44 cases, including 8 cases of AUS/FLUS and 18 of FN/SFN; 59% of the cases had no consensus. They agreed on 73 and 80% of the cases classified as benign and malignant, respectively, and on 58.3% of the SUS cases. The percentage of no consensus for each expert was between 32 and 39%. Conclusions: Disagreement regarding the use of TBSRTC terminology for classifying the results of thyroid FNA mainly occurred in the most-often criticized categories of AUS/FLUS and FN/SFN. © 2011 S. Karger AG, Basel.

Objective A sample of patients with a puerperal psychosis of an early manifestation is investigated in respect of special risks of suicide and infanticide. Methods During a 20-year period 96 patients who had been fallen ill with a puerperal psychosis within four weeks after delivery were admitted to a psychiatric university hospital. Patients with an acute exacerbation of a known schizophrenic disorder were excluded. In a subgroup of 37 patients states of a previous (affective, bipolar affective) psychotic illness were recorded already before the puerperal index episode, in a subgroup of 59 patients puerperal psychosis was the first manifestation of a psychotic illness. Suicide- and infanticide-relevant psychopathological symptoms were analysed (suicidal ideas/behaviour before/during inpatient treatment, general disorganized aggression, psychotic anxieties related to baby, infanticidal obsessions, aggressive ideas/behaviour towards baby, neglect, infanticidal impulses). Results Puerperal psychoses were distributed to the diagnostic categories of psychotic depressive disorder, bipolar affective disorder, and schizoaffective disorder. Six patients died due to suicide, tragically already some few days till weeks after discharge from psychiatric hospital, despite a pronounced or even complete remission of puerperal psychotic symptoms at the time of discharge. Three patients committed an extended suicide attempt that resulted in two infanticides. All isolated and extended suicides were committed in a state of depressive mood and presumably synthymic delusion. Conclusions Suicidal ideas and behaviour play a major role in patients with puerperal psychosis before and during inpatient treatment. An increased risk for mothers and babies may persist, however, even after a seemingly good symptomatic remission. Besides the clinical challenge of general prevention of puerperal psychosis the request of adequate models of inpatient treatment, carefully prepared discharge, close afterdischarge follow up, and continuous outpatient care have to be stressed.© Springer-Verlag Wien 2012.

Kralemann B.,University of Kiel | Fruhwirth M.,Human Research Institute of Health Technology and Prevention Research | Pikovsky A.,University of Potsdam | Rosenblum M.,University of Potsdam | And 4 more authors.
Nature Communications | Year: 2013

Recovering interaction of endogenous rhythms from observations is challenging, especially if a mathematical model explaining the behaviour of the system is unknown. The decisive information for successful reconstruction of the dynamics is the sensitivity of an oscillator to external influences, which is quantified by its phase response curve. Here we present a technique that allows the extraction of the phase response curve from a non-invasive observation of a system consisting of two interacting oscillators-in this case heartbeat and respiration-in its natural environment and under free-running conditions. We use this method to obtain the phase-coupling functions describing cardiorespiratory interactions and the phase response curve of 17 healthy humans. We show for the first time the phase at which the cardiac beat is susceptible to respiratory drive and extract the respiratory-related component of heart rate variability. This non-invasive method for the determination of phase response curves of coupled oscillators may find application in many scientific disciplines. © 2013 Macmillan Publishers Limited.

Ugurel S.,University of Würzburg | Ugurel S.,Medical University of Graz | Paschen A.,University of Duisburg - Essen | Becker J.C.,Medical University of Graz
Journal of Investigative Dermatology | Year: 2013

Chemotherapeutic drugs are clinically used to treat cancer because of their cytotoxic activities against tumor cells. Recently, however, evidence is accumulating-including the report of Hervieu et al. (2012) in the current issue of The Journal of Investigative Dermatology-indicating that at least some of these drugs have broader activities and that they should also be considered immunomodulatory agents. Indeed, Hervieu demonstrates that dacarbazine (DTIC) exerts immunostimulatory effects by inducing local activation of natural killer (NK) and T cells, suggesting that upon treatment with DTIC, the tumor participates in the initiation of an immune response: (i) DTIC treatment elicits the expression of ligands of the immunoreceptor NKG2D on melanoma cells; (ii) engagement of the ligands by NKG2D on NK cells leads to their activation, allowing enhanced tumor-cell killing and the release of IFN-γ; and (iii) IFN-γ in turn upregulates major histocompatibility complex class I expression on tumor cells, which favors their recognition by cytotoxic CD8+ T lymphocytes (CTLs). © 2013 The Society for Investigative Dermatology.

Moser G.,Medical University of Graz | Gauster M.,Medical University of Graz | Orendi K.,Medical University of Graz | Glasner A.,Aerztezentrum Seiersberg | And 2 more authors.
Human Reproduction | Year: 2010

BACKGROUND: Routes of trophoblast invasion seem to be clear, whereas specific invasive pathways need further elucidation. Extravillous trophoblasts (EVTs) transform spiral arteries to guarantee appropriate blood flow to the placenta in the second trimester. Embryo nutrition during the first trimester is thought to be histiotrophic, whereas proof that EVTs also invade uterine glands is lacking. We developed novel three-dimensional confrontation co-culture models to elucidate invasion of EVTs into uterine glands.METHODSFirst trimester decidua parietalis and placental villous explants were directly confronted and co-cultured for 72 h, or confronted indirectly after 72 h pre-culture for re-epithelialization of decidua pieces. Cryosections were stained by immunohistochemistry or immunofluorescent/immunohistochemical double labelling and compared with first trimester placentation sites in situ.RESULTSEVTs deeply invaded decidual tissues in direct confrontation assays and were found between the decidual epithelial cells and epithelial basement membrane. EVTs were also detected in the decidual stroma in direct proximity to glands, sometimes even replacing glandular epithelial cells. Similar observations were made in sections from the first trimester decidua/placental bed. In the invaded parts of sections of decidua basalis, 55 ± 7 (mean ± SEM; n = 10, range 6-11 weeks) of glandular cross sections were associated with or infiltrated by EVTs.CONCLUSIONSUsing novel confrontation co-culture assays, a potential new route of EVT invasion was detected. EVTs appear to break through the basement membrane of uterine glands to open their lumen towards the intervillous space. These data support the hypothesis of histiotrophic nutrition of the embryo prior to onset of maternal blood flow within the placenta. © 2010 The Author.

Agency: Cordis | Branch: FP7 | Program: CSA | Phase: ICT-2011.9.5 | Award Amount: 2.04M | Year: 2011

Data-rich, individualised medicine poses unprecedented challenges for IT, in hardware, storage and communication. We propose a data-driven, individualised medicine of the future, based on molecular/physiological/anatomical data from individual patients. We shall make general models of human pathways, tissues, diseases and ultimately of the human as a whole. Individualised versions of the models, produced for each patient, will then be used to identify personalised prevention/therapy schedules and side effects of drugs.\n\nTo develop this IT driven, data rich, individualised medicine of the future, this first-phase flagship project will prepare for the amalgamation of 5 major areas: medicine, from sample and diagnosis provision to clinical practice and patient consent, analytical techniques, covering functional genomics and imaging technology analyses on a routine basis, IT developments required to address the computational challenges, and integration, developing interfaces, modelling and machine learning tools required to integrate the data generated through the different analysis streams, and to inform relevant health providers. A coordination work package will address the administrative, educational, funding and translational components of the work.\n\nThis is the first time the huge IT implications of worldwide individualized patient care will be addressed and combined with up-to-date genomics and requirements from the medical field. The project outcomes will enable the calculation of health, disease, therapy and its effects for individual patients. These may revolutionize our health care with enormous (i) benefits for health (prevention, diagnosis and therapy), (ii) reduction in health care cost by individualising combinations of a limited number of drugs, and (iii) new commercial opportunities in the IT, analytic and health care sectors.

