Time filter

Source Type

Vienna, Austria

The Medical University of Vienna is a university located in Vienna, Austria. It is the direct successor of the faculty of medicine of the University of Vienna, founded in 1365 by Rudolf IV, Duke of Austria. Thus it is the oldest medical school in the German–speaking world, and it was the second medical faculty in the Holy Roman Empire, after the Charles University of Prague.The Medical University of Vienna is the largest medical organisation in Austria, as well as one of the top-level research institutions in Europe and provides Europe's largest hospital, the Vienna General Hospital, with all of its medical staff.It consists of 31 university clinics and clinical institutes, 12 medical-theoretical departments which perform around 48,000 operations each year. The Vienna General Hospital has about 100,000 patients treated as inpatients and 605,000 treated as outpatients each year.There have been seven Nobel prize laureates affiliated with the medical faculty, and fifteen in total with the University of Vienna. These include Robert Bárány, Julius Wagner-Jauregg and Karl Landsteiner, the discoverer of the ABO blood type system and the Rhesus factor. Sigmund Freud qualified as a doctor at the medical faculty and worked as a doctor and lecturer at the General Hospital, carrying out research into cerebral palsy, aphasia and microscopic neuroanatomy.In the 2014-15 Times Higher Education Rankings, Medical University of Vienna is listed among the top 15 medical schools in Europe and 49th in the world. .In 2014, there were 6,016 candidate applications for 660 places in medicine proper and 80 in dentistry, which corresponds to an admission rate of about 12 percent. Admission is based upon ranking in an admission test, called "MedAT", which is carried out every summer in conjunction with the two other public medical schools of Austria, Medical University of Graz and Innsbruck Medical University. Wikipedia.

Ekmekcioglu C.,Medical University of Vienna
Medical Hypotheses | Year: 2012

Depression is a highly prevalent mental illness, which is associated with substantial functional impairment. Many factors, like especially genetic risk and stressful life events, are being discussed to be involved in the pathogenesis of the disease. There is also evidence that elevated levels of proinflammatory cytokines, which are frequently found in depressed individuals, could contribute to the development of the disease. Patients with metabolic syndrome also show a chronic low grade of inflammation. In addition, epidemiological studies suggest that an unhealthy dietary eating pattern, consisting of high amounts of refined grains and softdrinks, red and processed meat, fatty dairy products, and little amounts of vegetables, fruits and fish is associated with higher levels of major inflammatory cytokines, like Interleukin-6, and the acute phase C-reactive protein, even after controlling for body mass index. Furthermore, several recent studies suggest that an unhealthy diet quality is associated with an increased risk of depression. Therefore the connection between regular consumption of unhealthy foods, chronic inflammation, and increased risk for depression seems plausible. © 2011 Elsevier Ltd.

Valent P.,Medical University of Vienna
Allergy: European Journal of Allergy and Clinical Immunology | Year: 2013

Mast cell activation (MCA) occurs in a number of different clinical conditions, including IgE-dependent allergies, other inflammatory reactions, and mastocytosis. MCA-related symptoms may be mild, moderate, severe, or even life-threatening. The severity of MCA depends on a number of different factors, including genetic predisposition, the number and releasability of mast cells involved in the reaction, the type of allergen, presence of specific IgE, and presence of certain comorbidities. In severe reactions, MCA can be documented by a substantial increase in the serum tryptase level above baseline. When symptoms are recurrent, are accompanied by an increase in mast cell-derived mediators in biological fluids, and are responsive to treatment with mast cell-stabilizing or mediator-targeting drugs, the diagnosis of mast cell activation syndrome (MCAS) is appropriate. Based on the underlying condition, these patients can further be classified into i) primary MCAS where KIT-mutated, clonal mast cells are detected, ii) secondary MCAS where an underlying inflammatory disease, often in the form of an IgE-dependent allergy, but no KIT-mutated mast cells, is found, and iii) idiopathic MCAS, where neither an allergy or other underlying disease, nor KIT-mutated mast cells are detectable. It is important to note that in many patients with MCAS, several different factors act together to lead to severe or even life-threatening anaphylaxis. Detailed knowledge about the pathogenesis and complexity of MCAS, and thus establishing the exact final diagnosis, may greatly help in the management and therapy of these patients. © 2013 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.

Wesierska-Gadek J.,Medical University of Vienna | Krame M.P.,University of Vienna
Future Medicinal Chemistry | Year: 2012

Malignant cells in chronic lymphocytic leukemia (CLL) and related diseases are heterogeneous and consist primarily of long-lived resting cells in the periphery and a minor subset of dividing cells in proliferating centers. Both cell populations have different molecular signatures that play a major role in determining their sensitivity to therapy. Contemporary approaches to treating CLL are heavily reliant on cytotoxic chemotherapeutics. However, none of the current treatment regimens can be considered curative. Pharmacological CDK inhibitors have extended the repertoire of potential drugs for CLL. Multi-targeted CDK inhibitors affect CDKs involved in regulating both cell cycle progression and transcription. Their interference with transcriptional elongation represses anti-apoptotic proteins and, thus, promotes the induction of apoptosis. Importantly, there is evidence that treatment with CDK inhibitors can overcome resistance to therapy. The pharmacological CDK inhibitors have great potential for use in combination with other therapeutics and represent promising tools for the development of new curative treatments for CLL. © 2012 Future Science Ltd.

Megraud F.,French Institute of Health and Medical Research | Megraud F.,University of Bordeaux 1 | Coenen S.,University of Antwerp | Versporten A.,University of Antwerp | And 7 more authors.
Gut | Year: 2013

Objective: Resistance to antibiotics is the major cause of treatment failure of Helicobacter pylori infection. A study was conducted to assess prospectively the antibacterial resistance rates of H pylori in Europe and to study the link between outpatient antibiotic use and resistance levels in different countries. Design: Primary antibiotic resistance rates of H pylori were determined from April 2008 to June 2009 in 18 European countries. Data on yearly and cumulative use over several years of systemic antibacterial agents in ambulatory care for the period 2000-8 were expressed in Defined Daily Doses (DDD) per 1000 inhabitants per day. The fit of models and the degree of ecological association between antibiotic use and resistance data were assessed using generalised linear mixed models. Results: Of 2204 patients included, H pylori resistance rates for adults were 17.5% for clarithromycin, 14.1% for levofloxacin and 34.9% for metronidazole, and were significantly higher for clarithromycin and levofloxacin in Western/Central and Southern Europe ( >20%) than in Northern European countries (<10%). Model fit improved for each additional year of antibiotic use accumulated, but the best fit was obtained for 2005. A significant association was found between outpatient quinolone use and the proportion of levofloxacin resistance (p=0.0013) and between the use of long-acting macrolides only and clarithromycin resistance (p=0.036). Conclusion: In many countries the high rate of clarithromycin resistance no longer allows its empirical use in standard anti-H pylori regimens. The knowledge of outpatient antibiotic consumption may provide a simple tool to predict the susceptibility of H pylori to quinolones and to macrolides and to adapt the treatment strategies.

Gnant M.,Medical University of Vienna
Breast Disease | Year: 2011

Among women worldwide, breast cancer is the most common malignancy and a leading cause of death, accounting for approximately 6% of all cancer deaths globally. The predilection of breast cancer to metastasize to bone provides a strong rationale that antiresorptive agents such as bisphosphonates may have the potential to prevent disease recurrence. Bisphosphonates are established therapies for bone loss and for preventing skeletal-related events (SREs) from bone metastases. Moreover, intravenous nitrogen-containing bisphosphonates, such as zoledronic acid, have been shown to block multiple steps in tumor metastasis (e.g., angiogenesis, invasion, and adhesion). Recent clinical data from ABCSG-12, ZO-FAST, and AZURE demonstrate that zoledronic acid can significantly improve disease-free survival (DFS) in the adjuvant breast cancer setting in women who are naturally postmenopausal or have endocrine therapy-induced menopause. Furthermore, the ABCSG-12 trial showed durable disease-free survival benefits 2 years after completion of adjuvant therapy. These data suggest a potential role for zoledronic acid beyond bone health in breast cancer. Although it is too early to determine which patients are most likely to benefit from the anticancer potential of bisphosphonates, future research will help further guide therapy in this setting. © 2011/2012 IOS Press and the authors. All rights reserved.

Wesierska-Gadek J.,Medical University of Vienna | Skladanowski A.,Technical University of Gdansk
Future Medicinal Chemistry | Year: 2012

Many anticancer drugs reduce the integrity of DNA, forming strand breaks. This can cause mutations and cancer or cell death if the lesions are not repaired. Interestingly, DNA repair-deficient cancer cells (e.g., those with BRCA1/2 mutations) have been shown to exhibit increased sensitivity to chemotherapy. Based on this observation, a new therapeutic approach termed 'synthetic lethality' has been developed, in which radiation therapy or cytotoxic anticancer agents are employed in conjunction with selective inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1). Such combinations can cause severe genomic instability in transformed cells resulting in cell death. The synergistic effects of combining PARP-1 inhibition with anticancer drugs have been demonstrated. However, the outcome of this therapeutic strategy varies significantly between cancer types, suggesting that synthetic lethality may be influenced by additional cellular factors. This review focuses on the outcomes of the combined action of PARP-1 inhibitors and agents that affect the activity of DNA topoisomerases. © 2012 Future Science Ltd.

Ballmer-Weber B.K.,University of Zurich | Hoffmann-Sommergruber K.,Medical University of Vienna
Current Opinion in Allergy and Clinical Immunology | Year: 2011

Purpose of review: The purpose of this paper is to review and discuss studies on molecular diagnosis in fruit and vegetable allergy. Recent findings: Celeriac, carrot and tomato are the most prevalent allergenic vegetables, whereas fruit allergy is mainly induced by apple, peach and kiwi. Component-resolved molecular diagnosis has been recently applied in two well-defined patient groups with kiwifruit and celeriac allergy, respectively. In kiwifruit allergy Act d 1 and Act d 3 were identified as potential marker allergens for severe symptoms. For celeriac allergy, however, such markers are still missing. In both studies component-resolved molecular diagnosis approach improved in particular sensitivity compared to extract-based diagnostic test assays. Summary: Food and vegetable allergy can be acquired both via a direct sensitization over the gastrointestinal tract and via a primary sensitization to pollen or latex. The diagnosis of fruit and vegetable allergy in birch pollen-sensitized patients should not be excluded on a negative IgE testing to extracts. Bet v 1-related allergens are often under-represented in extracts. Few recombinant allergens derived from fruits and vegetables are nowadays commercially available and facilitate diagnosis of fruit and vegetable allergies. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Valenta R.,Christian Doppler Laboratory | Valenta R.,Center for Pathophysiology | Linhart B.,Center for Pathophysiology | Swoboda I.,Christian Doppler Laboratory | Niederberger V.,Medical University of Vienna
Allergy: European Journal of Allergy and Clinical Immunology | Year: 2011

The broad applicability of allergen-specific immunotherapy for the treatment and eventually prevention of IgE-mediated allergy is limited by the poor quality and allergenic activity of natural allergen extracts that are used for the production of current allergy vaccines. Today, the genetic code of the most important allergens has been deciphered; recombinant allergens equalling their natural counterparts have been produced for diagnosis and immunotherapy, and a large panel of genetically modified allergens with reduced allergenic activity has been characterized to improve safety of immunotherapy and explore allergen-specific prevention strategies. Successful immunotherapy studies have been performed with recombinant allergens and hypoallergenic allergen derivatives and will lead to the registration of the first recombinant allergen-based vaccines in the near future. There is no doubt that recombinant allergen-based vaccination strategies will be generally applicable to most allergen sources, including respiratory, food and venom allergens and allow to produce safe allergy vaccines for the treatment of the most common forms of IgE-mediated allergies. © 2011 John Wiley & Sons A/S.

Linhart B.,Center for Pathophysiology | Valenta R.,Center for Pathophysiology | Valenta R.,Medical University of Vienna
Current Opinion in Immunology | Year: 2012

Vaccines aim to establish or strengthen immune responses but are also effective for the treatment of allergy. The latter is surprising because allergy represents a hyper-immune response based on immunoglobulin E production against harmless environmental antigens, i.e., allergens. Nevertheless, vaccination with allergens, termed allergen-specific immunotherapy is the only disease-modifying therapy of allergy with long-lasting effects. New forms of allergy diagnosis and allergy vaccines based on recombinant allergen-derivatives, peptides and allergen genes have emerged through molecular allergen characterization. The molecular allergy vaccines allow sophisticated targeting of the immune system and may eliminate side effects which so far have limited the use of traditional allergen extract-based vaccines. Successful clinical trials performed with the new vaccines indicate that broad allergy vaccination is on the horizon and may help to control the allergy pandemic. © 2012 Elsevier Ltd.

Schneider-Stickler B.,Medical University of Vienna
HNO | Year: 2012

Voice disorders in the pediatric population are relatively common. The education of families, teachers and clinical staff on etiology and treatment of pediatric voice disorders have led to greater attention being paid to hoarseness in childhood and improving early detection of pediatric voice disorders. Pediatric voice problems can have a number of causes. Most commonly, childhood dysphonia is caused by vocal fold nodules due vocal ab- and misuse. Other reasons might be congenital laryngeal dysplasia, vocal fold cysts and laryngeal papilloma. Medical examination is necessary in order to initiate appropriate treatment. In the case of vocal fold cysts and laryngeal papilloma, phonosurgery is indicated. Vocal fold nodules should be treated by voice therapy in order to change vocal behaviour. If voice therapy fails, phonosurgical intervention is recommended, since vocal fold nodules can persist into adulthood with a negative impact on voice quality. © Springer-Verlag 2012.

Resch B.,Medical University of Graz | Michel-Behnke I.,Medical University of Vienna
Current Opinion in Cardiology | Year: 2013

PURPOSE OF REVIEW: Lower respiratory tract infections multiply morbidity and mortality within patients with significant congenital heart disease (CHD). For respiratory syncytial virus (RSV), one of the most important pathogens, immunoprophylaxis with palivizumab has successfully been introduced. The question is which patients will benefit most from this costly preventive treatment. RECENT FINDINGS: The era after the introduction of palivizumab has revealed a steep decrease in mortality. The markers of success - hospital stays, admission to the intensive care unit, days on mechanical ventilation, and death - consistently favor immunoprophylaxis. The key point of treatment success remains in all cases a careful patient selection, adherence to a time limit of 30 days between the injections and early use after cardiac surgery with cardiopulmonary bypass, as well as avoidance of nosocomial-acquired infections. Preventive therapy with palivizumab in patients with CHD has been investigated in terms of operating efficiency - with the lowest costs per quality-adjusted life years compared with preterm infants with or without bronchopulmonary dysplasia. SUMMARY: The burden of RSV disease will decline, once a vaccine is available. Meanwhile, immunoprophylaxis with palivizumab is a useful tool for high-risk patients to reduce comorbidity and fatal outcome. Pharmacoeconomic considerations measuring quality-adjusted life years indicate important information about cost-effectiveness. Copyright © 2013 2013 Lippincott Williams & Wilkins.

Auer-Grumbach M.,Medical University of Vienna
Handbook of Clinical Neurology | Year: 2013

Hereditary sensory and autonomic neuropathies (HSN/HSAN) are clinically and genetically heterogeneous disorders of the peripheral nervous system that predominantly affect the sensory and autonomic neurons. Hallmark features comprise not only prominent sensory signs and symptoms and ulcerative mutilations but also variable autonomic and motor disturbances. Autosomal dominant and autosomal recessive inheritance has been reported. Molecular genetics studies have identified disease-causing mutations in 11 genes. Some of the affected proteins have nerve-specific roles but underlying mechanisms have also been shown to involve sphingolipid metabolism, vesicular transport, structural integrity, and transcription regulation. Genetic and functional studies have substantially improved the understanding of the pathogenesis of the HSN/HSAN and will help to find preventive and causative therapies in the future. © 2013 Elsevier B.V.

Gnant M.,Medical University of Vienna
Current Oncology Reports | Year: 2012

Breast cancer, which preferentially metastasizes to bone, is the most common malignancy among women worldwide and is a leading cause of death. Clinical data from large, phase 3 trials (ie, ABCSG-12, ZO-FAST, and AZURE) demonstrate significantly improved disease-free survival with zoledronic acid in some patient populations with early breast cancer. Although the interim results from the AZURE trial did not show a disease-free survival benefit with zoledronic acid in the overall patient population, subset analyses showed that zoledronic acid significantly improved disease-free survival in women with established postmenopausal status at baseline. Similarly, subset analyses of the ABCSG-12 trial showed greater benefits from zoledronic acid in patients over 40 years of age who theoretically would have achieved more complete ovarian suppression. Together, these data support a potential role for zoledronic acid beyond bone health in breast cancer and suggest that the endocrine environment may influence the anticancer potential of zoledronic acid. © 2011 Springer Science+Business Media, LLC.