Rossi D.,Fondazione Poliambulanza Instituto Ospedaliero | Rossi D.,University of Milan | Pianta S.,Fondazione Poliambulanza Instituto Ospedaliero | Magatti M.,Fondazione Poliambulanza Instituto Ospedaliero | And 2 more authors.
PLoS ONE | Year: 2012

We previously demonstrated that cells isolated from the mesenchymal region of the human amniotic membrane (human amniotic mesenchymal tissue cells, hAMTC) possess immunoregulatory roles, such as inhibition of lymphocyte proliferation and cytokine production, and suppression of generation and maturation of monocyte-derived dendritic cells, as reported for MSC from other sources. The precise factors and mechanisms responsible for the immunoregulatory roles of hAMTC remain unknown. In this study, we aimed to identify the soluble factors released by hAMTC and responsible for the anti-proliferative effect on lymphocytes, and the mechanisms underlying their actions, in vitro. Conditioned medium (CM) was prepared under routine culture conditions from hAMTC (CM-hAMTC) and also from fragments of the whole human amniotic membrane (CM-hAM). We analyzed the thermostability, chemical nature, and the molecular weight of the factors likely responsible for the anti-proliferative effects. We also evaluated the participation of cytokines known to be involved in the immunomodulatory actions of MSC from other sources, and attempted to block different synthetic pathways. We demonstrate that the inhibitory factors are temperature-stable, have a small molecular weight, and are likely of a non-proteinaceous nature. Only inhibition of cyclooxygenase pathway partially reverted the anti-proliferative effect, suggesting prostaglandins as key effector molecules. Factors previously documented to take part in the inhibitory effects of MSCs from other sources (HGF, TGF-β, NO and IDO) were not involved. Furthermore, we prove for the first time that the anti-proliferative effect is intrinsic to the amniotic membrane and cells derived thereof, since it is manifested in the absence of stimulating culture conditions, as opposed to MSC derived from the bone marrow, which possess an anti-proliferative ability only when cultured in the presence of activating stimuli. Finally, we show that the amniotic membrane could be an interesting source of soluble factors, without referring to extensive cell preparation. © 2012 Rossi et al.

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2012.2.4.3-1 | Award Amount: 5.49M | Year: 2012

The aim of PCDIAB is to build and evaluate a bihormonal (insulin and glucagon) artificial pancreas (AP) with automated closed loop glycaemic control for insulin treated patients with diabetes. This will be a breakthrough in diabetes management. We will miniaturize our current prototype consisting of well-established continuous glucose monitors, an insulin pump and a glucagonpump. The housing will be redesigned with dedicated miniature motors and the software will be embedded. The algorithm will be improved and a continuous glucose sensor (CGM) per-formance alert will be developed. In parallel, glucagon pharmacology will be investigated and a stable liquid glu-cagon analogue will be developed. Furthermore, administration of insulin and glucagon together with continuous glucose monitoring at the same subcutaneous site will be investigated, to enable even further miniaturization in the future. Deliverables include description of system integration of the bihormonal AP system and of an online detection of continuous glucose monitor performance. In a multinational controlled trial the bihormonal AP will be compared with standard intensive insulin therapy in daily life. Impact of the project includes simplified diabetes care, improved quality of life for patients with diabetes, dimin-ished occurrence of diabetes related complications and diminished health costs in the long run. Also, the project will strengthen competitiveness of European industry across a complete value chain involving large, mid-sized and small companies, enabling Europe to lead progress in AP systems. Finally, the project will put European research and clinical organizations in leading positions with an increased number of high-skilled jobs in the medical device industry. Dissemination and exploitation comprises a website, a conference, patents and scientific publications. The bihormonal closed loop system and the glucagon analogue can be developed into a product and brought to the market.

van Eimeren L.,University of Western Ontario | Grabner R.H.,ETH Zurich | Koschutnig K.,Medical University of Graz | Reishofer G.,Medical University of Graz | And 2 more authors.
NeuroImage | Year: 2010

Both neuropsychological and functional neuroimaging studies have identified brain regions that are critical for the neurocognitive processes related to the calculation of arithmetic problems. In particular, the left angular gyrus (lAG) has been repeatedly implicated in arithmetic problem solving and found to be most activated during the retrieval of arithmetic facts. While significant progress has been made in determining the functional role of specific grey matter areas underlying calculation, very little is known about the relationship between these activated regions and their underlying white matter structures. In this study, we collected both diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI) data while participants performed a mental arithmetic task. Fractional anisotropy (FA) values were extracted from predefined, hypothesis-driven, white matter regions and correlated with fMRI activation values, which were extracted from anatomically defined grey matter regions. Results indicated structure-function relationships on multiple levels. Specifically, a link between the integrity of the left superior corona radiata (SCR) and neural activity in the lAG during calculation was observed, which was found to be particularly strong for problems that have a high probability of being solved via the retrieval of arithmetic facts (problems with a relatively small problem size). The findings reported provide a link between functional activation and structural integrity of grey and white matter regions in the left temporoparietal cortex, thereby contributing to our understanding of the role of both the function and structure of this brain region in calculation. © 2010 Elsevier Inc.

Valko P.O.,Beth Israel Deaconess Medical Center | Valko P.O.,University of Zürich | Gavrilov Y.V.,Beth Israel Deaconess Medical Center | Gavrilov Y.V.,University of Zürich | And 8 more authors.
Annals of Neurology | Year: 2013

Objective Narcolepsy is caused by loss of the hypothalamic neurons producing the orexin/hypocretin neuropeptides. One key target of the orexin system is the histaminergic neurons of the tuberomammillary nucleus (TMN), an essential wake-promoting system. As cerebrospinal fluid histamine levels may be low in patients with narcolepsy, we examined histaminergic neurons in patients with narcolepsy and in 2 mouse models of narcolepsy. Methods We counted the number of hypothalamic neurons producing orexin, melanin-concentrating hormone, and histamine in 7 narcolepsy patients and 12 control subjects using stereological techniques. We identified histaminergic neurons using immunostaining for histidine decarboxylase. We also examined these systems in 6 wild-type mice, 6 orexin/ataxin-3 transgenic mice, and 5 orexin ligand knockout mice. Results Compared to controls, narcolepsy patients had 94% more histaminergic TMN neurons (233,572 ± 49,476 vs 120,455 ± 10,665, p < 0.001). This increase was higher in 5 narcolepsy patients with >90% orexin neuron loss than in 2 patients with ≤75% orexin neuron loss (252,279 ± 46,264 vs 186,804 ± 1,256, p = 0.03). Similarly, the number of histaminergic TMN neurons was increased 53% in orexin ligand knockout mice compared to wild-type mice, whereas orexin/ataxin-3 transgenic mice showed an intermediate 28% increase. Interpretation This surprising increase in histaminergic neurons in narcolepsy may be a compensatory response to loss of excitatory drive from the orexin neurons and may contribute to some of the symptoms of narcolepsy such as preserved consciousness during cataplexy and fragmented nighttime sleep. In addition, this finding may have therapeutic implications, as medications that enhance histamine signaling are now under development. Ann Neurol 2013;74:794-804 © 2013 American Neurological Association.

Blaber A.P.,Simon Fraser University | Zuj K.A.,University of Waterloo | Goswami N.,Medical University of Graz
European Journal of Applied Physiology | Year: 2013

This review summarizes our current understanding of cerebral blood flow regulation with exposure to microgravity, outlines potential mechanisms associated with post-flight orthostatic intolerance, and proposes future directions for research and linkages with cerebrovascular disorders found in the general population. It encompasses research from cellular mechanisms (e.g. hind limb suspension: tissue, animal studies) to whole body analysis with respect to understanding human responses using space analogue studies (bed rest, parabolic flight) as well as data collected before, during, and after spaceflight. Recent evidence indicates that cerebrovascular autoregulation may be impaired in some astronauts leading to increased susceptibility to syncope upon return to a gravitational environment. The proposed review not only provides insights into the mechanisms of post-flight orthostatic intolerance, but also increases our understanding of the mechanisms associated with pathophysiological conditions (e.g. unexplained syncope) with clinical applications in relation to postural hypotension or intradialytic hypotension. © 2012 Springer-Verlag Berlin Heidelberg.

Frohlich-Reiterer E.E.,Medical University of Graz | Rosenbauer J.,Heinrich Heine University Düsseldorf | Bechtold-Dalla Pozza S.,Ludwig Maximilians University of Munich | Hofer S.E.,Innsbruck Medical University | And 2 more authors.
Archives of Disease in Childhood | Year: 2014

Objective: Increased weight gain has been reported prior to disease onset (accelerator hypothesis) and as a side effect of intensified insulin therapy in type 1 diabetes (T1D). Paediatric studies are complicated by the age-dependency and gender-dependency of BMI, and also by a trend towards obesity in the general population. The aim of this study was to evaluate factors related to the increase in BMI during the course of diabetes in children and adolescents with T1D in a large multicentre survey. Design: Within the DPV database (Diabetespatienten Verlaufsdokumentation) a standardised, prospective, computer-based documentation programme, data of 53 108 patients with T1D, aged <20 years, were recorded in 248 centres. 12 774 patients (53% male, mean age 13.4±3.9, mean diabetes duration 4.7±3.0 years and mean age at diabetes onset 8.7±4.0 years) were included in this analysis. Population-based German reference data were used to calculate BMI-SDS and define overweight and obesity. Results: 12.5% of T1D patients were overweight and 2.8% were obese. Multiple longitudinal regression analysis revealed that female gender, low BMI at diabetes onset, intensified insulin therapy and higher insulin dose, as well as pubertal diabetes onset, long diabetes duration and onset in earlier calendar years among girls, were related to higher BMI-SDS increase during the course of diabetes (p<0.01; all). Conclusions: Intensified insulin regimen is associated with weight gain during T1D treatment, in addition to demographic variables. Optimisation of diabetes management, especially in females, might limit weight gain in order to reduce overweight and obesity together with comorbidities among paediatric T1D patients.

Yumuk V.,Istanbul University | Fruhbeck G.,University of Navarra | Oppert J.M.,University Pierre and Marie Curie | Woodward E.,European Association for the Study of Obesity | Toplak H.,Medical University of Graz
Obesity Facts | Year: 2014

Obesity has proven to be a gateway to ill health. It has already reached epidemic proportions becoming one of the leading causes of death and disability in Europe and world-wide. Obesity plays a central role in the development of a number of risk factors and chronic diseases like hypertension, dyslipidaemia and type 2 diabetes mellitus inducing cardiovascular morbidity and mortality. Therefore weight management plays a central role in controlling the respective risk factors and their consequences. Obesity is a complex condition of multifactorial origin. Biological but also psychological and social factors interfere to lead to excess body weight and its deleterious outcomes. Obesity management cannot focus any more only on weight (and BMI) reduction. More attention is to be paid to waist circumference (or waist-to-hip ratio, especially in females), the improvement in body composition (measured with body composition tracking systems like BOD POD, dual energy X-ray absorptiometry or bioelectrical impedance analysis) which is focusing on ameliorating or maintaining fat-free mass and decreasing fat mass. Management of co-morbidities, improving quality of life and well-being of obese patients are also included in treatment aims. This statement emphasises the importance of a comprehensive approach to obesity management. © 2014 S. Karger GmbH, Freiburg.

Zalaudek I.,Medical University of Graz | Giacomel J.,Mends St Medical Center | Ferrara G.,Gaetano Rummo Hospital | Catrical C.,Santa Maria and San Gallicano Dermatologic Institute | Argenziano G.,The Second University of Naples
Journal of the American Academy of Dermatology | Year: 2010

Dermoscopy is a noninvasive tool that can be helpful in the diagnosis of nonpigmented skin tumors. This is because dermoscopy permits the visualization of key vascular structures that are usually not visible to the naked eye. Much work has concentrated on the identification of specific morphologic types of vessels that allow a classification into melanocytic versus nonmelanocytic and benign versus malignant nonpigmented skin tumors. Among a broad spectrum of different types of vascular patterns, six main morphologies can be identified. These are comma-like, dotted, linear-irregular, hairpin, glomerular, and arborizing vessels. With some exceptions, comma, dotted, and linear irregular vessels are associated with melanocytic tumors, while the latter three vascular types are generally indicative of keratinocytic tumors. Aside from vascular morphology, the architectural arrangement of vessels within the tumor and the presence of additional dermoscopic clues are equally important for the diagnosis. This article provides a general overview of the dermoscopic evaluation of nonpigmented skin tumors and is divided into two parts. Part I discusses the dermoscopic vascular patterns of benign and malignant melanocytic skin tumors. Part II discusses the dermoscopic vascular patterns of benign and malignant nonmelanocytic nonpigmented skin tumors. In each part, additional special management guidelines for melanocytic and nonmelanocytic nonpigmented skin tumors, respectively, will be discussed. Learning objectives: After completing this learning activity, participants should be able to categorize different vascular structures and the architectural arrangement of vessels within tumors and additional dermoscopic clues of nonpigmented skin tumors, recognize the diagnostic significance of vessels associated with nevi and melanoma, and appropriately manage nonpigmented melanocytic skin tumors. © 2009 by the American Academy of Dermatology, Inc.

Zalaudek I.,Medical University of Graz | Giacomel J.,Mends St Medical Center | Ferrara G.,Gaetano Rummo Hospital | Catrical C.,Santa Maria and San Gallicano Dermatologic Institute | Argenziano G.,The Second University of Naples
Journal of the American Academy of Dermatology | Year: 2010

Nonmelanoma skin cancer refers to a broad class of tumors, including actinic keratosis, basal cell carcinoma, and squamous cell carcinoma, and as a group these are the most frequent cancers occurring in light skinned humans. In contrast to the rarity of amelanotic melanoma, nonmelanoma skin cancer commonly lacks pigmentation. Although these tumors rarely cause death related to metastases, they commonly destroy underlying tissues and should be removed at the earliest possible stage. Dermoscopy improves the clinical diagnosis of nonpigmented skin tumors by allowing the visualization of specific vascular structures that are usually not visible to the naked eye. Dermoscopic vascular patterns of several nonmelanocytic nonpigmented skin tumors, such as sebaceous hyperplasia, seborrheic keratosis, clear cell acanthoma, Bowen disease, or nodular cystic basal cell carcinoma are highly specific, allowing a ready diagnosis in most cases. Others, such as actinic keratosis, pyogenic granuloma, or uncommon adnexal tumors, may be difficult to differentiate even with the aid of dermoscopy. For this reason, general guidelines have been established to assist in making the most appropriate management decision. In the second part of this review of dermoscopic vascular structures of nonpigmented skin tumors, the dermoscopic patterns associated with benign and malignant nonmelanocytic skin tumors and recommendations for the management of these tumors will be discussed. Learning objectives: After completing this learning activity, participants should be able to recognize the vascular morphology, architectural arrangement of vessels, and additional dermoscopic clues of nonmelanocytic nonpigmented skin tumors, recognize the diagnostic significance of vessels associated with benign and malignant nonmelanocytic tumors, and apply rules for the management of these tumors. © 2009 by the American Academy of Dermatology, Inc.

Valko P.O.,Beth Israel Deaconess Medical Center | Valko P.O.,University of Zürich | Gavrilov Y.V.,Beth Israel Deaconess Medical Center | Gavrilov Y.V.,University of Zürich | And 9 more authors.
Annals of Neurology | Year: 2015

The need for increased sleep after traumatic brain injury is a common and disabling complaint, yet its etiology is unknown. Previous studies have demonstrated diffuse damage to various hypothalamic systems, but the integrity of the histaminergic tuberomammillary nucleus, a major arousal-promoting system located in the posterior hypothalamus, has never been examined in head trauma patients. Here, we demonstrate that severe head trauma is associated with a marked loss (41%) of histaminergic neurons. Reduced histamine signaling may contribute to increased sleep need, and therapies that enhance histaminergic tone may improve arousal after head trauma or other conditions. © 2014 American Neurological Association.

Foldes-Papp Z.,Medical University of Graz | Baumann G.,German University in Cairo
Current Pharmaceutical Biotechnology | Year: 2011

We present a new approach to distinguish between non-ergodic and ergodic behavior. Performing ensemble averaging in a subpopulation of individual molecules leads to a mean value that can be similar to the mean value obtained in an ergodic system. The averaging is carried out by minimizing the variation between the sum of the temporal averaged mean square deviation of the simulated data with respect to the logarithmic scaling behavior of the subpopulation. For this reason, we first introduce a kind of Continuous Time Random Walks (CTRW), which we call Limited Continuous Time Random Walks (LCTRW) on fractal support. The random waiting time distributions are sampled at points which fulfill the condition N < 1, where N is the Poisson probability of finding a single molecule in the femtoliter-sized observation volume ΔV at the single-molecule level. Given a subpopulation of different single molecules of the same kind, the ratio T/ Tm between the measurement time T and the meaningful time Tm, which is the time for observing just one and the same single molecule, is the experimentally accessible quantity that allows to compare different molecule numbers in the subpopulation. In addition, the mean square displacement traveled by the molecule during the time t is determined by an upper limit of the geometric dimension of the living cell or its nucleus. © 2011 Bentham Science Publishers Ltd.