Druml W.,Medical University of Vienna
World Review of Nutrition and Dietetics | Year: 2013

Renal failure patients comprise a heterogenous group of subjects with widely differing metabolic patterns and nutritional requirements. These disease states include acute kidney injury (AKI), acute-on-chronic renal failure, chronic kidney disease, and regular hemodialysis therapy. Renal failure per se is associated with a broad spectrum of specific metabolic alterations; presents a panmetabolic disease process; and, especially in the case of AKI, induces a proinflammatory, pro-oxidative, and hypercatabolic state which exerts a profound impact on metabolism and morbidity/mortality. Besides the metabolic alterations induced by renal dysfunction and the often underrated/forgotten profound impact of renal replacement therapy, metabolism is also affected by the underlying disease process requiring intensive care unit therapy, other organ failures, and complications - especially infections. Certainly, nutrition support is not fundamentally different from other disease processes, but these variations in metabolism and nutrient requirements have to be considered when designing a nutrition regimen. Nutrition needs can differ widely between patients, as well as in the same patient during the course of disease. Thus, even more than in other subjects, the patient with renal failure requires an individualized approach in nutrition support, and because of the altered metabolism of many nutrients and intolerances for electrolytes and volume, the nutrition support in patients with renal failure requires much closer monitoring than in other disease states. Copyright © 2013 S. Karger AG, Basel.

Rosenhek R.,Medical University of Vienna
Seminars in Thoracic and Cardiovascular Surgery | Year: 2011

Watchful waiting is an established treatment strategy for asymptomatic patients with severe organic mitral regurgitation. It is based on indications for surgery that are based on current European Society of Cardiology and American Heart Association/American College of Cardiology guideline recommendations, which are defined by symptom onset, impairment of left ventricular function, and left ventricular enlargement. Excellent outcome is achieved when patients are periodically followed with clinical and echocardiographic examinations and when surgery is performed in expert centers. The strategy is based on the recognition of mitral regurgitation at an early symptomatic stage, avoiding a delayed referral of these patients. There is an ongoing debate about whether surgery should be performed in asymptomatic patients with preserved ventricular function. Ultimately, decision-making needs to be individualized and to take individual patient-related factors and local resources (including the natural history of the disease, the risk of surgery, and the likelihood of successful mitral valve repair) into consideration to obtain an optimal outcome with medical and surgical management. © 2011 Elsevier Inc.

Bobacz K.,Medical University of Vienna
Wiener Medizinische Wochenschrift | Year: 2013

Osteoarthritis (OA) is a joint disease of high prevalence and affects > 90 % of the population, depending on several risk factors. Symptomatic OA is less frequent, but requires an individually tailored therapeutic regimen consisting of non-pharmacological and pharmacological treatment modalities. Pharmacologic therapy, however, is mainly limited to analgetic and anti-inflammatory agents; structure modifying remedies do not exist. The therapeutic approach to hand-, knee- and hip-OA is basically similar and differs only at some minor points. Generally, topical agents or paracetamol are recommended as first-line agents. If unsuccessful oral non-steroidal anti-inflammatory drugs (NSAIDs) or COX-2-selctive inhibitors should be introduced. Tramadol is an option in the case patients will not respond satisfactorily to NSAIDs. Glucosamine and chondroitine sulphate are no longer recommended in knee and hip OA, but chondroitine might be efficient in treating hand OA. Oral NSAIDs should be prescribed with caution due to potential side effects. Opioids are not recommended as their benefits are outweighed by an increased risk for serious adverse events. © 2013 Springer-Verlag Wien.

Functional magnetic resonance imaging (fMRI) is currently the primary method for non-invasive functional localization in the brain. With the emergence of MR systems with field strengths of 4 Tesla and above, neuronal activation may be studied with unprecedented accuracy. In this article we present different approaches to use the improved sensitivity and specificity for expanding current fMRT resolution limits in space and time based on several 7 Tesla studies. In addition to the challenges that arise with ultra-high magnetic fields possible solutions will be discussed.

Lassmann H.,Medical University of Vienna
GLIA | Year: 2014

Glia cells are mediators as well as targets of the chronic inflammatory process in the central nervous system of multiple sclerosis (MS) patients. They are involved in the control of autoimmunity, in the propagation and termination of the inflammatory reaction, in the induction of demyelination and neurodegeneration, and in remyelination and scaring. Demyelination, as well as neuronal and GLIA cell damage are induced by different immunological mechanisms including components of the adaptive and innate immune system. Oxidative injury resulting in mitochondrial dysfunction is one important mechanism of tissue injury. It is in part driven by the inflammatory response and the production of oxygen radicals mainly in microglia and macrophages. With increasing age of the patients and disease progression, oxidative injury is further amplified by additional mechanisms including central nervous system damage related microglia activation, progressive mitochondrial damage, and age-dependent iron accumulation within the human central nervous system. The inflammatory mechanisms associated with lesion formation in MS are to a large extent reflected in experimental models of inflammatory demyelination, such as autoimmune encephalomyelitis. This is not the case for the amplification mechanisms of oxidative injury, which mainly operate in the progressive stage of the disease. © 2014 Wiley Periodicals, Inc.

Zellner M.,Medical University of Vienna
Acta neuropathologica communications | Year: 2014

Peripheral biomarkers play an indispensable role in quick and reliable diagnoses of any kind of disease. With the population ageing, the number of people suffering from age-related diseases is expected to rise dramatically over the coming decades. In particular, all types of cognitive deficits, such as Alzheimer's disease, will increase. Alzheimer's disease is characterised mainly by coexistence of amyloid plaques and neurofibrillary tangles in brain. Reliable identification of such molecular characteristics antemortem, however, is problematic due to restricted availability of appropriate sample material and definitive diagnosis is only possible postmortem. Currently, the best molecular biomarkers available for antemortem diagnosis originate from cerebrospinal fluid. Though, this is not convenient for routine diagnosis because of the required invasive lumbar puncture. As a consequence, there is a growing demand for additional peripheral biomarkers in a more readily accessible sample material. Blood platelets, due to shared biochemical properties with neurons, can constitute an attractive alternative as discussed here. This review summarises potential platelet Alzheimer's disease biomarkers, their role, implication, and alteration in the disease. For easy comparison of their performance, the Hedge effect size was calculated whenever data were available.

Niessner A.,Medical University of Vienna | Niessner A.,Emory University | Weyand C.M.,Emory University
Clinical Immunology | Year: 2010

Atherosclerosis has been considered a syndrome of dysregulated lipid storage until recent evidence has emphasized the critical contribution of the immune system. Dendritic cells (DC) are positioned at the interface of the innate and adaptive immune system. Recognition of danger signals in atheromas leads to DC activation. Activated DC regulate effector T cells which can kill plaque-resident cells and damage the plaque structure. Two types of DC have been identified in atherosclerotic lesions; classical myeloid DC (mDC) which mainly recognize bacterial signatures and plasmacytoid DC (pDC) which specialize in sensing viral fragments and have the unique potential of producing large amounts of type I interferon (IFN). In human atheromas, type I IFN upregulates expression of the cytotoxic molecule TRAIL which leads to apoptosis of plaque-resident cells. This review will elucidate the role of DC in atherogenesis and particularly in plaque rupture, the underlying pathophysiologic cause of myocardial infarction. © 2009 Elsevier Inc. All rights reserved.

Kyrle P.A.,Medical University of Vienna | Eichinger S.,Karl Landsteiner Institute of Thrombosis Research
Thrombosis and Haemostasis | Year: 2012

Venous thromboembolism (VTE) is a common and chronic disease with a considerable risk of recurrence. Patients with unprovoked (in the absence of a transient risk factor) VTE have a recurrence risk as high as 30% within five years after cessation of anticoagulation. Depending on patient selection the case-fatality rate of recurrence ranges between 3.6%-10%. Thus, indefinite anticoagulation treatment should be considered in these patients. However, anticoagulation confers a considerable risk of bleeding (fatal bleedings 0.1%-0.5%/year). It is therefore of utmost clinical importance to identify those patients, who will not benefit from indefinite anticoagulation, i.e. patients, in whom the bleeding risk during anticoagulant treatment is higher than the risk of recurrence. Several attempts to discriminate patients with a high from those with a low risk of recurrence including screening for acquired and inherited thrombotic risk factors or measurement of coagulation activation markers have either failed (thrombophilia screening) or were of moderate success (stratification according to D-dimer only). A novel approach for assessing risk of recurrent VTE consists of linking clinical patient characteristics with laboratory testing. Several such scoring models which can be used to assess the risk of recurrent VTE have been developed and await prospective validation before they can be applied in daily routine care. The aim of this report is to describe currently available scoring systems in more detail. © Schattauer 2012.

Kasper S.,Medical University of Vienna
International Journal of Psychiatry in Clinical Practice | Year: 2013

Objective. Silexan is a lavender oil preparation in gelatine capsules containing 80 mg. We reviewed the clinical trials investigating the anxiolytic efficacy and tolerability of Silexan as well as its safety and potential for drug interactions. Methods. Seven trials were included, among which four therapeutic trials had a treatment duration of 6 or 10 weeks. Results. In patients with subsyndromal anxiety or generalised anxiety disorder (GAD) an anxiolytic effect of Silexan was evident after 2 weeks. Patients treated with Silexan showed Hamilton Anxiety Scale (HAMA) total score decreases between 10.4 ± 7.1 and 12.0 ± 7.2 points at Week 6 and between 11.8 ± 7.7 and 16.0 ± 8.3 points at Week 10. Conclusions. HAMA total score reductions between baseline and end of treatment were significantly superior to placebo in patients with subsyndromal anxiety and comparable to lorazepam in its starting dose in patients with GAD. Silexan had beneficial effects on typical co-morbidity symptoms of anxiety disorders, for example, disturbed sleep, somatic complaints, or decreased quality of life. Except for mild gastrointestinal symptoms, the drug was devoid of adverse effects and did not cause drug interactions or withdrawal symptoms at daily doses of 80 or 160 mg. © 2013 Informa Healthcare.

Hassl A.R.,Medical University of Vienna
Wiener Klinische Wochenschrift | Year: 2010

Numerous specimens of the native, intestinal digenean fluke Pleurogenoides sp. (Lecithodendriidae, Plagiorchiida), a genus known for the simultaneous co-existence of genuine adults and progenetic, adult-like metacercaria, were found by chance parasitizing in the oesophagus of a recently imported, tropical Bristly Bush Viper (Atheris hispida). The snake had before been force-fed with native water frogs, the assumed definitive host of these flukes. Hence water frogs act as the second intermediate host or as a paratenic host for Pleurogenoides flukes, as they must house progenetic fluke larvae, which develop to genuine adults when transmitted to an appropriate consecutive host, the ancestral definitive host, a reptile. The European Pleurogenoides fluke species seem to display a facultative life-cycle diversification, they can adjust their life-history strategy according to their immediate transmission opportunities. This phenotypic plasticity allows the parasite to respond quickly to any changes in the abundance of a host; usually this biological oddity results in a life-cycle truncation by the elimination of the definitive host. © 2010 Springer-Verlag.

Cosyns B.,UZ Brussel | Droogmans S.,UZ Brussel | Rosenhek R.,Medical University of Vienna | Lancellotti P.,University of Liege
Heart | Year: 2013

Drug-induced valvular heart disease (DIVHD) was first described in the 1960s. Initially, associations with ergot derivatives used for migraine prevention, or with anorectic drugs, were described. Drugs used for the treatment of Parkinson's disease and endocrine diseases, like hyperprolactinemia, may also induce VHD. More recently, the use of 3,4-methylendioxymetamphetamine (MDMA, ' Ecstasy') and benfluorexhave been found to be associated with DIVHD. Although some of these drugs were withdrawn from the market, several cases of patients requiring valve surgery even years after the cessation of therapy have been reported. DIVHD is not infrequent, may be severe, and has been described in association with several drugs. Even after drug cessation, long-term implications of this type of VHD may persist. The present review underlines the need for a careful evaluation of the associated clinical and echocardiographic risk factors to allow early recognition so as not to delay appropriate management.

Huppa J.B.,Medical University of Vienna | Davis M.M.,Stanford University | Davis M.M.,Howard Hughes Medical Institute
Advances in Immunology | Year: 2013

The recognition of peptide/MHC antigens by T-cells has continued to challenge the imagination of immunologists, biochemists, and cell biologists alike. This is at least in part because T-cell recognition connects a diversity of issues and transcends many scientific disciplines. A fundamental unsolved issue is how T-cells manage to detect even a single molecule of an agonist pMHC complex, which is vastly outnumbered by endogenous pMHCs, many of which involve the same MHC molecule. They do so although TCRs are cross-reactive and typically low in affinity when measured in isolation. Importantly, T-cell antigen recognition takes place within the contact zone between a T-cell and the antigen-presenting cell, termed the immunological synapse. This bimembrane structure sets the stage for the antigen-binding events and all subsequent molecular recognition events. There is increasing evidence that the molecular dynamics of receptor-ligand interactions are not only dependent on the intrinsic properties of the binding partners but also become transformed by cell biological parameters such as the geometrical constraints within the immune synapse, mechanical forces, and local molecular crowding. To appreciate the complete picture, we think a multidisciplinary approach is imperative, which includes genetics, biochemistry, and structure determination and also biophysical analyses and the latest molecular imaging techniques. Here, we review earlier pioneering work and also recent developments in the fascinating and interdisciplinary science of T-cell antigen recognition. In many ways, this work may present a useful "roadmap" for work in other systems of cell-cell recognition, which underlie many fundamental biological phenomenons of interest. © 2013 Elsevier Inc.

Hiesmayr M.,Medical University of Vienna
Current Opinion in Clinical Nutrition and Metabolic Care | Year: 2012

Purpose of review: Nutrition risk assessment is of great importance to identify patients who may benefit from nutritional intervention to prevent ICU starvation and avoid side-effects of nutrition care. The full spectrum of nutrition risk assessment in ICU has not been defined in guidelines. Recent findings: Many patients are admitted to ICUs with nutritional deficits related to acute and chronic disease. The vast majority of patients who cannot resume sufficient oral feeding within a few days will lose body cell mass due to the severe and prolonged inflammatory process and insufficient nutrient intake. All patients staying longer than 1-2 days in the ICU need nutrition support, close monitoring and risk assessment. Risk assessment has to be constantly maintained throughout the ICU stay to manage properly risks associated with critical illness and nutrition care. Many patients are at risk to develop a refeeding syndrome, to experience serious motility disorders and finally dysphagia after extubation. The dramatic consequences of intra-abdominal hypertension may be decreased by early detection and treatment. There is a close interaction between evolution of critical illness, the associated inflammatory reaction, ICU treatments and nutrition care. Summary: Safe and efficient nutrition care may only be obtained when gastrointestinal function and metabolic tolerance of nutrients are regularly assessed. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Hammer H.F.,Medical University of Graz | Hammer J.,Medical University of Vienna
Gastroenterology Clinics of North America | Year: 2012

This article will focus on the role of the colon in the pathogenesis of diarrhea in carbohydrate malabsorption or physiologically incomplete absorption of carbohydrates, and on the most common manifestation of carbohydrate malabsorption, lactose malabsorption. In addition, incomplete fructose absorption, the role of carbohydrate malabsorption in other malabsorptive diseases, and congenital defects that lead to malabsorption will be covered. The article concludes with a section on diagnostic tools to evaluate carbohydrate malabsorption. © 2012 Elsevier Inc.

Krennmair G.,Medical University of Vienna
The International journal of oral & maxillofacial implants | Year: 2011

Implant success, peri-implant conditions, and prosthodontic maintenance requirements were evaluated and compared for mandibular overdentures supported by two implants and retained with ball or resilient telescopic crown attachments during a 5-year period. Twenty-five patients with an edentulous mandible each received two root-form dental implants in the mandibular interforaminal (canine) region. The type of denture attachment was chosen randomly; 13 patients received ball attachments and 12 patients received resilient telescopic crowns. Implant success and peri-implant conditions (bone resorption, pocket depth, Plaque Index, Gingival Index, Bleeding Index) as well as prosthodontic maintenance and patient satisfaction were evaluated annually during a 5-year follow-up period and compared with respect to the two retention modalities used. Implant success, peri-implant conditions, and subjective patient satisfaction scores did not differ between the two retention modalities used. However, during the 5-year observation period, significantly more postinsertion complications/interventions for maintenance purposes were registered in the ball group (87 interventions, 61.1%) than in the telescopic crown group (53 interventions, 37.9%; P < .01). Differences in prosthodontic maintenance efforts were most significant in the second and third years (P < .05) of the follow-up period but were similar at the end of the study for both anchorage systems. Both ball attachments and resilient telescopic crowns on isolated implants in the atrophic mandible are viable treatment options for implant-supported overdentures. No implant losses, good peri-implant conditions, and general patient satisfaction were noted. Although the frequency of technical complications was initially higher with ball attachments than with resilient telescopic crowns over a 5-year period, similar frequencies of maintenance efforts may be anticipated for both retention modalities.