Brunasso A.M.G.,Medical University of Graz | Brunasso A.M.G.,Galliera Hospital | Puntoni M.,Galliera Hospital | Aberer W.,Medical University of Graz | And 3 more authors.
British Journal of Dermatology | Year: 2013

Background In 2007 the International Psoriasis Council proposed that palmoplantar pustulosis (PPP) should be considered a separate condition from psoriasis, despite the presence of certain phenotypes common in both diseases. Objectives To describe and compare demographic and clinical characteristics among patients with PPP and palmoplantar plaque psoriasis. Methods This was a retrospective case series study from 2005 to 2010. The following data were obtained: age, sex, family history, smoking habits, nail involvement, joint involvement, disease duration, lesion morphology (plaque or pustular), histological diagnosis, comorbidities, and Physician's Global Assessment (PGA) score for extrapalmoplantar lesions. The sample size calculation indicated that 80 patients, 40 patients for each group (palmoplantar plaque psoriasis and PPP) were needed to see clinically relevant differences between groups. Results Ninety patients were selected, 51 with palmoplantar plaque psoriasis and 39 with PPP. No statistically significant differences were registered between patients affected by PPP and palmoplantar plaque psoriasis as regards age at onset of the disease (48 vs. 44 years; P = 0·4), disease duration (6 vs. 10 years; P = 0·1), family history of psoriasis (28% vs. 33%; P = 0·7), concomitant arthritis (26% vs. 25%; P = 1·0), or smoking habits (54% vs. 41%; P = 0·2). We observed a female predominance (P = 0·01) and a lesser frequency of nail involvement (P = 0·03) in patients affected by PPP. Conclusions Our data suggest a close relationship between PPP and psoriasis. The existing data concerning epidemiology, clinical presentation, genetics, histopathology and pathogenesis do not permit a clear distinction between these two entities, which seem to coincide in many aspects. PPP appears to have a marked predilection among female smokers. What's already known about this topic? Recently, palmoplantar pustulosis (PPP) has been proposed as a separate condition from psoriasis. What does this study add? We were not able to find significant differences between patients with PPP and those with palmoplantar plaque psoriasis regarding psoriasis, anamnesis, comorbidities or associated extrapalmoplantar psoriasis lesions. Our data suggest a close relationship between PPP and psoriasis. Available data concerning epidemiology, genetics, histopathology and pathogenesis do not permit a clear distinction between psoriasis and PPP. © 2013 The Authors. BJD © 2013 British Association of Dermatologists.

Kraus T.,Medical University of Graz | Fischerauer S.F.,Medical University of Graz | Hanzi A.C.,ETH Zurich | Uggowitzer P.J.,ETH Zurich | And 2 more authors.
Acta Biomaterialia | Year: 2012

This study investigates the bone and tissue response to degrading magnesium pin implants in the growing rat skeleton by continuous in vivo microfocus computed tomography (μCT) monitoring over the entire pin degradation period, with special focus on bone remodeling after implant dissolution. The influence of gas release on tissue performance upon degradation of the magnesium implant is also addressed. Two different magnesium alloys - one fast degrading (ZX50) and one slowly degrading (WZ21) - were used for evaluating the bone response in 32 male Sprague-Dawley rats. After femoral pin implantation μ CTs were performed every 4 weeks over the 24 weeks of the study period. ZX50 pins exhibited early degradation and released large hydrogen gas volumes. While considerable callus formation occurred, the bone function was not permanently harmed and the bone recovered unexpectedly quickly after complete pin degradation. WZ21 pins kept their integrity for more than 4 weeks and showed good osteoconductive properties by enhancing bone accumulation at the pin surface. Despite excessive gas formation, the magnesium pins did not harm bone regeneration. At smaller degradation rates, gas evolution remained unproblematic and the magnesium implants showed good biocompatibility. Online μCT monitoring is shown to be suitable for evaluating materials degradation and bone response in vivo, providing continuous information on the implant and tissue performance in the same living animal. © 2011 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Muller H.,University of Graz | Berg C.,University of Graz | Landa B.B.,CSIC - Institute for Sustainable Agriculture | Auerbach A.,University of Regensburg | And 3 more authors.
Frontiers in Microbiology | Year: 2015

Endophytes have an intimate and often symbiotic interaction with their hosts. Less is known about the composition and function of endophytes in trees. In order to evaluate our hypothesis that plant genotype and origin have a strong impact on both, endophytes of leaves from 10 Olea europaea L. cultivars from the Mediterranean basin growing at a single agricultural site in Spain and from nine wild olive trees located in natural habitats in Greece, Cyprus, and on Madeira Island were studied. The composition of the bacterial endophytic communities as revealed by 16S rRNA gene amplicon sequencing and the subsequent PCoA analysis showed a strong correlation to the plant genotypes. The bacterial distribution patterns were congruent with the plant origins in "Eastern" and "Western" areas of the Mediterranean basin. Subsequently, the endophytic microbiome of wild olives was shown to be closely related to those of cultivated olives of the corresponding geographic origins. The olive leaf endosphere harbored mostly Proteobacteria, followed by Firmicutes, Actinobacteria, and Bacteroidetes. The detection of a high portion of archaeal taxa belonging to the phyla Thaumarchaeota, Crenarchaeota, and Euryarchaeota in the amplicon libraries was an unexpected discovery, which was confirmed by quantitative real-time PCR revealing an archaeal portion of up to 35.8%. Although the function of these Archaea for their host plant remains speculative, this finding suggests a significant relevance of archaeal endophytes for plant-microbe interactions. In addition, the antagonistic potential of culturable endophytes was determined; all isolates with antagonistic activity against the olive-pathogenic fungus Verticillium dahliae Kleb. belong to Bacillus amyloliquefaciens. In contrast to the specific global structural diversity, BOX-fingerprints of the antagonistic Bacillus isolates were highly similar and independent of the olive genotype from which they were isolated. © 2015 Müller, Berg, Landa, Auerbach, Moissl-Eichinger and Berg.

Tripolt N.J.,Medical University of Graz | Narath S.H.,Joanneum Research | Eder M.,Medical University of Graz | Pieber T.R.,Medical University of Graz | And 2 more authors.
Cardiovascular Diabetology | Year: 2014

Background: Patients with rapid progression of carotid intima media thickness (CIMT) were shown to have a higher future risk for cardiovascular events.The aim of this study was to investigate the impact of multiple risk factor intervention on CIMT progression and to establish whether new cardiovascular surrogate measurements would allow prediction of CIMT changes.Materials and methods: In this prospective, open, 2-years study, we included 97 patients with type 2 diabetes and at least two insufficiently treated cardiovascular risk factors, i.e. HbA1c > 7.5% (58 mmol/mol); LDL-cholesterol >3.1 mmol/l or blood pressure >140/90 mmHg. Treatment was intensified according to current guidelines over 3 months with the aim to maintain intensification over 2 years.The primary outcome was the change in CIMT after 2 years. We also assessed markers of mechanical and biochemical endothelial function and endothelial progenitor cells before and after 3 months of treatment intensification. For testing differences between before and after multifactorial treatment measurements we used either the paired student's t-test or the Wilcoxon signed-rank test, depending on the distribution of the data. Additional, explorative statistical data analysis was done on CIMT progression building a linear multivariate regression model.Results: Blood glucose, lipids and blood pressure significantly improved during the first 3 months of intensified treatment, which was sustained over the 2-year study duration. Mean CIMT significantly decreased from baseline to 2 year (0.883 ± 0.120 mm vs. 0.860 ± 0.130 mm; p = 0.021). None of the investigated surrogate measures, however, was able to predict changes in IMT early after treatment intensification.Conclusions: Intensification of risk factor intervention in type 2 diabetes results in CIMT regression over a period of 2 years. None of the biomarkers used including endothelial function parameters or endothelial progenitor cells turned out to be useful to predict CIMT changes. Trial registration: Clinical Trial Registration - Unique identifier: NCT00660790. © 2014 Tripolt et al.; licensee BioMed Central Ltd.

Finsterer J.,Krankenanstalt Rudolfstiftung | Finsterer J.,Danube University Krems | Papic L.,Medical University of Graz | Auer-Grumbach M.,Medical University of Graz
Current Opinion in Neurology | Year: 2011

Purpose of Review: The aim is to review the most relevant findings published during the last year concerning clinical, genetic, pathogenic, and therapeutic advances in motor neuron disease, neuropathies, and neuromuscular junction disorders. Recent Findings: Studies on animal and cell models have improved the understanding of how mutated survival motor neuron protein in spinal muscular atrophy governs the pathogenetic processes. New phenotypes of SOD1 mutations have been described. Moreover, animal models enhanced the insight into the pathogenetic background of sporadic and familial amyotrophic lateral sclerosis. Novel treatment options for motor neuron disease have been described in humans and animal models. Considerable progress has been achieved also in elucidating the genetic background of many forms of inherited neuropathies and high clinical and genetic heterogeneity has been demonstrated. Mutations in MuSK and GFTP1 have been shown to cause new types of congenital myasthenic syndromes. A third type of autoantibodies (Lrp4) has been detected to cause myasthenia gravis. Summary: Advances in the clinical and genetic characterization of motor neuron diseases, neuropathies, and neuromuscular transmission defects have important implications on the fundamental understanding, diagnosis, and management of these disorders. Identification of crucial steps of the pathogenetic process may provide the basis for the development of novel therapeutic strategies. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Zalaudek I.,Medical University of Graz | Catricala C.,Santa Maria and San Gallicano Dermatologic Institute IFO of Rome | Moscarella E.,Santa Maria and San Gallicano Dermatologic Institute IFO of Rome | Argenziano G.,The Second University of Naples
Journal of Dermatology | Year: 2011

The evolution of nevi is a complex process involving several constitutional and environmental factors. Although histopathology is the gold standard for the diagnosis and classification of melanocytic nevi, the widespread use of in vivo diagnostic technologies such as dermoscopy and more recently of reflectance confocal microscopy, has enriched profoundly our knowledge regarding the morphological variability of nevi in different stages of their evolution. In addition, significant progress has been made in our understanding of genetic alterations and molecular pathways involved in the formation of melanocytic tumors. All this newly acquired knowledge increasingly questions whether morphologically different nevi are also histiogenetically different. In this article, we intend to extract some of the salient points from published clinical and molecular studies on melanocytic tumors and attempt to assimilate them into an integrative concept of nevogenesis. © 2011 Japanese Dermatological Association.