Peichl P.,Evangelisches Krankenhaus | Holzer L.A.,Evangelisches Krankenhaus | Maier R.,Thermenklinikum Baden | Holzer G.,Medical University of Vienna
Journal of Bone and Joint Surgery - Series A | Year: 2011

Background: Parathyroid hormone (PTH) has been shown to increase bone mineral density and to reduce the rate of fractures in patients with osteoporosis and also to improve fracture-healing. The purpose of the present prospective, randomized, controlled study was to evaluate the effect of PTH 1-84 on the course of pelvic fracture-healing and functional outcome in postmenopausal women. Methods: Sixty-five patients had a dual x-ray absorptiometry scan, radiographs, and a computed tomography scan to document pelvic fractures. Twenty-one patients received a once-daily injection of 100 mg of PTH 1-84 starting within two days after admission to the hospital, and forty-four patients served as the control group. All patients received 1000 mg of calcium and 800 IU of vitamin D. Computed tomography scans were repeated every fourth week until radiographic evidence of cortical bridging at the fracture site was confirmed. Functional outcome was assessed with use of a visual analog scale for pain and a Timed "Up and Go" test. Results: The mean time to fracture healing was 7.8 weeks for the treatment group, compared with 12.6 weeks for the control group (p < 0.001). At eight weeks, all fractures in the treatment group were healed and four fractures in the control group were healed (healing rate, 100% compared with 9.1%; p < 0.001). Both the visual analog scale score for pain and the result of the Timed "Up and Go" test improved in the study group as compared with the control group (p < 0.001). Conclusions: In elderly patients with osteoporosis, PTH 1-84 accelerates fracture-healing in pelvic fractures and improves functional outcome. Level of Evidence: Therapeutic Level II. See Instructions to Authors for a complete description of levels of evidence. Copyright © 2011 by The Journal of Bone and Joint Surgery, Incorporated.

Reinisch W.,Medical University of Vienna | Staun M.,Copenhagen University | Bhandari S.,Hull and East Yorkshire Hospitals NHS Trust | Munoz M.,University of Malaga
Journal of Crohn's and Colitis | Year: 2013

Iron deficiency anemia (IDA) frequently occurs in patients suffering from inflammatory bowel disease (IBD) and negatively impacts their quality of life. Nevertheless, the condition appears to be both under-diagnosed and undertreated. Regular biochemical screening of patients with IBD for anemia by the gastroenterology community has to be advocated. Oral iron is a low cost treatment however its effectiveness is limited by low bioavailability and poor tolerability. Intravenous (IV) iron rapidly replenishes iron stores and has demonstrated its safe use in a number of studies in various therapeutic areas. A broad spectrum of new IV iron formulations is now becoming available offering improved tolerability and patient convenience by rapidly restoring the depleted iron status of patients with IBD. The following article aims to review the magnitude of the problem of IDA in IBD, suggest screening standards and highlight existing and future therapies. © 2012.

Rink M.,University of Hamburg | Babjuk M.,Charles University | Catto J.W.F.,University of Sheffield | Jichlinski P.,University of Lausanne | And 5 more authors.
European Urology | Year: 2013

Context Controversy exists regarding the therapeutic benefit and cost effectiveness of photodynamic diagnosis (PDD) with 5-aminolevulinic acid (5-ALA) or hexyl aminolevulinate (HAL) in addition to white-light cystoscopy (WLC) in the management of non-muscle-invasive bladder cancer (NMIBC). Objective To systematically evaluate evidence regarding the therapeutic benefits and economic considerations of PDD in NMIBC detection and treatment. Evidence acquisition We performed a critical review of PubMed/Medline, Embase, and the Cochrane Library in October 2012 according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement. Identified reports were reviewed according to the Consolidated Standards of Reporting Trials (CONSORT) and Standards for the Reporting of Diagnostic Accuracy Studies (STARD) criteria. Forty-four publications were selected for inclusion in this analysis. Evidence synthesis Included reports used 5-ALA (in 26 studies), HAL (15 studies), or both (three studies) as photosensitising agents. PDD increased the detection of both papillary tumours (by 7-29%) and flat carcinoma in situ (CIS; by 25-30%) and reduced the rate of residual tumours after transurethral resection of bladder tumour (TURBT; by an average of 20%) compared to WLC alone. Superior recurrence-free survival (RFS) rates and prolonged RFS intervals were reported for PDD, compared to WLC in most studies. PDD did not appear to reduce disease progression. Our findings are limited by tumour heterogeneity and a lack of NMIBC risk stratification in many reports or adjustment for intravesical therapy use in most studies. Although cost effectiveness has been demonstrated for 5-ALA, it has not been studied for HAL. Conclusions Moderately strong evidence exists that PDD improves tumour detection and reduces residual disease after TURBT compared with WLC. This has been shown to improve RFS but not progression to more advanced disease. Further work to evaluate cost effectiveness of PDD is required. © 2013 European Association of Urology.

Stanek G.,Medical University of Vienna | Wormser G.P.,New York Medical College | Gray J.,University College Dublin | Strle F.,University of Ljubljana
The Lancet | Year: 2012

Lyme borreliosis (Lyme disease) is caused by spirochaetes of the Borrelia burgdorferi sensu lato species complex, which are transmitted by ticks. The most common clinical manifestation is erythema migrans, which eventually resolves, even without antibiotic treatment. However, the infecting pathogen can spread to other tissues and organs, causing more severe manifestations that can involve a patient's skin, nervous system, joints, or heart. The incidence of this disease is increasing in many countries. Laboratory evidence of infection, mainly serology, is essential for diagnosis, except in the case of typical erythema migrans. Diagnosed cases are usually treated with antibiotics for 2-4 weeks and most patients make an uneventful recovery. No convincing evidence exists to support the use of antibiotics for longer than 4 weeks, or for the persistence of spirochaetes in adequately treated patients. Prevention is mainly accomplished by protecting against tick bites. There is no vaccine available for human beings. © 2012 Elsevier Ltd.

Marberger M.,Medical University of Vienna
Advances in Therapy | Year: 2013

With the high prevalence of bothersome lower urinary tract symptoms (LUTS) in older men, clinical management has to be fairly simple and straightforward. In the absence of severe problems requiring immediate action, and after excluding possible other etiological factors by a simple diagnostic algorithm, the key parameter for therapeutic decisions is the severity of LUTS, in particular the degree of annoyance and irritation, and prostatic enlargement. Patients with bothersome LUTS request rapid improvement but also worry about possible deterioration, complications, and the need for surgery. With a prostate volume above 30-40 mL and/or prostate-specific antigen (PSA) serum >1.5 ng/mL, the combination of an alpha-1 blocker with a 5-alpha-reductase inhibitor (5-ARI) should be first-line treatment. With prostates <30 mL at baseline the issue whether the prostate really is the culprit becomes central. Given the rapid onset of action of alpha-1 blockers, a 4-6-week trial appears to be a logical approach. If the International Prostate Symptom Score does not improve and storage symptoms prevail, an overactive bladder appears more likely as causative factor and antimuscarinics are the next step. Based on available data this is recommended as add-on medication to the alpha-1 blocker. With no improvement, or increasing postvoid residual the diagnostic algorithm needs to be revisited and more extensive urodynamic evaluation may be needed. © 2013 The Author.

Witte M.E.,VU University Amsterdam | Mahad D.J.,University of Edinburgh | Lassmann H.,Medical University of Vienna | van Horssen J.,VU University Amsterdam
Trends in Molecular Medicine | Year: 2014

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Current treatments are very effective in reducing the neuroinflammatory attack, but fail to significantly halt disease progression and associated loss of neuronal tissue. In recent years, it has become increasingly clear that dysfunctional mitochondria are important contributors to damage and loss of both axons and neurons. Observations in animal and histopathological studies suggest that infiltrating leukocytes and activated microglia play a central role in neuronal mitochondrial dysfunction. This review provides a comprehensive overview on the current knowledge regarding mitochondrial dysfunction in MS. Importantly, more insight into the cause and consequences of impaired mitochondrial function provide a basis for mitochondrial-targeted medicine to combat progressive MS. © 2013 Elsevier Ltd.

Holzer M.,Medical University of Vienna
New England Journal of Medicine | Year: 2010

A 62-year-old man collapses on the street, and emergency medical personnel who are called to the scene find that he is not breathing and that he has no pulse. The first recorded cardiac rhythm is ventricular fibrillation. Advanced cardiac life-support measures, including intubation, a total dose of 2 mg of epinephrine, and six defibrillation attempts, restore spontaneous circulation 22 minutes after the onset of the event. On admission to the emergency department, his condition is hemodynamically stable and he has adequate oxygenation and ventilation, but he is still comatose. A neurologic examination reveals reactive pupils and a positive cough reflex. The core body temperature is 35.5°C. A diagnosis of the post-cardiac arrest syndrome with coma is made. An intensive care specialist evaluates the patient and recommends the immediate initiation of targeted temperature management. Copyright © 2010 Massachusetts Medical Society.

The males of Ischiomysis gen. nov. are unique among the currently known genera of the order Mysida by peculiar modifications of the ischium and praeischium of the eighth thoracic endopod. The type species, I. telmatactiphila sp. nov., forms compact aggregations above the oral disc of the club-tipped sea anemone Telmatactis cricoides from the island of São Tomé in the Gulf of Guinea. Less compact aggregations are formed by I. peterwirtzi sp. nov. from the island of São Vicente in the Cape Verde archipelago. Such looser aggregations were found in marine (micro)caves, wherein they extended over the anemones and adjacent rock recesses. An undetermined, visually similar mysid with similar distribution above the oral disc is documented by a colour photograph from Trindade, a small oceanic island in the tropical south-west Atlantic. Potential morphological relationships between the new genus and certain species of Heteromysis from the Caribbean and the Indian Ocean are discussed. © 2013 Koninklijke Brill NV, Leiden.

Gaujoux-Viala C.,University of Nimes | Nam J.,University of Leeds | Nam J.,NIHR Leeds Musculoskeletal Biomedical Research Unit | Ramiro S.,University of Amsterdam | And 5 more authors.
Annals of the Rheumatic Diseases | Year: 2014

Objectives To update a previous systematic review assessing the efficacy of conventional synthetic diseasemodifying antirheumatic drugs (csDMARDs) in rheumatoid arthritis (RA). Methods Two systematic reviews of the literature using PubMed, Embase and the Cochrane library were performed from 2009 until January 2013 to assess the efficacy of csDMARDs (as monotherapy or combination therapy) in adults with RA, and the efficacy of glucocorticoids in early RA. A third systematic review was performed until March 2013 to assess the efficacy of tofacitinib by meta-analysis. Results For glucocorticoids, of 222 hits, five publications relating to four new trials were analysed for efficacy, confirming that initial treatment of RA with lowdose prednisone plus methotrexate (MTX) results in better clinical and structural outcomes at 1 and 2 years than treatment with MTX alone. For csDMARDs, of 498 studies, only two new studies were randomised controlled trials comparing MTX monotherapy with MTX in combination with another csDMARD without differences in glucocorticoid usage. Using tight control principles, clinical outcomes were no better with immediate triple therapy than with 'step-up' therapy. For tofacitinib, the pooled analysis of 10 trials showed that tofacitinib was more efficacious on signs and symptoms, disability and appeared to be more efficacious on structural damage than control treatment with placebo (OR (95% CI) - American College of Rheumatology 20% (ACR20) response: 2.44 (1.97 to 3.02)) or treatment with MTX (ACR20 response: 2.38 (1.66 to 3.43)). Conclusions Addition of low-dose glucocorticoids to csDMARD therapy produces benefits in early RA. Under tight control conditions, combination therapy with csDMARDs is no better than MTX monotherapy. Tofacitinib is a new DMARD with proven efficacy.

Smolen J.S.,Medical University of Vienna
Clinical and Experimental Rheumatology | Year: 2012

Treatment to a target level of a variable known to be associated with bad disease outcome is a concept that has been applied for many years in several specialties. In rheumatology this has not been the case, primarily because of the complexity of measures assessing disease activity of RA and insufficient knowledge of optimal strategies. Meanhwile, however, our insights into the devastating role of active disease have expanded. In parallel, the use of composite measures of disease activity to control patients tightly and adapt therapy accordingly has provided the evidence that treating RA to a target value of low disease activity or remission conveys significant benefit. The background of the treat-to-target concept and future aspects are discussed. © Copyright Clinical and Experimental Rheumatology 2012.

Lang I.M.,Medical University of Vienna | Benza R.,Allegheny General Hospital
European Heart Journal | Year: 2012

As can be seen by the mounting literature, there has been immense progress in the field of pulmonary hypertension (PH) over the last three decades, illustrated by several important milestones including improved understanding of disease pathogenesis, new classifications of disease, advances in screening and diagnostic techniques, and new rules for staging and follow-up, which have subsequently led to improvements in patient outcomes. The objectives of this manuscript are to not only highlight these very recent advances but also point out areas of deficiencies or gaps in our knowledge that may serve a focal point for future discussion and investigation. © 2011 The Author.

Preusser M.,Medical University of Vienna | Lim M.,Johns Hopkins University | Hafler D.A.,Yale University | Reardon D.A.,Dana-Farber Cancer Institute | Sampson J.H.,Duke University
Nature Reviews Neurology | Year: 2015

Glioblastoma is the most common primary brain tumour in adults. Prognosis is poor: even with the current gold-standard first-line treatment - maximal safe resection and combination of radiotherapy with temozolomide chemotherapy - the median overall survival time is only approximately 15-17 months, because the tumour recurs in virtually all patients, and no commonly accepted standard treatment for recurrent disease exists. Several targeted agents have failed to improve patient outcomes in glioblastoma. Immunotherapy with immune checkpoint inhibitors such as ipilimumab, nivolumab, and pembrolizumab has provided relevant clinical improvements in other advanced tumours for which conventional therapies have had limited success, making immunotherapy an appealing strategy in glioblastoma. This Review summarizes current knowledge on immune checkpoint modulators and evaluates their potential role in glioblastoma on the basis of preclinical studies and emerging clinical data. Furthermore, we discuss challenges that need to be considered in the clinical development of drugs that target immune checkpoint pathways in glioblastoma, such as specific properties of the immune system in the CNS, issues with radiological response assessment, and potential interactions with established and emerging treatment strategies. © 2015 Macmillan Publishers Limited.

Hadjipanayis C.G.,Mount Sinai School of Medicine | Hadjipanayis C.G.,Phillips Ambulatory Care Center | Widhalm G.,Medical University of Vienna | Stummer W.,University of Munster
Neurosurgery | Year: 2015

The current neurosurgical goal for patients with malignant gliomas is maximal safe resection of the contrast-enhancing tumor. However, a complete resection of the contrast-enhancing tumor is achieved only in a minority of patients. One reason for this limitation is the difficulty in distinguishing viable tumor from normal adjacent brain during surgery at the tumor margin using conventional white-light microscopy. To overcome this limitation, fluorescence-guided surgery (FGS) using 5-aminolevulinic acid (5-ALA) has been introduced in the treatment of malignant gliomas. FGS permits the intraoperative visualization of malignant glioma tissue and supports the neurosurgeon with real-time guidance for differentiating tumor from normal brain that is independent of neuronavigation and brain shift. Tissue fluorescence after oral administration of 5-ALA is associated with unprecedented high sensitivity, specificity, and positive predictive values for identifying malignant glioma tumor tissue. 5-ALA-induced tumor fluorescence in diffusely infiltrating gliomas with non-significant magnetic resonance imaging contrast-enhancement permits intraoperative identification of anaplastic foci and establishment of an accurate histopathological diagnosis for proper adjuvant treatment. 5-ALA FGS has enabled surgeons to achieve a significantly higher rate of complete resections of malignant gliomas in comparison with conventional white-light resections. Consequently, 5-ALA FGS has become an indispensable surgical technique and standard of care at many neurosurgical departments around the world. We conducted an extensive literature review concerning the surgical benefit of using 5-ALA for FGS of malignant gliomas. According to the literature, there are a number of reasons for the neurosurgeon to perform 5-ALA FGS, which will be discussed in detail in the current review. © 2015 by the Congress of Neurological Surgeons.

Birbach A.,Medical University of Vienna
PLoS ONE | Year: 2013

Transgene expression from short promoters in transgenic animals can lead to unwanted transgene expression patterns, often as a byproduct of random integration of the expression cassette into the host genome. Here I demonstrate that the often used PB-Cre4 line (also referred to as "Probasin-Cre"), although expressing exclusively in the male prostate epithelium when transmitted through male mice, can lead to recombination of loxP-flanked alleles in a large variety of tissues when transmitted through female mice. This aberrant Cre activity due to Cre expression in the oocytes leads to different outcomes for maternally or paternally transmitted loxP-flanked alleles: Maternally inherited loxP-flanked alleles undergo recombination very efficiently, making female PB-Cre4 mice an efficient monoallelic "Cre deleter line". However, paternally inherited loxP-flanked alleles are inefficiently recombined by maternal PB-Cre4, giving rise to mosaic expression patterns in the offspring. This mosaic recombination is difficult to detect with standard genotyping approaches of many mouse lines and should therefore caution researchers using PB-Cre4 to use additional approaches to exclude the presence of recombined alleles. However, mosaic recombination should also be useful in transgenic "knockout" approaches for mosaic gene deletion experiments. © 2013 Andreas Birbach.

Carbone D.P.,Ohio State University | Gandara D.R.,University of California at Davis | Antonia S.J.,H. Lee Moffitt Cancer Center and Research Institute | Zielinski C.,Medical University of Vienna | Paz-Ares L.,Institute Biomedicina Of Seville
Journal of Thoracic Oncology | Year: 2015

As the leading cause of cancer death worldwide, lung cancer continues to impose a major burden on healthcare systems and cause significant challenges for clinicians and patients. Most patients present with advanced disease at the time of diagnosis and have a poor prognosis, with the vast majority surviving less than 5 years. Although new therapies have been introduced in recent years that target molecular disease drivers present in a subset of patients, there is a significant need for treatments able to improve response and extend survival while minimizing effects on quality of life. Recent evidence of clinical efficacy for immunotherapeutic approaches for lung cancer suggests that they will become the next major therapeutic advance for this disease. Non-small-cell lung cancer, which accounts for approximately 85% of lung cancer cases, has historically been considered a nonimmunogenic disease; however, as with several other malignancies, recent data show that much of this lack of immune responsiveness is functional rather than structural (i.e., possible to overcome therapeutically). This review explores the key elements of the immune system involved in non-small-cell lung cancer and briefly examines immunotherapeutic strategies in development to shift the balance of immune activity away from a tumor-induced immune-suppressive state toward an active antitumor immune response. © 2015 by the International Association for the Study of Lung Cancer.

Harrison C.,Guys and St Thomas NHS Foundation Trust | Kiladjian J.-J.,University Paris Diderot | Al-Ali H.K.,University of Leipzig | Gisslinger H.,Medical University of Vienna | And 10 more authors.
New England Journal of Medicine | Year: 2012

BACKGROUND: Treatment options for myelofibrosis are limited. We evaluated the efficacy and safety of ruxolitinib, a potent and selective Janus kinase (JAK) 1 and 2 inhibitor, as compared with the best available therapy, in patients with myelofibrosis. METHODS: We assigned 219 patients with intermediate-2 or high-risk primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis to receive oral ruxolitinib or the best available therapy. The primary end point and key secondary end point of the study were the percentage of patients with at least a 35% reduction in spleen volume at week 48 and at week 24, respectively, as assessed with the use of magnetic resonance imaging or computed tomography. RESULTS: A total of 28% of the patients in the ruxolitinib group had at least a 35% reduction in spleen volume at week 48, as compared with 0% in the group receiving the best available therapy (P<0.001); the corresponding percentages at week 24 were 32% and 0% (P<0.001). At 48 weeks, the mean palpable spleen length had decreased by 56% with ruxolitinib but had increased by 4% with the best available therapy. The median duration of response with ruxolitinib was not reached, with 80% of patients still having a response at a median follow-up of 12 months. Patients in the ruxolitinib group had an improvement in overall quality-of-life measures and a reduction in symptoms associated with myelofibrosis. The most common hematologic abnormalities of grade 3 or higher in either group were thrombocytopenia and anemia, which were managed with a dose reduction, interruption of treatment, or transfusion. One patient in each group discontinued treatment owing to thrombocytopenia, and none discontinued owing to anemia. Nonhematologic adverse events were rare and mostly grade 1 or 2. Two cases of acute myeloid leukemia were reported with the best available therapy. CONCLUSIONS: Continuous ruxolitinib therapy, as compared with the best available therapy, was associated with marked and durable reductions in splenomegaly and disease-related symptoms, improvements in role functioning and quality of life, and modest toxic effects. An influence on overall survival has not yet been shown. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT00934544.). Copyright © 2012 Massachusetts Medical Society.

Leitgeb R.A.,Medical University of Vienna
Advances in Imaging and Electron Physics | Year: 2011

Important developments and current topics in the field of Optical Coherence Tomography (OCT) are discussed. Cheaper light sources that combine large spectra, high power, and compact design will promote the commercialization and clinical acceptance. Forthcoming technical advancements might be enhancing penetration depth through combination with optoacoustics, increasing imaging speed through parallelization such as multispot illumination, developing novel exogenous contrast agents approved for clinical use. In addition, functional extensions such as PSOCT and DOCT are already close to being accepted as clinical diagnostic tools. Finally, the development of miniature delivery probes will be an important technological step toward in situ biopsy and intravascular application. exponential increase in OCT publication and patent output is expected in the near future, giving rise to exciting new technology, biomedical and industrial applications, and results in fundamental research.

Providing critical care to cancer patients requires a high degree of practical multidisciplinary teamwork between intensivists and cancer specialists. Intensivists should have a solid basic knowledge of malignant diseases as well as of the typical complications of the underlying illness and its therapies. Hemato-oncologists should evaluate the transfer of these patients to the intensive care unit early in the course of emerging organ dysfunctions. Both parties should have a realistic impression of the short-term intensive care and long-term oncologic options and perspectives of the respective patient. Good cooperation between intensivists and cancer specialists is the basis for meaningful decisions on admission, planning of individual therapeutic aims, successful patient management, and tailored therapy, with a smooth transition into a palliative care setting whenever appropriate. © 2013 Springer-Verlag Berlin Heidelberg.

Whittle N.,University of Innsbruck | Hauschild M.,University of Innsbruck | Lubec G.,Medical University of Vienna | Holmes A.,U.S. National Institutes of Health | Singewald N.,University of Innsbruck
Journal of Neuroscience | Year: 2010

Fear extinction is impaired in neuropsychiatric disorders, including posttraumatic stress disorder. Identifying drugs that facilitate fear extinction in animal models provides leads for novel pharmacological treatments for these disorders. Zinc (Zn) is expressed in neurons in a cortico-amygdala circuit mediating fear extinction, and modulates neurotransmitter systems regulating extinction. We previously found that the 129S1/SvImJ mouse strain (S1) exhibited a profound impairment in fear extinction, coupled with abnormalities in the activation of the extinction circuit. Here, we tested the role of Zn in fear extinction in S1 and C57BL/6N reference strain (B6) by feeding the mice a Zn-restricted diet (ZnR) and testing for fear extinction, as well as neuronal activation of the extinction circuit via quantification of the immediate-early genes c-Fos and Zif268. Results showed that (preconditioning or postconditioning) ZnR completely rescued deficient extinction learning and long-term extinction retrieval in S1 and expedited extinction learning in B6, without affecting fear acquisition or fear expression. The extinction- facilitating effects of ZnR were associated with the normalization of Zif268 and/or c-Fos expression in cortico-amygdala regions of S1. Specifically, ZnR increased activity in infralimbic cortex, lateral and basolateral amygdala nuclei, and lateral central amygdala nucleus, and decreased activity in prelimbic and insular cortices and medial central amygdala nucleus. ZnR also increased activation in the main intercalated nucleus and decreased activation of the medial paracapsular intercalated mass in S1. Our findings reveal a novel role for Zn in fear extinction and further support the utility of the S1 model for identifying extinction facilitating drugs. Copyright © 2010 the authors.

Schmid M.P.,Medical University of Vienna
Strahlentherapie und Onkologie : Organ der Deutschen Röntgengesellschaft ... [et al] | Year: 2013

Grey zones, which are defined as tissue with intermediate signal intensity in the area of primary hyperintense tumour extension, can be seen during radiation with or without chemotherapy on the T2-weighted MRI in patients with cervical cancer. The purpose of this study was to systematically measure the tumour volume at the time of diagnosis and the residual tumour volume at the time of brachytherapy without and with consideration of the grey zones and to estimate tumour regression during external beam radiotherapy (EBRT). T2-weighted MRI datasets of 175 patients with locally advanced cervical cancer (FIGO stage IB-IVA), who underwent combined external beam radiotherapy and brachytherapy with or without concomitant chemotherapy were available for this study. The gross tumour volume at the time of diagnosis (GTV(init)) and at the time of first brachytherapy without (GTV(res)) and with (GTV(res)+ GZ) consideration of grey zones were measured for each patient. A descriptive statistical analysis was performed and tumour regression rates without (R) and with consideration of grey zones (R(GZ)) were calculated. Further, the role of prognostic factors on GTV(init), GTV(res), GTV(res)+ GZ and tumour regression rates was investigated. The median GTV(init), GTV(res), GTV(res)+ GZ in all patients were 44.4 cm(3), 8.2 cm(3), 20.3 cm(3), respectively. The median R was 78.5% and the median R(GZ) was 50.1%. The histology and FIGO staging showed a significant impact on GTV(init), GTV(res) and GTV(res)+ GZ. Grey zones represent a substantial proportion of the residual tumour volume at the time of brachytherapy. Differentiation of high signal intensity mass and surrounding intermediate signal intensity grey zones may be reasonable.

Reinisch W.,Medical University of Vienna | Wang Y.,Schering | Oddens B.J.,Merck And Co. | Link R.,Biologics
Alimentary Pharmacology and Therapeutics | Year: 2012

Background Secondary loss of response to anti-TNF-α therapy is observed in Crohn's disease patients. Aim Serum C-reactive protein (CRP) levels at baseline and after infliximab induction therapy at week 14 were assessed as predictors for maintained response or remission through 54 weeks of treatment in patients with Crohn's disease who responded to induction therapy. Methods ACCENT I was a multicenter, randomised, placebo-controlled study. Patients who received infliximab induction (weeks 0, 2 and 6) and maintenance (5 or 10 mg/kg every 8 weeks beginning at week 14) therapy were considered. Patients in clinical response or remission to induction therapy at week 14 (n = 212 or n = 138 respectively) were analysed. Associations between CRP levels (cut-off points 0.5-3.0 mg/dL), baseline disease variables and maintained clinical response or remission during maintenance therapy were assessed. Results A significant association was observed between baseline CRP levels and maintained remission. Forty-five percent of patients with baseline CRP ≥ 0.7 mg/dL vs. 22.0% with CRP < 0.7 mg/dL maintained remission (P = 0.012). CRP normalisation during infliximab treatment (decrease from 0.5 mg/dL at baseline to < 0.5 mg/dL at week 14) resulted in higher probability of maintained response (P < 0.001) or remission (P = 0.052). At week 14 low CRP levels were associated with maintained response (56.6% of patients with CRP < 0.5 mg/dL vs. 37.2% with higher CRP, P = 0.005). No optimal predictive CRP cut-off point was observed. Conclusions High baseline CRP levels increased the likelihood of maintained remission. Normalised CRP levels at week 14 increased the likelihood of maintained response or remission during 1 year of infliximab maintenance therapy (Clinical trial: NCT00207662). © 2012 Blackwell Publishing Ltd.

Hoivik M.L.,University of Oslo | Reinisch W.,Medical University of Vienna | Cvancarova M.,University of Oslo | Moum B.,University of Oslo
Alimentary Pharmacology and Therapeutics | Year: 2014

Background The point prevalence estimates of anaemia in patients with inflammatory bowel disease (IBD) range between 6% and 74%. The variation is probably due to differences in the definition of anaemia and the study populations. Aim To retrospectively determine the prevalence of anaemia at diagnosis and at the 1-, 5-and 10-year follow-ups in patients with IBD from a prospectively followed, population-based inception cohort (the IBSEN Study). To compare the prevalence of anaemia after a 10-year disease course with the prevalence of anaemia in the background population, and to assess clinical factors associated with anaemia at diagnosis and during follow-up. Methods Newly diagnosed IBD patients were included in a population-based, prospective cohort. Follow-up was performed at 1, 5 and 10 years. All visits included clinical examinations and blood samples. Anaemia was defined according to the WHO. Results A total of 756 patients (UC, n = 519 and CD, n = 237) were included; 48.8% of CD and 20.2% of UC patients were anaemic at diagnosis (P < 0.001). The proportion of patients with anaemia decreased during the disease course in all patients, except in women with CD. After 10 years of disease, the relative risk for anaemia was increased in all groups, except for women with UC. The variables associated with anaemia were generally unchanged during the disease course, and elevated CRP was the strongest predictor of risk. Conclusions Anaemia was more common in CD than in UC. The prevalence of anaemia decreased during the disease course. Women with CD were at high risk for anaemia. Elevated CRP was independently associated with anaemia. © 2013 John Wiley & Sons Ltd.

Bublin M.,Medical University of Vienna
Advances in Food and Nutrition Research | Year: 2013

While kiwifruit has a high nutritive and health value' a small proportion of the world's population appears to be allergic to the fruit. IgE-mediated kiwifruit allergy is often associated with birch and grass pollinosis as well as with latex allergy. Isolated allergy to kiwifruit is also relatively common and often severe.Eleven green kiwifruit (Actinidia deliciosa cv. Hayward) allergens recognized to date are termed as Act d 1 through Act d 11. Bet v 1 homologue (Act d 8) and profilin (Act d 9) are important allergens in polysensitized subjects' whereas actinidin (Act d 1) is important in kiwifruit monosensitized subjects. Differences in allergenicity have been found among kiwifruit cultivars. Allergy sufferers might benefit from the selection and breeding of low-allergenic kiwifruit cultivars. © 2013 Elsevier Inc.

In the context of an increasing repertoire of multiple sclerosis (MS) therapeutics, choosing the appropriate treatment for an individual patient is becoming increasingly challenging. Natalizumab, a humanized monoclonal antibody directed against alpha4beta1 integrin, has proven short-term and long-term efficacies in terms of relapse rate reduction, prevention of disability progression, and reduction of magnetic resonance imaging-detectable activity. It is well tolerated and has further been shown to improve patients’ quality of life. Its use is limited by the risk of progressive multifocal leukoencephalopathy (PML), which occurs at an overall incidence of 3.78 cases per 1,000 patients. Three major risk factors for the occurrence of natalizumab-associated PML have been identified: John Cunningham virus (JCV) seropositivity, prior use of immunosuppressants, and treatment duration $2 years. Therefore, in patients considered for natalizumab therapy, as well as in patients receiving natalizumab, effective control of MS activity has to be balanced against the risk of an opportunistic central nervous system infection associated with a high risk of significant morbidity or death. Discontinuation of natalizumab is an issue in daily clinical practice, since it is an option to reduce the PML risk. However, after cessation of natalizumab therapy, currently, there is no approved strategy for avoiding postnatalizumab disease reactivation available. In this paper, short-term and long-term safety and efficacy data are reviewed. Issues in daily clinical practice, such as selection of patients, monitoring of patients, and natalizumab discontinuation, are discussed. © 2015 Kornek.

Ay C.,Medical University of Vienna
Thrombosis research | Year: 2010

There is a close interrelation between cancer and haemostasis, which is characterized by changes in the haemostatic system, mostly an activation of coagulation in cancer patients. Venous thromboembolism (VTE) is a frequent complication of cancer and in particular of anticancer therapy and is associated with significant morbidity and mortality. As the occurrence of VTE in cancer patients is a life-threatening condition, clinical parameters or laboratory tests predictive of VTE might be helpful for early identification of patients at high or low risk of VTE in order to allow a tailored therapy assessment. Recently, some candidate laboratory parameters or biomarkers, such as blood count, P-selectin, D-Dimer, prothrombin fragment 1+2, clotting factor VIII and tissue factor, have been identified as predictors of the VTE risk in cancer. Interventional trials based on risk assessment with the use of biomarkers or risk scoring models are needed to demonstrate effectiveness and safety of tailored thromboprophylaxis.