Heidenreich B.,German Cancer Research Center | Nagore E.,University of Valencia | Rachakonda P.S.,German Cancer Research Center | Garcia-Casado Z.,Instituto Valenciano Of Oncologia | And 6 more authors.
Nature communications | Year: 2014

We previously reported a disease segregating causal germline mutation in a melanoma family and recurrent somatic mutations in metastasized tumours from unrelated patients in the core promoter region of the telomerase reverse transcriptase (TERT) gene. Here we show that the TERT promoter mutations, besides causing an increased gene expression, associate with increased patient age, increased Breslow thickness and tumour ulceration in 287 primary melanomas. The mutations are more frequent at both intermittently and chronically sun-exposed sites than non-exposed sites and tend to co-occur with BRAF and CDKN2A alterations. The association with parameters generally connected with poor outcome, coupled with high recurrence and mechanistic relevance, raises the possibility of the eventual use of TERT promoter mutations in the disease management.

Resch B.,Medical University of Graz | Sommer C.,Medical University of Graz | Nuijten M.J.C.,Ars Accessus Medica | Seidinger S.,Abbott Laboratories | And 3 more authors.
Pediatric Infectious Disease Journal | Year: 2012

Objective: To assess the cost-effectiveness of palivizumab, a monoclonal antibody against respiratory syncytial virus (RSV), in infants at high risk for severe RSV lower respiratory tract infection, such as premature infants, infants with bronchopulmonary dysplasia, and those with congenital heart disease, based on long-term epidemiologic data from Austria. Methods: A decision-tree model was used, and the analysis was based on a lifetime follow-up investigating cost-effectiveness of palivizumab versus no RSV infection prevention. The primary perspective of the study was that of the healthcare system, the second that of society. Cost and effects were discounted by 5%. The base case analysis included only direct medical costs, and a scenario analysis included various indirect costs. Results: Analyses were based on epidemiologic data on a total of 1579 children hospitalized because of RSV lower respiratory tract infection during 16 seasons. The incremental cost-effectiveness ratio for the first outcome measure (life years gained) amounted to discounted costs of €34,956 (for all preterm infants), €35,056 (for <33 weeks' gestational age [wGA] infants), €35,233 (for 33-35 wGA infants), €35,611 (for infants with bronchopulmonary dysplasia), and €8956 (for infants with congenital heart disease). Use of palivizumab compared with no prophylaxis had an incremental cost-utility ratio of €26,212, €26,292, €24,392, €24,654, and €8484, respectively, per quality-adjusted life years. Results from the society perspective were more cost-effective in all study populations. An additional scenario analysis with 7 injections for the 33 to 35 wGA group revealed cost-effectiveness as well. Conclusions: Our results based on nationwide long-term epidemiologic data suggest that palivizumab is cost-effective in prevention of RSV disease in high-risk infants. © 2012 Lippincott Williams & Wilkins.

Huppertz B.,Medical University of Graz | Meiri H.,TeleMarpe Ltd. | Gizurarson S.,University of Iceland | Osol G.,University of Vermont | Sammar M.,ORT Braude College
Human Reproduction Update | Year: 2013

Pre-eclampsia affects 2-7% of all pregnant women and is a major cause of maternal and fetal morbidity and mortality. The etiology of pre-eclampsia is still unknown but it is well documented that impaired placentation is a major contributor to its development. One of the placenta-specific proteins is placental protein 13 (PP13). Lower first trimester levels of maternal serum PP13 and its encoding placental mRNA are associated with the development of both early and late-onset severe pre-eclampsia. In cases where this protein is mutated, the frequency of pre-eclampsia is higher.methods: 19 out of 68 studies on PP13, published between January 2006 and September 2012, were used to evaluate the value of maternal blood PP13 as a marker of pre-eclampsia. results: A meta-analysis presented in this review shows that low serum levels of PP13 in the first trimester of pregnancy can predict the development of pre-eclampsia later in pregnancy. Although some functions of this protein have been assessed in in vitro experiments, the in vivo functions of PP13 are still unknown, especially when circulating in the maternal bloodstream. A recent pilot study has shown that in gravid rats PP13 causes significant vasodilatation, reduced blood pressure and increased maternal uterine artery remodeling. conclusion: Reviewing these effects of PP13, the authors propose the use of PP13 as a new drug candidate. Replenishing PP13 in those women with low serum levels early in pregnancy may help prepare their vasculature for pregnancy. This novel pharmacological approach to combat pre-eclampsia is presented as a new direction to transfer from individualized risk to personalized prevention. © The Author 2013. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.

Arevalo H.,Johns Hopkins University | Plank G.,Medical University of Graz | Helm P.,Medtronic Inc. | Halperin H.,Johns Hopkins University | Trayanova N.,Johns Hopkins University
PLoS ONE | Year: 2013

Ventricular tachycardia, a life-threatening regular and repetitive fast heart rhythm, frequently occurs in the setting of myocardial infarction. Recently, the peri-infarct zones surrounding the necrotic scar (termed gray zones) have been shown to correlate with ventricular tachycardia inducibility. However, it remains unknown how the latter is determined by gray zone distribution and size. The goal of this study is to examine how tachycardia circuits are maintained in the infarcted heart and to explore the relationship between the tachycardia organizing centers and the infarct gray zone size and degree of heterogeneity. To achieve the goals of the study, we employ a sophisticated high-resolution electrophysiological model of the infarcted canine ventricles reconstructed from imaging data, representing both scar and gray zone. The baseline canine ventricular model was also used to generate additional ventricular models with different gray zone sizes, as well as models in which the gray zone was represented as different heterogeneous combinations of viable tissue and necrotic scar. The results of the tachycardia induction simulations with a number of high-resolution canine ventricular models (22 altogether) demonstrated that the gray zone was the critical factor resulting in arrhythmia induction and maintenance. In all models with inducible arrhythmia, the scroll-wave filaments were contained entirely within the gray zone, regardless of its size or the level of heterogeneity of its composition. The gray zone was thus found to be the arrhythmogenic substrate that promoted wavebreak and reentry formation. We found that the scroll-wave filament locations were insensitive to the structural composition of the gray zone and were determined predominantly by the gray zone morphology and size. The findings of this study have important implications for the advancement of improved criteria for stratifying arrhythmia risk in post-infarction patients and for the development of new approaches for determining the ablation targets of infarct-related tachycardia. © 2013 Arevalo et al.

Lidder S.,Guys and St Thomas NHS Foundation Trust | Masterson S.,Queens Hospital | Dreu M.,Medical University of Graz | Clement H.,AUVA Trauma Hospital Graz | Grechenig S.,University of Regensburg
Journal of Orthopaedic Trauma | Year: 2014

Objectives: The posterolateral approach to the distal tibia allows excellent visualization, direct reduction, and stabilization of posterior malleolar fractures. Concomitant fractures of the lateral malleolus may be internally fixed through the same approach. The approach may also be used for pilon fractures and for bone grafting in nonunions. This study aims to establish the safe zone of proximal dissection to avoid injury to the peroneal vessels when performing the posterolateral approach to the distal tibia. Methods: Twenty-six unpaired adult lower limbs were dissected using the posterolateral approach to the distal tibia. The peroneal artery was identified, as it coursed through the interosseous membrane on deep dissection and the level of its bifurcation was noted over the tibia. Perpendicular measurements were made from these points to the tibial plafond and distal fibula. Results: The peroneal artery bifurcated at 83 ± 21 mm (range, 41-115 mm) proximal to the tibial plafond and 103 ± 21 mm (range, 61-136 mm) from the distal fibula. The peroneal artery perforated through the interosseous membrane 64 ± 18 mm (range, 41-96 mm) proximal to the tibial plafond and 81 ± 20 mm (range, 42-113 mm) from the distal fibula. Conclusions: The posterolateral approach to the distal tibia allows direct reduction of posterior malleolus fractures. The peroneal artery may bifurcate and perforate through the interosseous membrane as little as 41 mm from the tibial plafond. Dissection around this region should be performed with care due to the wide variation in vasculature, however, once the peroneal artery is mobilized, a buttress plate can easily be placed beneath it. Copyright © 2013 by Lippincott Williams & Wilkins.