RATIONALE:: Mechanisms of coronary occlusion in ST-elevation acute coronary syndrome (STE-ACS) are poorly understood. We have previously reported that neutrophil (polymorphonuclear cells [PMNs]) accumulation in culprit lesion site (CLS) thrombus is a predictor of cardiovascular outcomes.OBJECTIVE:: The goal of the present study was to characterize PMN activation at the CLS. We examined the relationships between CLS neutrophil extracellular traps (NETs), bacterial components as triggers of NETosis, activity of endogenous deoxyribonuclease (DNase), ST-segment resolution (STR), and infarct size.METHODS AND RESULTS:: We analyzed coronary thrombectomies from 111 STE-ACS patients undergoing primary percutaneous coronary intervention. Thrombi were characterized by immunostaining, flow cytometry, bacterial profiling, immunometric and enzymatic assays.Compared to femoral PMNs, CLS PMNs were highly activated and formed aggregates with platelets. Nucleosomes, double-stranded DNA (dsDNA), neutrophil elastase, myeloperoxidase and myeloid-related protein 8/14 were increased in CLS plasma, and NETs contributed to the scaffolds of particulate coronary thrombi. Copy numbers of Streptococcus species correlated positively with amount of dsDNA. Thrombus NET burden correlated positively with infarct size and negatively with STR, while CLS DNase activity correlated negatively with infarct size and positively with STR. Recombinant DNase accelerated lysis of coronary thrombi ex vivo.CONCLUSIONS:: PMNs are highly activated in STE-ACS and undergo NETosis at the CLS. Coronary NET burden and DNase activity are predictors of STR and myocardial infarct size. © 2014 American Heart Association, Inc.

Kutalek R.,Medical University of Vienna
Wiener Klinische Wochenschrift | Year: 2012

Diversity in medicine is a concept that aims at improving the health care of patients and at enhancing health equity. Ethnic and racial disparities have been documented in many contexts, thus diversity competence is specifically relevant when regarding the health of migrants, ethnic minorities and other vulnerable groups. Diversity competence considers socio-economic factors in health care, as well as the influence of ethnic and cultural background on how health and illness are perceived. It should therefore be a core concern for all health practitioners and a central focus in any health institution. © 2012 Springer-Verlag Wien.

Wieser T.,Medical University of Vienna
European journal of pain (London, England) | Year: 2012

About 4% of the population suffer from daily or near daily headache, which in most cases evolved from an episodic type of headache. The impact of psychological factors on this process is unknown. It seems reasonable to assume, that besides somatic and social conditions psychological factors like pain-related coping and cognition play an important role, as has been shown for other pain conditions. We performed a cross sectional study on pain coping behaviour in 211 patients with migraine and tension type headache. Pain-related cognition and coping was investigated using the Kiel Pain Inventory. Prevalence of depression, medication intake and headache characteristics were analysed in regard to chronicity of headache. Overall pain intensity was high in the patient sample. The level of depression increased with headache frequency. Dysfunctional coping, characterized by fear and avoidance is frequently used by headache patients. As in low back pain, also endurance is highly prevalent. Other features known to be associated with chronic headache, like depression and medication overuse, could be confirmed. Dysfunctional coping was seen with high prevalence in the entire patient sample (66%). Against our hypothesis, it was not confined to chronic forms of headache. In respect to our data, we discuss the role of avoidance and endurance coping in headache and its possible role in chronicity. © 2011 European Federation of International Association for the Study of Pain Chapters.

Rees A.,Medical University of Vienna
Molecular Immunology | Year: 2015

Moh Daha has been instrumental for initiating and coordinating many European consortia in the area of immunopathogenesis of glomerulonephritis including a number with the author. This review provides a personal history of these developments, ending with INTRICATE, an FP7 medium scale project investigating ANCA-associated vasculitis (AAV). The current status of this research and recent insight in the autoimmune reactions and autoantigens in AAV are briefly summarized. © 2015.

BACKGROUND: Kidney function is an important aspect for patient outcome after heart transplantation (HTX). Acute kidney injury (AKI) is defined by changes in serum creatinine (SCr) and diuresis with risk/injury/failure/loss/end stage (RIFLE), acute kidney injury network (AKIN), or kidney disease: improving global outcomes (KDIGO) scores. METHODS: We investigated the effect of perioperative AKI on 1-year mortality after HTX over a period of 10 years at a single-center university hospital. Multivariable Cox proportional-hazards regression analyzed the association between 1-year mortality and potential risk factors. Receiver operating curves for 1-year mortality were calculated to determine sensitivity and specificity of scores. RESULTS: Sixty of 346 patients (17%) died within the first year. Acute kidney injury was a predictor of mortality only in the high-risk AKI groups of all scores: Hazard ratios (95% confidence interval) for RIFLE F: 7.164 (3.307-15.523); KDIGO/AKIN stage 3: 3.492 (2.006-6.081). Within each score, we identified patient groups, which had no elevated risk for an adverse outcome despite their allocation to the milder forms of AKI. In multivariable regression analysis, primary graft dysfunction was the predominant perioperative risk factor for 1-year mortality. CONCLUSIONS: In contrast to other patient cohorts, mild forms of perioperative AKI are of subordinate influence on patient outcome in HTX. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Knoebl P.,Medical University of Vienna
Wiener Medizinische Wochenschrift | Year: 2010

Host defense and blood coagulation are tightly connected and interacting systems, necessary for the integrity of an organism. Complex mechanisms regulate the intensity of a host response to invading pathogens or other potentially dangerous situations. Under regular conditions, this response is limited in time and located to the site of injury. Sometimes, however, systemic host response is overwhelming and disproportional and causes damage, not cure. Dependent on the genetical predisposition of the host, its current immunocompetence, or the type of injury, the reaction leads to the clinical picture of the different degrees of sepsis. Septic organ dysfunction is caused by intravascular fibrin deposition as a result of coagulation activation, anticoagulant breakdown, and shut down of fibrinolysis. This article describes the major pathophysiologic reactions in these situations and presents www.SepDIC.eu, an online tool on sepsis and associated coagulopathy.© Springer-Verlag 2010.

Bublin M.,Medical University of Vienna
Current allergy and asthma reports | Year: 2014

Peanut seeds are currently widely used as source of human food ingredients in the United States of America and in European countries due to their high quality protein and oil content. This article describes the classification and molecular biology of peanut seed allergens with particular reference to their cross-reactivities. Currently, the IUIS allergen nomenclature subcommittee accepts 12 peanut allergens. Two allergens belong to the cupin and four to the prolamin superfamily, and six are distributed among profilins, Bet v 1-like proteins, oleosins, and defensins. Clinical observations frequently report an association of peanut allergy with allergies to legumes, tree nuts, seeds, fruits and pollen. Molecular cross-reactivity has been described between members of the Bet v 1-like proteins, the non-specific lipid transfer proteins, and the profilins. This review also addresses the less well-studied cross-reactivity between cupin and prolamin allergens of peanuts and of other plant food sources and the recently discovered cross-reactivity between peanut allergens of unrelated protein families.

Kasper S.,Medical University of Vienna | Moller H.-J.,Ludwig Maximilians University of Munich | Hale A.,University of Kent
European Archives of Psychiatry and Clinical Neuroscience | Year: 2010

The objective of the European Post-marketing Observational Serdolect ® (EPOS) Study was to compare the safety of treatment with Serdolect (sertindole) with that of usual treatment in patients with schizophrenia, in normal European clinical practice. The EPOS was a multicentre, multinational, referenced, cohort study. Patients were enrolled at 226 centres in ten European countries. The study was prematurely terminated in 1998 as a result of the temporary market suspension of sertindole. Termination of the study reduced the number of patients recruited from the planned 12,000 to 2,321. While the power of the study was weakened, it did provide useful mortality information, which may be useful for future long-term studies. Crude mortality in the sertindole and non-sertindole groups was 1.45 (95% confidence interval, CI 0.53-3.16) and 1.50 (CI 0.72-2.76) deaths/100 patient-years exposed, respectively. There were no more cardiac deaths in the sertindole group than in the non-sertindole group. QT interval prolongation did not translate into an increased risk of death. Sertindole was well tolerated and caused few extrapyramidal symptoms. Although CIs remained large, this post-marketing study does not provide any evidence against the use of sertindole under normal conditions. Sertindole was well tolerated and posed no significant safety problems. © 2009 Springer-Verlag.

Horl W.H.,Medical University of Vienna
Pharmaceuticals | Year: 2010

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the isoenzymes COX-1 and COX-2 of cyclooxygenase (COX). Renal side effects (e.g., kidney function, fluid and urinary electrolyte excretion) vary with the extent of COX-2-COX-1 selectivity and the administered dose of these compounds. While young healthy subjects will rarely experience adverse renal effects with the use of NSAIDs, elderly patients and those with co-morbibity (e.g., congestive heart failure, liver cirrhosis or chronic kidney disease) and drug combinations (e.g., renin-angiotensin blockers, diuretics plus NSAIDs) may develop acute renal failure. This review summarizes our present knowledge how traditional NSAIDs and selective COX-2 inhibitors may affect the kidney under various experimental and clinical conditions, and how these drugs may influence renal inflammation, water transport, sodium and potassium balance and how renal dysfunction or hypertension may result. © 2010 by the authors.

Skolarikos A.,Sismanoglio Hospital | Straub M.,TU Munich | Knoll T.,University of Tubingen | Sarica K.,Dr Lutfi KIrdar Research and Teaching Hospital | And 4 more authors.
European Urology | Year: 2015

Context An optimum metabolic evaluation strategy for urinary stone patients has not been clearly defined. Objective To evaluate the optimum strategy for metabolic stone evaluation and management to prevent recurrent urinary stones. Evidence acquisition Several databases were searched to identify studies on the metabolic evaluation and prevention of stone recurrence in urolithiasis patients. Special interest was given to the level of evidence in the existing literature. Evidence synthesis Reliable stone analysis and basic metabolic evaluation are highly recommended in all patients after stone passage (grade A). Every patient should be assigned to a low- or high-risk group for stone formation. It is highly recommended that low-risk stone formers follow general fluid and nutritional intake guidelines, as well as lifestyle-related preventative measures to reduce stone recurrences (grade A). High-risk stone formers should undergo specific metabolic evaluation with 24-h urine collection (grade A). More specifically, there is strong evidence to recommend pharmacological treatment of calcium oxalate stones in patients with specific abnormalities in urine composition (grades A and B). Treatment of calcium phosphate stones using thiazides is only highly recommended when hypercalciuria is present (grade A). In the presence of renal tubular acidosis (RTA), potassium citrate and/or thiazide are highly recommended based on the relative urinary risk factor (grade A or B). Recommendations for therapeutic measures for the remaining stone types are based on low evidence (grade C or B following panel consensus). Diagnostic and therapeutic algorithms are presented for all stone types based on the best level of existing evidence. Conclusion Metabolic stone evaluation is highly recommended to prevent stone recurrences. Patient summary In this report, we looked at how patients with urolithiasis should be evaluated and treated in order to prevent new stone formation. Stone type determination and specific blood and urine analysis are needed to guide patient treatment. © 2014 European Association of Urology. All rights reserved.

Acute liver failure is a very complex type of disease with a mortality of up to 90%, leading to numerous severe disturbances of the whole organism. Bleeding because of absent synthesis of various coagulation factors and disseminated intravascular coagulation, acute kidney failure, circulatory failure with vasopressor dependence, respiratory failure with adult respiratory distress syndrome, neurological failure up to coma because of hepatic encephalopathy, and a very high risk of infection and sepsis frequently result from the initial state of isolated liver failure. High urgency liver transplantation is a highly efficient therapy if performed in time. However, increasing the rate of spontaneous recovery of the patients' own liver, and reducing the need for liver transplantation is preferable and would further improve the outcome of acute liver failure. Extracorporeal liver support by multipass albumin dialysis or plasmapheresis and filtering systems may offer a possibility to fulfill these aims of therapy. A prospective study in 88 patients with acute liver failure has shown a nonsignificant trend in improvement of survival after acute liver failure by multipass albumin dialysis and filtering. Other retrospective studies have shown benefits in improving hepatic encephalopathy and brain oedema. Further, an increase in the rate of spontaneous recovery of liver function has been described. With regional citrate anticoagulation for multipass albumin dialysis and filtering, the need for systemic anticoagulation - a potentially very harmful measure in these patients - can be eliminated and the rate of filter clotting can extremely effectively be reduced. © 2011 John Wiley & Sons A/S.

Romeyke T.,Medical University of Vienna | Stummer H.,Waldhausklinik Deuringen
Journal of Evidence-Based Complementary and Alternative Medicine | Year: 2015

The aim of this report is to provide the reader an overview of the complex therapy currently used within the German health system. Complex therapies in inpatient care in Germany establish the basis for an integrative and interdisciplinary provision of services. They define minimal criteria for the organization of a hospital, enable the integration of different therapeutic approaches, and therefore, lead to an intensive and holistic treatment by a specially trained team. The German model can be viewed as a pilot program for the introduction of integrative patient-centered care in other hospitals around the world. © The Author(s) 2014.

Hahn D.,University of Edinburgh | Hahn D.,Medical University of Vienna | Kudla G.,University of Edinburgh | Tollervey D.,University of Edinburgh | Beggs J.D.,University of Edinburgh
Genes and Development | Year: 2012

Brr2p is one of eight RNA helicases involved in pre-mRNA splicing. Detailed understanding of the functions of Brr2p and other spliceosomal helicases has been limited by lack of knowledge of their in vivo substrates. To address this, sites of direct Brr2p-RNA interaction were identified by in vivo UV cross-linking in budding yeast. Cross-links identified in the U4 and U6 small nuclear RNAs (snRNAs) suggest U4/U6 stem I as a Brr2p substrate during spliceosome activation. Further Brr2p cross-links were identified in loop 1 of the U5 snRNA and near splice sites and 3′ ends of introns, suggesting the possibility of a previously uncharacterized function for Brr2p in the catalytic center of the spliceosome. Consistent with this, mutant brr2-G858R reduced second-step splicing efficiency and enhanced cross-linking to 3′ ends of introns. Furthermore, RNA sequencing indicated preferential inhibition of splicing of introns with structured 3′ ends. The Brr2-G858Rp cross-linking pattern in U6 was consistent with an open conformation for the catalytic center of the spliceosome during first-to-second-step transition. We propose a previously unsuspected function for Brr2p in driving conformational rearrangements that lead to competence for the second step of splicing. © 2012 by Cold Spring Harbor Laboratory Press.

Reekers J.A.,University of Amsterdam | Lammer J.,Medical University of Vienna
Diabetes/Metabolism Research and Reviews | Year: 2012

Diabetic foot ulceration (DFU) is recognized as one of the most serious complications of diabetes. Active revascularisation plays a crucial role in achieving ulcer healing. Non-surgical, minimally invasive, revascularisation options for DFU have expanded over the last decade and have become a prominent tool to prevent amputation. Endovascular treatment of arterial DFU lesions is mainly concentrated in the below-the-knee arteries. The outcome of both open surgery and endovascular treatment is broadly spoken the same for the endpoints ulcer healing and limb salvage and is between 78% and 85%. The choice between endovascular treatment and open surgery should always be the outcome of a team discussion. Local expertise plays an important role in these discussions. In many institutions, the endovascular approach has currently become the first choice treatment option. The revascularisation of below-the-knee vessels needs experienced hands, team discussion and the right set of devices. Centralisation in DFU centres is therefore probably the best guaranty for the best outcome. © 2012 John Wiley & Sons, Ltd.

Heilig P.,Medical University of Vienna
Spektrum der Augenheilkunde | Year: 2010

Summary: Light Pollution can be prevented. It has to be prevented - for the sake and for the benefit of ecology, economy and sensory physiology. And the beauty and the magnificence of the world heritage Starry Sky. © 2010 Springer-Verlag.

Hadji P.,University of Marburg | Coleman R.,Academic Unit of Clinical Oncology | Gnant M.,Medical University of Vienna | Green J.R.,Novartis
Annals of Oncology | Year: 2012

Recent data from the AZURE, ABCSG-12, and ZO-FAST clinical trials have challenged our understanding of the potential anticancer activity of zoledronic acid (ZOL). Although the results of these studies may appear to be conflicting on the surface, a deeper look into commonalities among the patient populations suggest that some host factors (i.e. patient age and endocrine status) may contribute to the anticancer activity of ZOL. Indeed, data from these large clinical trials suggest that the potential anticancer activity of ZOL may be most robust in a low-estrogen environment. However, this may be only part of the story and many questions remain to be answered to fully explain the phenomenon. Does estrogen override the anticancer activity of ZOL seen in postmenopausal women? Are hormones other than estrogen involved that contribute to this effect? Does the role of bone turnover in breast cancer (BC) growth and progression differ in the presence of various estrogen levels? Here, we present a review of the multitude of factors affected by different endocrine environments in women with BC that may influence the potential anticancer activity of ZOL. © The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

Frey M.,Medical University of Vienna
Handchirurgie, Mikrochirurgie, plastische Chirurgie : Organ der Deutschsprachigen Arbeitsgemeinschaft für Handchirurgie : Organ der Deutschsprachigen Arbeitsgemeinschaft für Mikrochirurgie der Peripheren Nerven und Gefässe : Organ der Vereinigung der Deutschen Plastischen Chirurgen | Year: 2010

This overview on the currently most effective reconstructive techniques for reanimation of the unilaterally or bilaterally paralysed face includes all important techniques of neuromuscular reconstruction as well as of supplementary static procedures, which contribute significantly to the efficiency and quality of the functional overall result. Attention is paid to the best indications at the best time since onset of the facial palsy, depending on the age of the patient, the cause of the lesion, and the compliance of the patient for a long-lasting and complex rehabilitation programme. Immediate neuromuscular reconstruction of mimic function is favourable by nerve suture or nerve grafting of the facial nerve, or by using the contralateral healthy facial nerve via cross-face nerve grafting as long as the time since onset of the irreversible palsy is short enough that the paralysed mimic muscles can still be reinnervated. For the most frequent indication, the unilateral irreversible and complete palsy, a three-stage concept is described including cross-face nerve grafting, free functional gracilis muscle transplantation, and several supplementary procedures. In patients with limited life expectancy, transposition of the masseteric muscles is favoured. Bilateral facial palsy is treated by bilateral free gracilis muscle transplantation with the masseteric nerve branches for motor reinnervation. Functional upgrading in incomplete lesions is achieved by cross-face nerve grafting with distal end-to-side neurorrhaphy or by functional muscle transplantation with ipsilateral facial nerve supply. (c) Georg Thieme Verlag KG Stuttgart-New York.

Dorner T.E.,Medical University of Vienna
Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco | Year: 2011

The identification of individual characteristics that predict success in smoking cessation is necessary to improve the effectiveness of smoking cessation efforts. The aim of this study was to identify the factors that predict success in smoking cessation in people who attended 2, 3, 4, or 5 sessions of a smoking cessation program. The participants comprised 2,471 people who attended at least 2 consultations during a 5-week smoking cessation program. Success in smoking cessation was defined as self-reported abstinence and having an exhaled carbon monoxide level ≤10 parts per million at the final consultation. Baseline characteristics were compared using univariate analysis of variance and the chi-square test. A stepwise multivariate logistic regression model was used to analyze the effect of baseline characteristics and the slopes of the withdrawal symptoms on the success in smoking cessation. Participating in a higher number of sessions gradually increased the chance of smoking cessation from 12.1% to 61.2% (p < .0001). Logistic regression analysis revealed that the independent predictors of success in smoking cessation were being male; low nicotine dependence; smoking few cigarettes per day at baseline; having no history of depression; having low values for craving for cigarettes, irritability, frustration, anger, or nocturnal awakening at baseline; decreased craving for cigarettes and restlessness with time; and use of nicotine replacement therapy (NRT). People who attended more sessions tended to be older. Attending more sessions of a smoking cessation program, NRT, and coping with withdrawal and psychosocial symptoms increases the chance of short-term success in smoking cessation.

Dong G.,Medical University of Vienna
Open Biology | Year: 2015

Centrioles are short microtubule-based organelles with a conserved ninefold symmetry. They are essential for both centrosome formation and cilium biogenesis in most eukaryotes. A core set of five centriolar proteins has been identified and their sequential recruitment to procentrioles has been established. However, structures at atomic resolution for most of the centriolar components were scarce, and the underlying molecular mechanisms for centriole assembly had been a mystery-until recently. In this review, I briefly summarize recent advancements in high-resolution structural characterization of the core centriolar components and discuss perspectives in the field. © 2015 The Authors.

Lorenz-Depiereux B.,Helmholtz Center for Environmental Research | Schnabel D.,Charite - Medical University of Berlin | Tiosano D.,Rambam Medical Center | Tiosano D.,Technion - Israel Institute of Technology | And 3 more authors.
American Journal of Human Genetics | Year: 2010

The analysis of rare genetic disorders affecting phosphate homeostasis led to the identification of several proteins that are essential for the renal regulation of phosphate homeostasis; for example, fibroblast growth factor 23 (FGF23), which inhibits renal phosphate reabsorption and 1,25-dihydroxyvitamin D synthesis. Here, we report presumable loss-of-function mutations in the ENPP1 gene (ectonucleotide pyrophosphatase/phosphodiesterase) in members of four families affected with hypophosphatemic rickets. We provide evidence for the conclusion that ENPP1 is the fourth gene-in addition to PHEX, FGF23, and DMP1-that, if mutated, causes hypophosphatemic rickets resulting from elevated FGF23 levels. Surprisingly, ENPP1 loss-of-function mutations have previously been described in generalized arterial calcification of infancy, suggesting an as yet elusive mechanism that balances arterial calcification with bone mineralization. © 2010 The American Society of Human Genetics.

Masic F.,Medical University of Vienna
Acta Informatica Medica | Year: 2012

Introduction: Almost the entire human creativity today, from the standpoint of its efficiency and expediency, is conditioned with the existence of information systems. Most information systems are oriented to the management and decision-making, including health information system. System of health and health insurance together form one of the most important segments of society and its functioning as a compact unit. Increasing requirements for reducing health care costs while preserving or improving the quality of services provided represent a difficult task for the health system. Material and methods: Using descriptive metods by retreiiving literature we analyzed the latest solutions in information and telecommunications technology is the basis for building an effective and efficient health system. Computerization does not have the primary objective of saving, but the rationalization of spending in health care. It is estimated that at least 20-30% of money spent in health care can be rationally utilized. Computerization should give the necessary data and indicators for this rationalization. Very important are the goals of this project and the achievement of other uses and benefits, improving overall care for patients and policyholders, increasing the speed and accuracy of diagnosis in determining treatment using electronic diagnostic and therapeutic guidelines. Results and discussion: Computerization in dentistry began similarly as in other human activities-recording large amounts of data on digital media, and by replacing manual data processing to machine one. But specifics of the dental profession have led to the specifics of the application of information technology (IT), and continue to require special development of dental oriented and applied IT. Harmonization of dental software with global standards will enable doctors and dentists to with a few mouse clicks via the internet reach the general medical information about their patients from the central national health database. Standardization will also allow access to general medical and dental history data on citizens of foreign countries who seek help of doctors or dentists during their vacation. Such a method of using IT will provide a higher level of health services and better health care. Also, the identification procedures in mass disasters availability of data can contribute to accelerate the identification of victims. Dental information systems lately are based on Web applications to facilitate data exchange. Electronic patient record contains basic information and entering of this data is automatically created the protocol of patients that can be printed. Besides these general data Electronic patient record also contains history data related to allergies and other diseases which existence can significantly affect the treatment, data on current diagnosis, location of a pathological process in the tooth refers to the following location (mesial, distal, vestibular, oral, occlusal), teething, therapy of the tooth, type of material used with location on the tooth. The system may defined also the surgical procedures that were performed on the teeth such as tooth extraction or tooth root resection with the ability to accurately indicate that the root is resected. Implants, upgrades, grinding teeth, and independent crown can be defined for each tooth and its rightful place if a tooth is missing. Specially designed graphical representation of teeth enables to enter data by first clicking on the tooth or place where it is and also on that occasion to open a menu with options. Control of data entry prevents entry of illogical data. Conclusion: The system according to the HL7 standard represents electronic documents which eliminate the need for paper documents and a variety of daily and monthly reports of doctors who are still in use today, and the doctor and nurse are almost completely freed of administrative tasks. © AVICENA 2012.

Seidel S.,Medical University of Vienna
The Cochrane database of systematic reviews | Year: 2013

This is an updated version of the original Cochrane review published in Issue 4, 2008. The role of antipsychotics as adjuvant analgesics is a subject of longstanding controversy. Neuroleptanalgesia (that is a state of quiescence, altered awareness, and analgesia produced by a combination of taking an opioid analgesic and an antipsychotic), an established term for the management of acute pain, was shown to negatively influence disease course and total mortality in unstable angina patients. Nevertheless, antipsychotics are used to treat chronic pain (for example chronic headache, fibromyalgia and diabetic neuropathia). With atypical antipsychotics, a new class of antipsychotics, both fewer extrapyramidal side effects and additional benefits may be available. To assess the analgesic efficacy and adverse effects of antipsychotics in acute or chronic pain in adults. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, PsycINFO, and EMBASE in October 2011 and January 2013. Randomised controlled trials (RCTs) of adults prescribed any dose of an oral antipsychotic for acute or chronic pain, where subjective pain assessment was described as either the primary or a secondary outcome, were included in this review. Data were extracted by two independent review authors, and results were compared for differences. Discrepancies were resolved by discussion. All trials were quality scored according to the methods set out in section six of the Cochrane Handbook for Systematic Reviews of Interventions. A total of 770 participants were involved in the 11 included studies. Data from five included randomised double-blind studies showed beneficial effects of antipsychotics in the treatment of acute and chronic pain. Quantitative analysis of these studies showed a significant reduction of mean pain intensity after administration of the antipsychotic compared to placebo or another active compound, weighted mean difference (WMD) -1.78 (95% CI -2.71 to -0.85) for the continuous data; and relative risk (RR) 0.43 (95% CI 0.25 to 0.73), number needed to treat to benefit (NNT) 2.6 for the dichotomous data. Nevertheless, the test for heterogeneity was significant for both the continuous data (P = 0.0007) and the dichotomous data (P = 0.04). Obviously this makes the calculated NNT less reliable and caution is warranted when interpreting these results.The most frequently reported adverse effects were extrapyramidal (that is involuntary movements, parkinsonism and akathisia) and sedating effects. The recent search found five new studies which were all excluded, so the review remains the same as previously.Antipsychotics might be used as an add-on therapy in the treatment of painful conditions. Nevertheless, extrapyramidal and sedating side effects have to be considered before using antipsychotics for treating painful conditions.Results for antipsychotics in the treatment of different painful conditions are mixed and most sample sizes in the reviewed RCTs are small. Further studies on atypical antipsychotics in larger double-blind placebo-controlled studies that include standardised pain assessment and documentation are warranted.

The 18th meeting of the International Scientific Working Group on Tick-Borne Encephalitis (ISW-TBE)-a group of neurologists, general practitioners, clinicians, travel physicians, virologists, pediatricians and epidemiologists-was held under the title '. Tick-borne encephalitis-still on the map'. The conference agenda was divided into six sessions: 'National Implementation of EU notifiable disease status', 'Virology', 'Epidemiology and Risk areas & Poster Walk Epidemiological Update', 'Clinic', 'Environmental Factors' and 'New Findings and Diagnosis'. Key topics such as 'TBE as a notifiable disease-results of the third European survey', 'TBE vaccines over the years', 'Overview of flaviviruses', 'TBE virus phylogenetics', 'Current epidemiological developments and investigations', 'Clinical aspects', 'TBE in veterinary medicine', 'Laboratory diagnostic', 'Occupational risk', 'Allergy, obesity, and vaccination' were presented and extensively discussed. © 2016 Elsevier GmbH.

Today, the risk of getting tick-borne encephalitis (TBE) is still underestimated in many parts of Europe and worldwide. Therefore, the 14th meeting of the International Scientific Working Group on Tick-Borne Encephalitis (ISW-TBE) - a group of neurologists, general practitioners, clinicians, travel physicians, virologists, pediatricians, and epidemiologists - was held under the title " Tick-borne encephalitis: an underestimated risk...still" . Among the discussed issues were: TBE, an underestimated risk in children, a case report in two Dutch travelers, the very emotional report of a tick victim, an overview of the epidemiological situation, investigations to detect new TBE cases in Italy, TBE virus (TBEV) strains circulation in Northern Europe, TBE Program of the European Centre for Disease Prevention and Control (ECDC), efforts to increase the TBE vaccination rate in the Czech Republic, positioning statement of the World Health Organization (WHO), and TBE in dogs.To answer the question raised above: Yes, the risk of getting TBE is underestimated in children and adults, because awareness is still too low. It is still underestimated in several areas of Europe, where, for a lack of human cases, TBEV is thought to be absent. It is underestimated in travelers, because they still do not know enough about the risk, and diagnostic awareness in non-endemic countries is still low. © 2012 .

This paper presents a review of the development of optical coherence tomography (OCT), its principles and important applications. Basic OCT systems are described and the physical foundations of OCT signal properties and signal recording systems are reviewed. Recent examples of OCT applications in ophthalmology, cardiology, gastroenterology and dermatology outline the relevance of this advanced imaging modality in the medical field. © 2009.

Pirker R.,Medical University of Vienna
Translational Lung Cancer Research | Year: 2012

Cetuximab improved survival when added to first-line platinum-based chemotherapy in patients with advanced non-small cell lung cancer. In order to determine those patients who will derive the greatest benefit from the addition of cetuximab, the associations of clinical and tumor features with clinical outcome were determined. High EGFR expression of tumor cells based on an immunohistochemistry score was shown to predict benefit of cetuximab. Among patients with high EGFR expression, the hazard ratio for death was 0.73 in favor of chemotherapy plus cetuximab compared to chemotherapy alone. Among patients with low EGFR expression, no difference in survival was observed between patients treated with chemotherapy plus cetuximab compared to those treated with chemotherapy alone. The treatment interaction test was significant. KRAS mutation status and EGFR copy numbers were without predictive value. Patients with EGFR-activating mutations in their tumors had longer survival independent of the use of cetuximab. In conclusion, EGFR expression levels lend themselves as predictive biomarkers for the selection of those patients who will benefit from the addition of cetuximab to first-line chemotherapy with platinum-based doublets. © Translational lung cancer research. All rights reserved.

Attems J.,Northumbria University | Walker L.,Northumbria University | Jellinger K.A.,Medical University of Vienna
Acta Neuropathologica | Year: 2014

Olfactory dysfunction is a common and early symptom of many neurodegenerative diseases, particularly of Parkinson's disease and other synucleinopathies, Alzheimer's disease (AD), and mild cognitive impairment heralding its progression to dementia. The neuropathologic changes of olfactory dysfunction in neurodegenerative diseases may involve the olfactory epithelium, olfactory bulb/tract, primary olfactory cortices, and their secondary targets. Olfactory dysfunction is related to deposition of pathological proteins, α-synuclein, hyperphosphorylated tau protein, and neurofilament protein in these areas, featured by neurofibrillary tangles, Lewy bodies and neurites inducing a complex cascade of molecular processes including oxidative damage, neuroinflammation, and cytosolic disruption of cellular processes leading to cell death. Damage to cholinergic, serotonergic, and noradrenergic systems is likely involved, since such damage is most marked in those diseases with severe anosmia. Recent studies of olfactory dysfunction have focused its potential as an early biomarker for the diagnosis of neurodegenerative disorders and their disease progression. Here, we summarize the current knowledge on neuropathological and pathophysiological changes of the olfactory system in the most frequent neurodegenerative diseases, in particular AD and synucleinopathies. We also present neuropathological findings in the olfactory bulb and tract in a large autopsy cohort (n = 536, 57.8 % female, mean age 81.3 years). The severity of olfactory bulb HPτ, Aβ, and αSyn pathology correlated and increased significantly (P < 0.001) with increasing neuritic Braak stages, Thal Aβ phases, and cerebral Lewy body pathology, respectively. Hence, further studies are warranted to investigate the potential role of olfactory biopsies (possibly restricted to the olfactory epithelium) in the diagnostic process of neurodegenerative diseases in particular in clinical drug trials to identify subjects showing early, preclinical stages of neurodegeneration and to stratify clinically impaired cohorts according to the underlying cerebral neuropathology. © 2014 Springer-Verlag.

Pollak D.D.,Medical University of Vienna
Nature protocols | Year: 2010

Fear conditioning is one of the most widely used animal models for studying the neurobiological basis of fear and anxiety states. Conditioned inhibition of fear (or learned safety), however, is a relatively unexplored behavioral paradigm addressing the aspect of regulation of fear, which is central to survival and mental health. Although fear conditioning is achieved by pairing a previously neutral, conditioned stimulus (CS) with an aversive, unconditioned stimulus (US), learned safety training consists of a series of explicitly unpaired CS-US presentations. Animals are trained for 3 d, one session per day, and learn to associate the CS with protection from the impending danger of the aversive events. The entire procedure can be completed within 7 d. The protocol has been successfully used to study the molecular underpinnings of a behavioral intervention for depression. This paradigm complements currently used animal tests in neuropsychiatric research addressing the dysregulation of emotional behaviors in genetic, pharmacological or environmental mouse models of human affective disorders.

Wiche G.,University of Vienna | Osmanagic-Myers S.,University of Vienna | Osmanagic-Myers S.,Medical University of Vienna | Castanon M.J.,University of Vienna
Current Opinion in Cell Biology | Year: 2015

Intermediate filaments (IFs) are involved in multiple cellular processes that are essential for the maintenance of cell and tissue integrity as well as response and adaption to stress. Mainly through pathological manifestations in patients and the analysis of genetic mouse models, it became evident that cytolinker proteins of the plakin protein family are essential for many of the functions ascribed to IFs. As discussed in this review, one of them, plectin, affects the assembly properties, interaction potential, compartmentalization, and linkage properties of IFs, making it to a key player for IF functionality. The far reaching consequences of IFs not being well-connected for skin and muscular integrity, migration, and mechanotransduction are highlighted. © 2014 Published by Elsevier Ltd.