Mangge H.,Medical University of Graz | Zelzer S.,Medical University of Graz | Puerstner P.,Medical University of Graz | Schnedl W.J.,General Practice for Internal Medicine | And 3 more authors.
Obesity | Year: 2013

Objective: The obesity prevalence is growing worldwide and largely responsible for cardiovascular disease, the most common cause of death in the western world. The rationale of this study was to distinguish metabolically healthy from unhealthy overweight/obese young and adult patients as compared to healthy normal weight age matched controls by an extensive anthropometric, laboratory, and sonographic vascular assessment. Design and Methods: Three hundred fifty five young [8 to ≤ 18 years, 299 overweight/obese(ow/ob), 56 normal weight (nw)] and 354 adult [>18-60 years, 175 (ow/ob), 179 nw)] participants of the STYJOBS/EDECTA (STYrian Juvenile Obesity Study/Early DEteCTion of Atherosclerosis) cohort were analyzed. STYJOBS/ EDECTA (NCT00482924) is a crossectional study to investigate metabolic/cardiovascular risk profiles in normal and ow/ob people free of disease exceptmetabolic syndrome (MetS). Results: From 299 young ow/ob subjects (8-≤ 18 years), 108 (36%), and from 175 adult ow/ob subjects (>18-60 years), 79 (45%) had positive criteria for MetS. In both age groups, prevalence of MetS was greater among males. Overweight/obese subjects were divided into "healthy" (no MetS criterion except anthropometry fulfilled) and "unhealthy" (MetS positive). Although percentage body fat did not differ between "healthy" and "unhealthy" ow/ob, nuchal and visceral fat were significantly greater in the "unhealthy" group which had also significantly higher values of carotid intima media thickness (IMT). With MetS as the dependent variable, two logistic regressions including juveniles ≤18 years or adults >18 years were performed. The potential predictor variables selected with the exception of age and gender by t test comparisons included IMT, ultrasensitive c-reactive protein (US-CRP), IL-6, malondialdehyde (MDA), oxidized LDL, leptin, adiponectin, uric acid (UA), aldosterone, cortisol, transaminases, fibrinogen. In both groups, uric acid and in adults only, leptin and adiponectin, turned out as the best predictor. Conclusion: Serum levels of UA are a significant predictor of unhealthy obesity in juveniles and adults.

Auprich M.,Medical University of Graz | Bjartell A.,Skåne University Hospital | Chun F.K.-H.,University of Hamburg | De La Taille A.,CHU Henri Mondor | And 6 more authors.
European Urology | Year: 2011

Context: Newly discovered biomarkers ideally should prove clinical usefulness, provide additional detection, staging, and prognosis information to improve individual risk assessment, and potentially permit targeted cancer therapy. Objective: To review, display, and evaluate the current evidence regarding the biologic and analytic approach of urinary prostate cancer gene 3 (PCA3) in prostate cancer (PCa) detection, staging, and prognosis, and its therapeutic potential. Evidence acquisition: A systematic and comprehensive Medline search was performed using the Medical Subject Headings search terms PCA3, DD3, UPM3, prostate cancer, cell-lines, prostate tissue, prostate biopsy, detection, diagnosis, radical prostatectomy, staging, grading, progression, and gene therapy. Results were restricted to English-language papers published within the period 1999-2011. Evidence synthesis: The PCA3 gene is highly overexpressed in specific PCa cell lines and prostatic tumours. In 2006, a simple and robust urine test (Progensa) became commercially available. Despite its costs, prostate cancer antigen 3 (PCA3) is superior to prostate-specific antigen (PSA) and percent free PSA in the early detection of PCa. PCA3 improves the diagnostic accuracy of externally validated nomograms among men with an elevated PSA undergoing biopsy. PCA3 independently predicts low-volume disease and pathologically insignificant PCa but is not associated with locally advanced disease and is limited in the prediction of aggressive cancer. Preliminary data demonstrate that combining PCA3 with other new biomarkers further improves diagnostic and prognostic accuracy. Finally, findings of the first PCA3-Gene-ViroTherapy study suggest therapeutic potential by exploiting PCA3 overexpression. Conclusions: PCA3, integrated in novel biopsy nomograms or risk stratification tools, can be used to counsel or confirm biopsy indications. If confirmed in further studies, using PCA3 together with established staging risk factors could assist clinicians in specific pretreatment decision making. So far no evidence for the usefulness of PCA3 in active surveillance programs has been presented. © 2011 European Association of Urology.

Stewart B.,University of Washington | Khanduri P.,St Stephens Hospital | McCord C.,Columbia University | Ohene-Yeboah M.,Kwame Nkrumah University Of Science And Technology | And 3 more authors.
British Journal of Surgery | Year: 2014

Background: Surgical disease is inadequately addressed globally, and emergency conditions requiring surgery contribute substantially to the global disease burden. Methods: This was a review of studies that contributed to define the population-based health burden of emergency surgical conditions (excluding trauma and obstetrics) and the status of available capacity to address this burden. Further data were retrieved from the Global Burden of Disease Study 2010 and the University of Washington's Institute for Health Metrics and Evaluation online data. Results: In the index year of 2010, there were 896 000 deaths, 20 million years of life lost and 25 million disability-adjusted life-years from 11 emergency general surgical conditions reported individually in the Global Burden of Disease Study. The most common cause of death was complicated peptic ulcer disease, followed by aortic aneurysm, bowel obstruction, biliary disease, mesenteric ischaemia, peripheral vascular disease, abscess and soft tissue infections, and appendicitis. The mortality rate was higher in high-income countries (HICs) than in low- and middle-income countries (LMICs) (24·3 versus 10·6 deaths per 100 000 inhabitants respectively), primarily owing to a higher rate of vascular disease in HICs. However, because of the much larger population, 70 per cent of deaths occurred in LMICs. Deaths from vascular disease rose from 15 to 25 per cent of surgical emergency-related deaths in LMICs (from 1990 to 2010). Surgical capacity to address this burden is suboptimal in LMICs, with fewer than one operating theatre per 100 000 inhabitants in many LMICs, whereas some HICs have more than 14 per 100 000 inhabitants. Conclusion: The global burden of surgical emergencies is described insufficiently. The bare estimates indicate a tremendous health burden. LMICs carry the majority of emergency conditions; in these countries the pattern of surgical disease is changing and capacity to deal with the problem is inadequate. The data presented in this study will be useful for both the surgical and public health communities to plan a more adequate response. © 2013 BJS Society Ltd.

Hafner C.,University of Regensburg | Houben R.,University of Würzburg | Baeurle A.,University of Würzburg | Ritter C.,University of Würzburg | And 3 more authors.
PLoS ONE | Year: 2012

Merkel cell carcinoma (MCC) is a highly aggressive skin cancer with an increasing incidence. The understanding of the molecular carcinogenesis of MCC is limited. Here, we scrutinized the PI3K/AKT pathway, one of the major pathways activated in human cancer, in MCC. Immunohistochemical analysis of 41 tumor tissues and 9 MCC cell lines revealed high levels of AKT phosphorylation at threonine 308 in 88% of samples. Notably, the AKT phosphorylation was not correlated with the presence or absence of the Merkel cell polyoma virus (MCV). Accordingly, knock-down of the large and small T antigen by shRNA in MCV positive MCC cells did not affect phosphorylation of AKT. We also analyzed 46 MCC samples for activating PIK3CA and AKT1 mutations. Oncogenic PIK3CA mutations were found in 2/46 (4%) MCCs whereas mutations in exon 4 of AKT1 were absent. MCC cell lines demonstrated a high sensitivity towards the PI3K inhibitor LY-294002. This finding together with our observation that the PI3K/AKT pathway is activated in the majority of human MCCs identifies PI3K/AKT as a potential new therapeutic target for MCC patients. © 2012 Hafner et al.

Grabner R.H.,ETH Zurich | Ansari D.,University of Western Ontario | Koschutnig K.,Medical University of Graz | Reishofer G.,Medical University of Graz | Ebner F.,Medical University of Graz
Human Brain Mapping | Year: 2013

While the left angular gyrus (lAG) has been repeatedly implicated in mental arithmetic, its precise functional role has not been established. On the one hand, it has been speculated that the lAG is involved in task-specific processes. On the other hand, the observation of relative deactivation during arithmetic has led to the contention that differential lAG activation reflects task-unrelated difficulty effects associated with the default mode network (DMN). Using functional magnetic resonance imaging, we investigated the neural correlates of the associative confusion effect that allowed us to dissociate effects of task difficulty and task-related arithmetic processes on lAG activation. The associative confusion effect is characterized by poorer performance while verifying addition and multiplication equations whose solutions are associated with the other operation (confusion equations: e.g., "9 × 6 = 15") compared with solutions unrelated to both operations (non-confusion equations: e.g., "9 × 6 = 52"). Comparing these two conditions revealed higher activation of the anterior lAG (areas PGa, PFm, and PF) and the left dorsolateral prefrontal cortex for the confusion problems. This effect displayed only slight anatomical overlap with the well-established reverse problem-size effect (small minus large problems) and task-related deactivation in the parietal cortex. The finding of greater lAG activity (less deactivation) in the more difficult task condition is inconsistent with the hypothesis that lAG activation during mental arithmetic reflects task difficulty related modulations of the DMN. Instead, the present findings provide further support for the symbol-referent mapping hypothesis, suggesting that the lAG mediates the automatic mapping of arithmetic problems onto solutions stored in memory. © 2011 Wiley Periodicals, Inc.

Holzer L.A.,Medical University of Graz | Cor A.,University of Primorska | Pfandlsteiner G.,Klinikum Klagenfurt am Worthersee | Holzer G.,Medical University of Vienna
Acta Orthopaedica | Year: 2013

Background and purpose - Dupuytren's disease (DD) is a benign fibroproliferative process that affects the palmar fascia. The pathology of DD shows similarities with wound healing and tumor growth; hypoxia and angiogenesis play important roles in both. We investigated the role of angiogenic proteins in DD. Patients and methods - The expression of vascular endothelial growth factor (VEGF), its receptors vascular endothelial growth factor receptor 1 (VEGFR1) and vascular endothelial growth factor receptor 2 (VEGFR2), hypoxia-inducible factor alfa (HIF-1α), and alfa-smooth muscle actin (α-SMA) were analyzed immunohistochemically in fragments of excised Dupuytren's tissue from 32 patients. We compared these values to values for expression in a control group. Results - 15 of 32 samples could be attributed to the involutional phase (α-SMA positive), whereas 17 samples were considered to be cords at the residual phase (α-SMA negative). In the involutional phase, the HIF-1α and VEGFR2 expression was statistically significantly higher than in the residual phase and in the controls. Interpretation - Both the VEGFR2 receptor and HIF-1α were expressed in α-SMA positive myofibroblast-rich nodules with characteristics of DD in the active involutional phase. Thus, hypoxia and (subsequently) angiogenesis may have a role in the pathophysiology of DD. © 2011 Nordic Orthopaedic Federation.

Sadoghi P.,Medical University of Graz | Rosso C.,University of Basel | Rosso C.,Beth Israel Deaconess Medical Center | Valderrabano V.,University of Basel | And 3 more authors.
Journal of Orthopaedic Research | Year: 2013

To systematically review the current in-vivo evidence for the use of platelet-concentrates (PRP) in the treatment of Achilles tendinopathy and Achilles tendon ruptures in animal models and human applications. A systematic search of PubMed, CINAHL, EMBASE, CCTR, and CDSR was performed for animal and human studies on the effect of platelet-concentrates in the treatment of Achilles tendinopathy and ruptures using the terms "Achilles tendon and platelet." The systematic search revealed a total of 149 papers. After excluding duplicates and cases of overlapping data, studies not focusing on in vivo evidence in terms of treatment or outcome, studies without any intervention, studies with unacceptable high attrition, one Chinese and one Swedish study, the remaining 14 manuscripts were included. The key finding of our study is evidence in support of a statistically significant effect of platelet concentrates in the treatment of Achilles tendon ruptures in vivo in animal models and human application, consistent with a medium to large sized effect. This effect is most likely attributable to fastened and enhanced scar tissue maturation. There was no evidence for a beneficial effect of platelets in Achilles tendinopathy. © 2012 Orthopaedic Research Society.

Methods, systems and kits for the early diagnosis or prediction of systemic inflammatory response syndrome (SIRS) including sepsis in asymptomatic patients, such as patients undergoing a surgical intervention, are provided. Some embodiments include a method and system for the detection or diagnosis of SIRS, or detection or diagnosis of a risk to suffer from or develop SIRS, in an asymptomatic patient comprising the steps of determining the level of IL-6 (or a variant thereof) in a sample from the patient; comparing the level of IL-6 (or a variant thereof) to a reference level; detecting or diagnosing SIRS or diagnosing a risk to suffer from or develop SIRS, wherein the sample is isolated at least 2 times at short intervals and the determining and comparing steps are both repeated for each sample. Also provided are methods, systems and kits for therapy monitoring and mortality prediction.

Agency: Cordis | Branch: FP7 | Program: CP | Phase: ICT-2009.5.1 | Award Amount: 16.32M | Year: 2010

The REACTION project will develop an integrated approach to improved long term management of diabetes; continuous blood glucose monitoring, clinical monitoring and intervention strategies, monitoring and predicting related disease indicators, complemented by education on life style factors such as obesity and exercise and, ultimately, automated closed-loop delivery of insulin.\nThe REACTION platform will feature an interoperable peer-to-peer communication platform based on a (SoA) service oriented architecture all functionalities, including devices, are represented as services and applications consisting of a series of services orchestrated to perform a desired workflow. The REACTION platform also features a Model Drive Application Development environment based on extensive use of dynamic ontologies and advanced Data Management capabilities with algorithms for clinical assessment and rule-based data processing.\nThe intelligent, interoperable platform developed by REACTION will provide integrated, professional, management and therapy services to diabetes patients in different healthcare regimes across Europe, including 1) professional decision support for in-hospital environments, 2) safety monitoring for dosage and compliance, 3) long term management of outpatients in clinical schemes, 4) care of acute diabetic conditions and 5) support for self management and life-style changes for diabetic patients.\nA range of REACTION services will be developed targeted to insulin-dependent type 1 diabetic patients. The services aim to improve continuous blood glucose monitoring (CGM) and insulin therapy, by both basal dose adjustment and contextualised glycaemic control based on patient activity, nutrition, stress level, etc. Decision support will assist healthcare professionals, patients and informal carers to better manage diabetes therapy and make correct choices about e.g. good blood glucose control, nutrition and exercise.

Han G.,University of Colorado at Denver | Li F.,University of Colorado at Denver | Li F.,Shanghai University of Traditional Chinese Medicine | Singh T.P.,Medical University of Graz | And 2 more authors.
International Journal of Biological Sciences | Year: 2012

TGFβ1 was initially identified as a potent chemotactic cytokine to initiate inflammation, but the autoimmune phenotype seen in TGFβ1 knockout mice reversed the dogma of TGFβ1 being a pro-inflammatory cytokine to predominantly an immune suppressor. The discovery of the role of TGFβ1 in Th17 cell activation once again revealed the pro-inflammatory effect of TGFβ1. We developed K5.TGFβ1 mice with latent human TGFβ1 overexpression targeted to epidermal keratinocytes by keratin 5. These transgenic mice developed significant skin in-flammation. Further studies revealed that inflammation severity correlated with switching TGFβ1 transgene expression on and off, and genome wide expression profiling revealed striking similarities between K5.TGFβ1 skin and human psoriasis, a Th1/Th17-associated in-flammatory skin disease. Our recent study reveals that treatments alleviating inflammatory skin phenotypes in this mouse model reduced Th17 cells, and antibodies against IL-17 also lessen the inflammatory phenotype. Examination of inflammatory cytokines/chemokines af-fected by TGFβ1 revealed predominantly Th1-, Th17-related cytokines in K5.TGFβ1 skin. However, the finding that K5.TGFβ1 mice also express Th2-associated inflammatory cyto-kines under certain pathological conditions raises the possibility that deregulated TGFβ sig-naling is involved in more than one inflammatory disease. Furthermore, activation of both Th1/Th17 cells and regulatory T cells (Tregs) by TGFβ1 reversely regulated by IL-6 highlights the dual role of TGFβ1 in regulating inflammation, a dynamic, context and organ specific process. This review focuses on the role of TGFβ1 in inflammatory skin diseases. © Ivyspring International Publisher.