Rossmanith W.,Medical University of Vienna
Biochimica et Biophysica Acta - Gene Regulatory Mechanisms | Year: 2012

Mitochondrial tRNAs are generally synthesized as part of polycistronic transcripts. Release of tRNAs from these precursors is thus not only required to produce functional adaptors for translation, but also responsible for the maturation of other mitochondrial RNA species. Cleavage of mitochondrial tRNAs appears to be exclusively accomplished by endonucleases. 5'-end maturation in the mitochondria of different Eukarya is achieved by various kinds of RNase P, representing the full range of diversity found in this enzyme family. While ribonucleoprotein enzymes with RNA components of bacterial-like appearance are found in a few unrelated protists, algae, and fungi, highly degenerate RNAs of dramatic size variability are found in the mitochondria of many fungi. The majority of mitochondrial RNase P enzymes, however, appear to be pure protein enzymes. Human mitochondrial RNase P, the first to be identified and possibly the prototype of all animal mitochondrial RNases P, is composed of three proteins. Homologs of its nuclease subunit MRPP3/PRORP, are also found in plants, algae and several protists, where they are apparently responsible for RNase P activity in mitochondria (and beyond) without the help of extra subunits. The diversity of RNase P enzymes is contrasted by the uniformity of mitochondrial RNases Z, which are responsible for 3'-end processing. Only the long form of RNase Z, which is restricted to eukarya, is found in mitochondria, even when an additional short form is present in the same organism. Mitochondrial tRNA processing thus appears dominated by new, eukaryal inventions rather than bacterial heritage. This article is part of a Special Issue entitled: Mitochondrial Gene Expression. © 2011 Elsevier B.V.

Varadkar S.,University College London | Bien C.G.,Epilepsy Center Bethel | Kruse C.A.,University of California at Los Angeles | Jensen F.E.,University of Pennsylvania | And 5 more authors.
The Lancet Neurology | Year: 2014

Rasmussen's encephalitis is a rare chronic neurological disorder, characterised by unilateral inflammation of the cerebral cortex, drug-resistant epilepsy, and progressive neurological and cognitive deterioration. Neuropathological and immunological studies support the notion that Rasmussen's encephalitis is probably driven by a T-cell response to one or more antigenic epitopes, with potential additional contribution by autoantibodies. Careful analysis of the association between histopathology and clinical presentation suggests that initial damage to the brain is mediated by T cells and microglia, suggesting a window for treatment if Rasmussen's encephalitis can be diagnosed early. Advances in neuroimaging suggest that progression of the inflammatory process seen with MRI might be a good biomarker in Rasmussen's encephalitis. For many patients, families, and doctors, choosing the right time to move from medical management to surgery is a real therapeutic dilemma. Cerebral hemispherectomy remains the only cure for seizures, but there are inevitable functional compromises. Decisions of whether or when surgery should be undertaken are challenging in the absence of a dense neurological deficit, and vary by institutional experience. Further, the optimum time for surgery, to give the best language and cognitive outcome, is not yet well understood. Immunomodulatory treatments seem to slow rather than halt disease progression in Rasmussen's encephalitis, without changing the eventual outcome. © 2014 Elsevier Ltd.

Katschnig H.,Medical University of Vienna
Epidemiology and Psychiatric Sciences | Year: 2011

Routinely collected and reported indicators for health service utilization have traditionally been event/episode related and hospital centered. This is also the case for service utilization by persons with mental disorders, for whom national and international databases usually report rates of hospital discharges, mean length of stay for hospital episode and the like. Such event/episode-related indicators are of limited use for planning and improving services for persons with mental disorders. It is argued that new reporting systems are needed that allow the monitoring of the pathways of persons with mental disorders through the service system. It is shown how - owing to recent developments in techniques of 'pseudonymization' and the ever-increasing computer power for dealing with large volumes of patient data - such a system can be established and how it can contribute to analyzing empirically such mental health-care issues as 'heavy utilizers', 'revolving door psychiatry', 'continuity of care', 'de-institutionalization' and the like. Results of a record linkage study for the total population of a federal state of Austria monitoring both psychiatric and non-psychiatric health service utilization are reported. Some unexpected findings include the high utilization of non-psychiatric services by patients discharged from a psychiatric hospital bed, results which could not have been found by psychiatric case registers which usually only monitor utilization of psychiatric services. © Cambridge University Press 2011.

Wekerle T.,Medical University of Vienna
Blood | Year: 2013

In this issue of Blood, Tazawa et al demonstrate that invariant natural killer T (iNKT) cells play a critical role in the production of antibodies against the blood group A antigen. Interrupting iNKT cell function with an anti-CD1d antibody prevents anti-A antibody formation, revealing a potential therapeutic target for ABO-incompatible transplantations. © 2013 by The American Society of Hematology.

Olszewski U.,Ludwig Boltzmann Society | Deally A.,University College Dublin | Tacke M.,University College Dublin | Hamilton G.,Ludwig Boltzmann Society | Hamilton G.,Medical University of Vienna
Neoplasia (United States) | Year: 2012

First-line treatment of small cell lung cancer (SCLC) with combination chemotherapy consisting of cisdiamminedichloroplatinum(II) (cisplatin) and etoposide is frequently followed by early relapses and a dismal prognosis. Survival of a fraction of tumor cells and development of chemoresistance may be influenced by an initial cellular stress response against the administered xenobiotics. Therefore, we compared the short-term effects of cisplatin and non-cross-resistant bis-[(p-methoxybenzyl)cyclopentadienyl] titanium(IV) dichloride (Titanocene Y) on phosphorylation of 46 sites of a total of 38 signaling proteins in tumor suppressor protein 53 (p53)-wild-type NCI-H526 SCLC cells. The functional significance of selected kinases for the cytotoxicity of both drugs was tested using specific inhibitors and an activator. The cisplatin-induced cellular stress response involved activation of p38α mitogen-activated protein kinase, whereas Titanocene Y-triggered signaling affected c-Jun N-terminal kinase. Phosphorylation of adenosine monophosphate (AMP)-activated protein kinase α1 (AMPKα1) was increased by both drugs, which promoted cell survival, as indicated by results obtained using AMPK inhibitor compound C and AMPK activator 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside. This is in good agreement with previous reports, where AMPKα1 was demonstrated to represent an important factor for the sensitivity to cisplatin in colon and ovarian cancers, most likely by induction of autophagy. Thus, AMPKα1 constitutes a potential target to be exploited for chemotherapeutic treatment of SCLC to circumvent resistance to metal-based compounds. © 2012 Neoplasia Press, Inc. All rights reserved.

Kemp S.,University of Amsterdam | Berger J.,Medical University of Vienna | Aubourg P.,Assistance Publique des Hopitaux de Paris | Aubourg P.,University of Paris Descartes
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2012

X-linked adrenoleukodystrophy (X-ALD) is the most frequent peroxisomal disease. The two main clinical phenotypes of X-ALD are adrenomyeloneuropathy (AMN) and inflammatory cerebral ALD that manifests either in children or more rarely in adults. About 65% of heterozygote females develop symptoms by the age of 60. years. Mutations in the ABCD1 gene affect the function of the encoded protein ALDP, an ATP-binding-cassette (ABC) transporter located in the peroxisomal membrane protein. ALDP deficiency impairs the peroxisomal beta-oxidation of very long-chain fatty acids (VLCFA) and facilitates their further chain elongation by ELOVL1 resulting in accumulation of VLCFA in plasma and tissues. While all patients have mutations in the ABCD1 gene, there is no general genotype-phenotype correlation. Environmental factors and a multitude of modifying genes appear to determine the clinical manifestation in this monogenetic but multifactorial disease. This review focuses on the clinical, biochemical, genetic and pathophysiological aspects of X-ALD. This article is part of a Special Issue entitled: Metabolic Functions and Biogenesis of Peroxisomes in Health and Disease. © 2012 Elsevier B.V..

Schmidinger M.,Medical University of Vienna
American Society of Clinical Oncology educational book / ASCO. American Society of Clinical Oncology. Meeting | Year: 2014

Targeted agents have substantially improved outcomes in metastatic clear cell renal cell carcinoma. However, due to multiple mechanisms of evasive resistance, almost all patients progress at some point and may require subsequent therapies. Various agents have been explored after failure of first-line treatment in randomized clinical trials. However, so far few questions about the optimal sequence have been answered. Both everolimus and axitinib have been considered standard of care after failure of first-line VEGF-TKI; sorafenib has been proposed as an additional option. In clinical practice, several factors may influence the choice of subsequent treatment: these include considerations on appropriate drug exposure in first-line, gained insights on prognostic and predictive factors as well as mechanisms of resistance. Once the decision in second-line has been made and treatment has been initiated, treating physicians may already be challenged by the question of what to offer in third- and later lines. Treatment beyond second-line treatment isn't supported by strong evidence, and at this stage of disease, retrospective reports on rechallenge may help to guide decisions. In addition, local treatment approaches including metastasectomy and stereotactic radiosurgery may help to optimize outcomes in all treatment lines.

Schernthaner G.,Rudolfstiftung Hospital | Mogensen C.E.,Aarhus University Hospital | Schernthaner G.-H.,Medical University of Vienna
Diabetes and Vascular Disease Research | Year: 2014

Diabetic nephropathy (DN) affects an estimated 20%-40% of patients with type 2 diabetes mellitus (T2DM). Key modifiable risk factors for DN are albuminuria, anaemia, dyslipidaemia, hyperglycaemia and hypertension, together with lifestyle factors, such as smoking and obesity. Early detection and treatment of these risk factors can prevent DN or slow its progression, and may even induce remission in some patients. DN is generally preceded by albuminuria, which frequently remains elevated despite treatment in patients with T2DM. Optimal treatment and prevention of DN may require an early, intensive, multifactorial approach, tailored to simultaneously target all modifiable risk factors. Regular monitoring of renal function, including urinary albumin excretion, creatinine clearance and glomerular filtration rate, is critical for following any disease progression and making treatment adjustments. Dipeptidyl peptidase (DPP)-4 inhibitors and sodium-glucose cotransporter 2 (SGLT2) inhibitors lower blood glucose levels without additional risk of hypoglycaemia, and may also reduce albuminuria. Further investigation of the potential renal benefits of DPP-4 and SGLT2 inhibitors is underway. © 2014 The Author(s).

Yanez-Cuna J.O.,Research Institute of Molecular Pathology IMP | Dinh H.Q.,Gregor Mendel Institute of Molecular Plant Biology | Dinh H.Q.,Medical University of Vienna | Kvon E.Z.,Research Institute of Molecular Pathology IMP | And 2 more authors.
Genome Research | Year: 2012

The regulation of gene expression is mediated at the transcriptional level by enhancer regions that are bound by sequence-specific transcription factors (TFs). Recent studies have shown that the in vivo binding sites of single TFs differ between developmental or cellular contexts. How this context-specific binding is encoded in the cis -regulatory DNA sequence has, however, remained unclear. We computationally dissect context-specific TF binding sites in Drosophila, Caenorhabditis elegans, mouse, and human and find distinct combinations of sequence motifs for partner factors, which are predictive and reveal specific motif requirements of individual binding sites. We predict that TF binding in the early Drosophila embryo depends on motifs for the early zygotic TFs Vielfaltig (also known as Zelda) and Tramtrack. We validate experimentally that the activity of Twist-bound enhancers and Twist binding itself depend on Vielfaltig motifs, suggesting that Vielfaltig is more generally important for early transcription. Our finding that the motif content can predict context-specific binding and that the predictions work across different Drosophila species suggests that characteristic motif combinations are shared between sites, revealing context-specific motif codes ( cis-regulatory signatures), which appear to be conserved during evolution. Taken together, this study establishes a novel approach to derive predictive cis-regulatory motif requirements for individual TF binding sites and enhancers. Importantly, the method is generally applicable across different cell types and organisms to elucidate cis-regulatory sequence determinants and the corresponding trans-acting factors from the increasing number of tissue- and cell-type-specific TF binding studies.

Schmid-Schwap M.,Medical University of Vienna
Journal of orofacial pain | Year: 2013

To explore potential differences in characteristics of patients that might account for sex-specific differences in temporomandibular disorders (TMD). A total of 502 patients presenting with TMD during 2000 to 2002 at the Outpatient Unit for Functional Disorders of the Medical University of Vienna underwent detailed evaluation of their medical history and assessment of clinical findings. The data obtained were assessed for sex-specific differences by analysis of variance and multiple regression. Overall, 404 females (mean age ± SD: 40 ± 16 years; range 12 to 96 years) and 98 males (mean age 41 ± 16 years; range 16 to 78 years) were included. Their rating of their pain on a visual analog scale (VAS) showed a significantly higher pain intensity for females than for males (P = .004). Clinical assessment showed a significantly lower degree of mouth opening for females than for males (P < .001). While no sex-specific differences were noted for clicking phenomena of the temporomandibular joint (TMJ) and for the bite class of the patients, bite anomalies were significantly more frequent in male patients (P = .03). Palpation of masticatory muscles and the TMJ revealed significantly higher tenderness on palpation in female as compared to male patients (P = .001). Grouping by clicking, crepitation, and bruxism also showed greater pain (VAS) and more tenderness on palpation in females versus males. Females also showed peaks of prevalence of TMD in the age group below 25 years and in the group 55 to 60 years, whereas males had a more even age distribution. No external factors, such as exposure to stress, were found that moderated the sex difference. Female TMD patients showed greater pain and muscle tenderness on palpation as compared to male TMD patients. They also showed a different age distribution of prevalence of TMD. These results were independent of subjective symptoms, clinical findings, and external factors.

Kim N.H.,University of California at San Diego | Lang I.M.,Medical University of Vienna
European Respiratory Review | Year: 2012

Chronic thromboembolic pulmonary hypertension (CTEPH) is a form of pulmonary hypertension caused by obstruction and vascular remodelling of pulmonary arteries following pulmonary embolism. Risk factors that predispose patients to CTEPH include the size of the initial thrombus and numerous associated host or medical conditions. Haemostatic risk factors include elevated levels of factor VIII and phospholipid antibodies or intrinsic abnormalities in fibrinogen. Medical conditions that are associated with an increased risk of CTEPH include a history of splenectomy, cancer, ventriculoatrial shunt, chronic inflammatory disease, antiphospholipid antibodies and hypothyroidism. Although CTEPH is potentially curable by pulmonary endarterectomy (PEA), up to 40% of patients evaluated for PEA may be denied surgery depending on the level of surgical experience and disease accessibility after pre-operative assessment. Furthermore, an estimated 10-15% of patients are at risk for residual pulmonary hypertension following PEA surgery, due to significant concomitant small-vessel disease. However, pre-operative identification of small-vessel involvement remains a challenge. The current medications effective in the treatment of pulmonary arterial hypertension have not demonstrated efficacy in CTEPH. Accordingly, identification of CTEPH, followed by early referral for evaluation and treatment by an experienced PEA centre, is recommended. © ERS 2012.

Taniuchi I.,RIKEN | Ellmeier W.,Medical University of Vienna
Advances in Immunology | Year: 2011

The helper versus cytotoxic-lineage choice of CD4+CD8+ DP thymocytes correlates with MHC restriction of their T cell receptors and the termination of either CD8 or CD4 coreceptor expression. It has been hypothesized that transcription factors regulating the expression of the Cd4/Cd8 coreceptor genes must play a role in regulating the lineage decision of DP thymocytes. Indeed, progress made during the past decade led to the identification of several transcription factors that regulate CD4/CD8 expression that are as well important regulators of helper/cytotoxic cell fate choice. These studies provided insight into the molecular link between the regulation of coreceptor expression and lineage decision. However, studies initiated by the identification of ThPOK, a central transcription factor for helper T cell development, have offered another perspective on the cross-regulation between these two processes. Here, we review advances in our understanding of regulatory circuits composed of transcription factors and their link to epigenetic mechanisms, which play essential roles in specifying and sealing cell lineage identity during the CD4/CD8 commitment process of DP thymocytes. © 2011 Elsevier Inc.