Agency: Cordis | Branch: H2020 | Program: SGA-CSA | Phase: WIDESPREAD-1-2014 | Award Amount: 460.64K | Year: 2015

The clinical and genetic investigations of diseases of the Cypriot population as well as eHealth are a priority of the Smart Specialization Strategy of the Cyprus government. This strategy can best be served by creating a Centre of Excellence (CoE) with two main spear heads: A contemporary Biobank and a research facility for developing the Cyprus Human Genome Project. Biobanks are organized collections of medical records and biological material of all types, aimed to support biomedical research, serving as repositories and distribution centers. Cyprus, as a Low Performing Member State, was the last country that started a Biobank, when 4 years ago we were competitively funded by the European Regional Development Fund & the Republic of Cyprus through the Cyprus Research Promotion Foundation. That project provided 2m, 0.4m of which was for creating a seed infrastructure for Biobanking. The rest was used for research in inherited kidney diseases. The money for Biobanking was too little for supporting a contemporary operation of recruiting adequate numbers of patients with complete records and promoting translational research. Here, we propose to upgrade the existing small infrastructure and turning it into a CoE with the assistance of Advanced Partners who led a similar operation Europe-wide, Prof. K. Zatloukal, coordinator of the Biobanking & BioMolecular Resources Research Infrastructure that recently became an ERIC (European Research Infrastructure Consortium) directed by Jan-Eric Litton (BBMRI-ERIC) located in Graz, Austria. The previous activity allowed us to comprehend the problems associated with patient recruitment and record collection. This can now serve as a starting point for upgrading it into a larger scale operation of European standard, aimed at leading the Cyprus Human Genome Project, part of which will be the sequencing of 1000 Cypriot genomes. This CoE will provide the prospects for innovative research and lead Cyprus into the European Research Area.

Agency: Cordis | Branch: FP7 | Program: CP-IP | Phase: HEALTH.2010.1.1-1 | Award Amount: 15.65M | Year: 2010

Given contemporary understanding of the complexity of the causal architecture of common chronic diseases, the next stage of bioclinical scientific progress will depend critically on large-scale pooled analyses of high quality data from many biobanks and bioclinical studies. Such analyses will only be possible if we are able to harmonise and standardise the collection, storage, and management of data and bio-samples across biobanking studies. Recent consortium-based meta-analyses of genome-wide association studies (GWAS) have clearly demonstrated that it is possible to pool and analyse genomic data with broad indicators of disease status. But if health care science is to move quickly towards the exciting goals that have been envisaged for public health, clinical science, and personalised medicine a far greater challenge must now be overcome. That is, the standardization and harmonization of data and key measures of life-style, social circumstances and environment, as well as critical sub-components of the phenotypes associated with common complex diseases. This is the mission of BioSHaRE-EU. BioSHaRE-EU will work hand-in-hand with BBMRI (Biobanking and Bio-molecular Resources Research Infrastructure) and P3G (Public Population Project in Genomics), to build directly on extensive precursor work in the field of harmonisation and standardisation. The project will deliver tools to harmonize phenotypes of complex diseases, as well as lifestyle and environmental factors. In addition, it provides statistical methods and biostatistical tools for meta-analysis of large scale studies. These tools and methods will be developed and implemented in five large partner-biobanks: HUNT, KORA, LifeGene, LifeLines, UK-biobank. BioSHaRE-EU will also implement these in additional disease consortia of clinical biobanks, and other population-based biobanks.

Agency: Cordis | Branch: FP7 | Program: NOE | Phase: ICT-2011.5.3 | Award Amount: 3.23M | Year: 2011

SemanticHealthNet will develop a scalable and sustainable pan-European organisational and governance process for the semantic interoperability of clinical and biomedical knowledge, to help ensure that EHR systems are optimised for patient care, public health and clinical research across healthcare systems and institutions.\nThrough a clinically-driven workplan, exemplified in cardiovascular medicine, SemanticHealthNet will capture the needs for evidence-based, patient-centred integrated care and for public health, encapsulating existing European consensus in the management of chronic heart failure and cardiovascular prevention. Experts in EHR architectures, clinical data structures, terminologies and ontology will combine, tailor and pilot their best-of-breed resources in response to the needs articulated by clinicians and public health physicians.\nThese exemplars will be cross-referenced with other domains and stakeholder perspectives via Clinical and Industrial Advisory Boards and interactions with other projects in Topic 5.3. The project will generalise and formalise the methods and best practices in how to combine and adapt informatics resources to support semantic interoperability, and how these can be developed and supported at scale. Health authorities, clinical professionals, ministries, vendors, purchasers, insurers are involved to ensure the project approach and results are realistically adoptable and viable, building on the SemanticHEALTH and CALLIOPE roadmaps.\nA business model to justify strategic investments, including the opportunity costs for key stakeholders such as SDOs, industry, will be defined. This, and links with epSOS II and the eHealth Governance Initiative, will inform the shape of the Virtual Organisation that this Network will establish to sustain semantic interoperability developments and their adoption.\nThe consortium comprises more than 40 internationally recognised experts, including from USA and Canada, ensuring a global impact.

Stronegger W.J.,Medical University of Graz | Titze S.,University of Graz | Oja P.,UKK Institute
Health and Place | Year: 2010

The aim of our study was to identify perceptions of the residential environment and their association with physical activity for specific purposes and with self-rated health in an urban context. A representative survey of inhabitants of Graz (a mid-sized Austrian city) aged 15-60 years (n=997) was conducted. We found a perceived high social-environmental quality of the residential environment to be associated with higher levels of self-rated health and leisure time physical activity. Both leisure time physical activity and satisfaction with environmental quality were independently linked with self-rated health. Furthermore, a high level of satisfaction with the individual's local infrastructure may support the residents to engage in higher levels of physical activity for transportation, whereas the preferred mode of transportation may be gender-specific: men tend to use the bicycle while women walk. Our results suggest that local infrastructure facilities should be designed so as to ensure accessibility by both walking and cycling. © 2010 Elsevier Ltd.

Buttgereit F.,Charité - Medical University of Berlin | Dejaco C.,Medical University of Graz | Matteson E.L.,Rochester College | Dasgupta B.,Southend University Hospital
JAMA - Journal of the American Medical Association | Year: 2016

Importance Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) are related inflammatory disorders occurring in persons aged 50 years and older. Diagnostic and therapeutic approaches are heterogeneous in clinical practice. OBJECTIVE To summarize current evidence regarding optimal methods for diagnosing and treating PMR and GCA. EVIDENCE REVIEW MEDLINE, EMBASE, and Cochrane databases were searched from their inception dates to March 30, 2016. Screening by 2 authors resulted in 6626 abstracts, of which 50 articlesmet the inclusion criteria. Study quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool or American College of Cardiology Foundation/American Heart Association methodology. FINDINGS Twenty randomized clinical trials for therapy (n = 1016 participants) and 30 imaging studies for diagnosis and/or assessing response to therapy (n = 2080 participants) were included. The diagnosis of PMR is based on clinical features such as new-onset bilateral shoulder pain, including subdeltoid bursitis, muscle or joint stiffness, and functional impairment. Headache and visual disturbances including loss of vision are characteristic of GCA. Constitutional symptoms and elevated inflammatory markers (>90%) are common in both diseases. Ultrasound imaging enables detection of bilateral subdeltoid bursitis in 69%of PMR patients. In GCA, temporal artery biopsy remains the standard for definitive diagnosis. Ultrasound and magnetic resonance imaging (MRI) of large vessels revealing inflammation-induced wall thickening support the diagnosis of GCA (specificity 78%-100% for ultrasound and 73%-97%for MRI). Glucocorticoids remain the primary treatment, but the optimal initial dose and tapering treatment regimens are unknown. According to consensus-based recommendations, initial therapy for PMR is prednisone, 12.5 to 25mg/day or equivalent, and 40 to 60mg/day for GCA, followed by individualized tapering regimens in both diseases. Adjunctivemethotrexate may reduce cumulative glucocorticoid dosage by 20%to 44%and relapses by 36%to 54%in both PMR and GCA. Use of tocilizumab as additional treatment with prednisone showed a 2-to 4-fold increase in remission rates of GCA in a randomized clinical trial (N = 30). CONCLUSIONS AND RELEVANCE Diagnosis of PMR/GCA is made by clinical features and elevated inflammatory markers. In PMR, ultrasound imagingmay improve diagnostic accuracy. In GCA, temporal artery biopsymay not be required in patients with typical disease features accompanied by characteristic ultrasound or MRI findings. Consensus-based recommendations suggest glucocorticoids as the most effective therapy for PMR/GCA. Methotrexate may be added to glucocorticoids in patients at risk for relapse and in those with glucocorticoid-related adverse effects or need for prolonged glucocorticoid therapy. © 2016 American Medical Association. All rights reserved.

Bauer C.,University of Graz | Pock T.,University of Graz | Sorantin E.,Medical University of Graz | Bischof H.,University of Graz | Beichel R.,University of Iowa