Lassmann H.,Medical University of Vienna
Journal of the Neurological Sciences | Year: 2011

Many new therapies have become available for multiple sclerosis patients during the last decade. They are mainly effective in the early relapsing stage of the disease. Despite this undisputed progress, there are still major deficits in the treatment of the patients. Effective anti-inflammatory treatments profoundly decrease disease activity, although this may occur on the expense of a partially impaired immune surveillance of the central nervous system. Furthermore, the clinical outcome of recent trials does not always meet the expectations of the neuroimmunological community. This suggests that preclinical testing in experimental models, although useful and necessary, has its limitations. For treatment of the progressive stage of the disease blood brain barrier penetration of drugs appears to be one crucial issue. Additionally, little is known on the immunological mechanisms of slow burning inflammation present in the brain of patients with progressive MS. Finally, it is suggested that neuroprotective strategies, which target mitochondrial injury and its downstream effects on neurons and axons are promising future therapeutic options. © 2010 Elsevier B.V. All rights reserved.

Cip J.,Innsbruck Medical University | Widemschek M.,Innsbruck Medical University | Benesch T.,Medical University of Vienna | Martin A.,Innsbruck Medical University
Clinical Orthopaedics and Related Research | Year: 2013

Background: Mechanical autotransfusion systems for washed shed blood (WSB) were introduced to reduce the need for postoperative allogenic blood transfusions (ABTs). Although some authors have postulated decreased requirements for ABT by using autologous retransfusion devices, other trials, mostly evaluating retransfusion devices for unwashed shed blood (USB), verified a small or no benefit in reducing the need for postoperative ABT. Because of these contradictory findings it is still unclear whether autologous retransfusion systems for WSB can reduce transfusion requirements. Questions/purposes: We therefore asked whether one such autologous transfusion system for WSB can reduce the requirements for postoperative ABT. Methods: In a prospective, randomized, controlled study, we enrolled 151 patients undergoing TKA. In Group A (n = 76 patients), the autotransfusion system was used for a total of 6 hours (intraoperatively and postoperatively) and the WSB was retransfused after processing. In Control Group B (n = 75 patients), a regular drain without suction was used. We used signs of anemia and/or a hemoglobin value less than 8 g/dL as indications for transfusion. If necessary, we administered one or two units of allogenic blood. Results: Twenty-three patients (33%) in Group A, who received an average of 283 mL (range, 160-406 mL) of salvaged blood, needed a mean of 2.1 units of allogenic blood, compared with 23 patients (33%) in Control Group B who needed a mean of 2.1 units of allogenic blood. Conclusions: We found the use of an autotransfusion system did not reduce the rate of postoperative ABTs. Level of Evidence: Level II, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence. © 2012 The Association of Bone and Joint Surgeons®.

Valent P.,Medical University of Vienna
Oncotarget | Year: 2010

The diagnosis, classification, and prognostication of patients with myelodysplastic syndromes (MDS) are usually based on clinical parameters, analysis of peripheral blood and bone marrow smears, and cytogenetic determinants. However, a thorough histologic and immunohistochemical examination of the bone marrow is often required for a final diagnosis and exact classification in these patients. Notably, histology and immunohistology may reveal dysplasia in megakaryocytes or other bone marrow lineages and/or the presence of clusters of CD34-positive precursor cells. In other cases, histology may reveal an unrelated or co-existing hematopoietic neoplasm, or may support the conclusion the patient is suffering from acute myeloid leukemia rather than MDS. Moreover, histologic investigations and immunohistology may reveal an increase in tryptase-positive cells, a coexisting systemic mastocytosis, or bone marrow fibrosis, which is of prognostic significance. To discuss diagnostic algorithms, terminologies, parameters, and specific issues in the hematopathologic evaluation of MDS, a Working Conference involving a consortium of US and EU experts, was organized in June 2010. The outcomes of the conference and resulting recommendations provided by the faculty, are reported in this article. These guidelines should assist in the diagnosis, classification, and prognostication in MDS in daily practice as well as in clinical trials.

My mentor H. H. Kornhuber (1928-2009) and I recorded - in 1964 in Freiburg, Germany - brain potentials preceding willed, volitional actions: Bereitschaftspotential, BP, so named worldwide - a German word in the English language. The BP was not a serendipitous discovery - we were purposefully searching for signs of self-active intention and will. The original experimental setup of the BP with photos, and the historical scientific background are described. The publication in 1965 became a citation classic; 3 further citation classics appeared. Clinical application: BP in Parkinson's disease. The BP analogue in the MEG (Magnetoencephalography) 'Bereitschaftsmagnetfeld' was found by us. Libet's experiments are critically reviewed. Visual tracking movements of Lang et al. revealed evidence that the SMA (supplementary motor area) is starting the tracking movement but is not executing it, the SMA is delegating this to the 'expert' visual cortex. Cunnington et al. recorded the Bereitschafts-BOLD effect in the fMRI, the curve looks like the BP. Kornhuber and I found that also the CMA (cingulate motor area) is active preceding actions. Cunnington has news on that.

Bechmann L.P.,University of Duisburg - Essen | Hannivoort R.A.,University of Groningen | Gerken G.,University of Duisburg - Essen | Hotamisligil G.S.,Harvard University | And 2 more authors.
Journal of Hepatology | Year: 2012

It is widely known that the liver is a central organ in lipogenesis, gluconeogenesis and cholesterol metabolism. However, over the last decades, a variety of pathological conditions highlighted the importance of metabolic functions within the diseased liver. As observed in Western societies, an increase in the prevalence of obesity and the metabolic syndrome promotes pathophysiological changes that cause non-alcoholic fatty liver disease (NAFLD). NAFLD increases the susceptibility of the liver to acute liver injury and may lead to cirrhosis and hepatocellular cancer. Alterations in insulin response, β-oxidation, lipid storage and transport, autophagy and an imbalance in chemokines and nuclear receptor signaling are held accountable for these changes. Furthermore, recent studies revealed a role for lipid accumulation in inflammation and ER stress in the clinical context of liver regeneration and hepatic carcinogenesis. This review focuses on novel findings related to nuclear receptor signaling - including the vitamin D receptor and the liver receptor homolog 1 - in hepatic lipid and glucose uptake, storage and metabolism in the clinical context of NAFLD, liver regeneration, and cancer. © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Cazzola M.,University of Pavia | Kralovics R.,Austrian Academy of Sciences | Kralovics R.,Medical University of Vienna
Blood | Year: 2014

Our understanding of the genetic basis of myeloproliferative neoplasms began in 2005, when the JAK2 (V617F) mutation was identified in polycythemia vera, essential thrombocythemia, and primary myelofibrosis. JAK2 exon 12 and MPL exon 10 mutations were then detected in subsets of patients, and subclonal driver mutations in other genes were found to be associated with disease progression. Recently, somatic mutations in the gene CALR, encoding calreticulin, have been found in most patients with essential thrombocythemia or primary myelofibrosis with nonmutated JAK2 and MPL. The JAK-STAT pathway appears to be activated in all myeloproliferative neoplasms, regardless of founding driver mutations. These latter, however, have different effects on clinical course and outcomes. Thus, evaluation of JAK2, MPL, and CALR mutation status is important not only for diagnosis but also for prognostication. These genetic data should now also be considered in designing clinical trials. © 2014 by The American Society of Hematology.

Mosti G.,Clinica MD Barbantini | Partsch H.,Medical University of Vienna
European Journal of Vascular and Endovascular Surgery | Year: 2012

Background: Graduated compression is routinely employed as standard therapy for chronic venous insufficiency. Aim: The study aims to compare the haemodynamic efficiency of a multi-component graduated compression bandage (GCB) versus a negative graduated compression bandage (NGCB) applied with higher pressure over the calf. Methods: In 20 patients, all affected by greater saphenous vein (GSV) incompetence and candidates for surgery (Clinical, etiologic, anatomic and pathophysiologic data, CEAP C2-C5), the ejection fraction of the venous calf pump was measured using a plethysmographic method during a standardised walking test without compression, with GCB and NGCB, all composed of the same short-stretch material. Sub-bandage pressures were measured simultaneously over the distal leg and over the calf. Results: NGCBs with median pressures higher at the calf (62 mmHg) than at the distal leg (50 mmHg) achieved a significantly higher increase of ejection fraction (median +157%) compared with GCB, (+115%) with a distal pressure of 54 mmHg and a calf pressure of 28 mmHg (P < 0.001). Conclusions: Patients with severe venous incompetence have a greater haemodynamic benefit from NGCB, especially during standing and walking, than from GCB. © 2012 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.

Messner B.,Medical University of Vienna | Bernhard D.,Innsbruck Medical University
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2014

Smoking represents one of the most important preventable risk factors for the development of atherosclerosis. The present review aims at providing a comprehensive summary of published data from clinical and animal studies, as well as results of basic research on the proatherogenic effect of smoking. Extensive search and review of literature revealed a vast amount of data on the influence of cigarette smoke and its constituents on early atherogenesis, particularly on endothelial cells. Vascular dysfunction induced by smoking is initiated by reduced nitric oxide (NO) bioavailability and further by the increased expression of adhesion molecules and subsequent endothelial dysfunction. Smoking-induced increased adherence of platelets and macrophages provokes the development of a procoagulant and inflammatory environment. After transendothelial migration and activation, macrophages take up oxidized lipoproteins arising from oxidative modifications and transdifferentiate into foam cells. In addition to direct physical damage to endothelial cells, smoking induces tissue remodeling, and prothrombotic processes together with activation of systemic inflammatory signals, all of which contribute to atherogenic vessel wall changes. There are still great gaps in our knowledge about the effects of smoking on cardiovascular disease. However, we know that smoking cessation is the most effective measure for reversing damage that has already occurred and preventing fatal cardiovascular outcomes. © 2013 American Heart Association, Inc.

OBJECTIVE: The aim of the present study was to explore how contextual factors affect the everyday activities of women and men with rheumatoid arthritis (RA), as evident in their life stories. METHODS: Fifteen people with RA, who had retired early due to the disease, were interviewed up to three times, according to a narrative biographic interview style. The life stories of the participants, which were reconstructed from the biographical data and from the transcribed 'told story' were analysed from the perspective of contextual factors, including personal and environmental factors. The rigour and accuracy of the analysis were enhanced by reflexivity and peer-review of the results. RESULTS: The life stories of the participants in this study reflected how contextual factors (such as gender, the healthcare system, the support of families and social and cultural values) shaped their everyday activities. In a society such as in Austria, which is based on traditional patriarchal values, men were presented with difficulties in developing a non-paid-work-related role. For women, if paid work had to be given up, they were more likely to engage in alternative challenging activities which enabled them to develop reflective skills, which in turn contributed to a positive and enriching perspective on their life stories. Health professionals may thus use some of the women's strategies to help men. CONCLUSION: Interventions by health professionals in people with RA may benefit from an approach sensitive to personal and environmental factors.

Bock C.,Austrian Academy of Sciences | Bock C.,Medical University of Vienna | Lengauer T.,Max Planck Institute for Informatics
Nature Reviews Cancer | Year: 2012

Drug resistance is a common cause of treatment failure for HIV infection and cancer. The high mutation rate of HIV leads to genetic heterogeneity among viral populations and provides the seed from which drug-resistant clones emerge in response to therapy. Similarly, most cancers are characterized by extensive genetic, epigenetic, transcriptional and cellular diversity, and drug-resistant cancer cells outgrow their non-resistant peers in a process of somatic evolution. Patient-specific combination of antiviral drugs has emerged as a powerful approach for treating drug-resistant HIV infection, using genotype-based predictions to identify the best matched combination therapy among several hundred possible combinations of HIV drugs. In this Opinion article, we argue that HIV therapy provides a 'blueprint' for designing and validating patient-specific combination therapies in cancer. © 2012 Macmillan Publishers Limited. All rights reserved.

Ebenbichler G.R.,Medical University of Vienna
American Journal of Physical Medicine and Rehabilitation | Year: 2016

OBJECTIVE: To investigate the excess risk of degeneration and segmental instability in operated segments late after lumbar disc surgery in patients with presurgically stable segments, and whether local pathological findings relate to patients’ back health. DESIGN: This retrospective analysis reports on 69 patients 12 years after first-time, uncomplicated lumbar disc surgery. Two independent radiologists evaluated the patients’ lumbar functional x-rays; the Back Pain Rating Score (LBP-RS) assessed back-specific function. RESULTS: At 12 years after lumbar disc surgery, degenerative changes as well as segmental instability occurred significantly more frequently in the operated than nonoperated lumbar segments, but there was no association between increased degeneration and segmental instability rates. The risk for acquiring segmental instability was significantly associated with surgery (odds ratio, 6.5; 95% confidence interval, 1.5–28.8). Prevalence of segmental instabilities was associated with better LBP-RS scores. Analyses of LBP-RS subscores revealed a clear association of segmental instability with physical function, but not with pain or activities of daily living. CONCLUSIONS: Lumbar disc surgery seems to be associated with an increased risk of degeneration and segmental instability in the long term. This structural impairment, however, seems functionally well compensated and does not seem to be a relevant causal factor for a chronic back pain syndrome. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

Aletaha D.,Medical University of Vienna
Arthritis Research and Therapy | Year: 2012

Remission is key to prevent progression of rheumatoid arthritis, but it is still rarely seen in clinical practice, not to speak of sustained remission, which is the best possible disease outcome of rheumatoid arthritis. New strategies and recommendations focus on achievement of remission, but it is unclear how long remission can actually be maintained in clinical practice. A study by Prince and colleagues gives insights into this question, and raises some other questions for the future. © 2012 BioMed Central Ltd.

Gohring J.,Medical University of Vienna | Fulcher N.,Gregor Mendel Institute of Molecular Plant Biology | Jacak J.,Johannes Kepler University | Jacak J.,Upper Austria University of Applied Sciences | Riha K.,Gregor Mendel Institute of Molecular Plant Biology
Nucleic Acids Research | Year: 2014

Telomeres comprise the protective caps of natural chromosome ends and function in the suppression of DNA damage signaling and cellular senescence. Therefore, techniques used to determine telomere length are important in a number of studies, ranging from those investigating telomeric structure to effects on human disease. Terminal restriction fragment (TRF) analysis has for a long time shown to be one of the most accurate methods for quantification of absolute telomere length and range from a number of species. As this technique centers on standard Southern blotting, telomeric DNA is observed on resulting autoradiograms as a heterogeneous smear. Methods to accurately determine telomere length from telomeric smears have proven problematic, and no reliable technique has been suggested to obtain mean telomere length values. Here, we present TeloTool, a new program allowing thorough statistical analysis of TRF data. Using this new method, a number of methodical biases are removed from previously stated techniques, including assumptions based on probe intensity corrections. This program provides a standardized mean for quick and reliable extraction of quantitative data from TRF autoradiograms; its wide application will allow accurate comparison between datasets generated in different laboratories. © 2013 The Author(s) 2013. Published by Oxford University Press.

Background:To assess the prognostic value of preoperative C-reactive protein (CRP) serum levels for prognostication of biochemical recurrence (BCR) after radical prostatectomy (RP) in a large multi-institutional cohort.Methods:Data from 7205 patients treated with RP at five institutions for clinically localized prostate cancer (PCa) were retrospectively analyzed. Preoperative serum levels of CRP within 24 h before surgery were evaluated. A CRP level ⩾0.5 mg dl-1 was considered elevated. Associations of elevated CRP with BCR were evaluated using univariable and multivariable Cox proportional hazards regression models. Harrel's C-index was used to assess prognostic accuracy (PA).Results:Patients with higher Gleason score on biopsy and RP, extracapsular extension, seminal vesicle invasion, lymph node metastasis, and positive surgical margins status had a significantly elevated preoperative CRP compared to those without these features. Patients with elevated CRP had a lower 5-year BCR survival proportion as compared to those with normal CRP (55% vs 76%, respectively, P<0.0001). In pre- and postoperative multivariable models that adjusted for standard clinical and pathologic features, elevated CRP was independently associated with BCR (P<0.001). However, the addition of preoperative CRP did not improve the accuracy of the standard pre- and postoperative models for prediction of BCR (70.9% vs 71% and 78.9% vs 78.7%, respectively).Conclusions:Preoperative CRP is elevated in patients with pathological features of aggressive PCa and BCR after RP. While CRP has independent prognostic value, it does not add prognostically or clinically significant information to standard predictors of outcomes.Prostate Cancer and Prostatic Diseases advance online publication, 26 January 2016; doi:10.1038/pcan.2015.60. © 2016 Macmillan Publishers Limited

Ferenci P.,Medical University of Vienna
Nature Reviews Gastroenterology and Hepatology | Year: 2015

Interferon-free regimes are now the treatment of choice for patients with chronic hepatitis C; previously patients who were 'difficult-to-treat' using interferon-containing treatments can now safely be treated with such therapies. More than 90% of patients infected with HCV genotype 1 or 4, compensated cirrhosis, or who have had liver transplantation, can be cured with the use of sofosbuvir combined with simeprevir, daclatasvir or ledipasvir, or by the combination of paritaprevir with ritonavir, ombitasvir and with or without dasabuvir. Addition of ribavirin seems to shorten treatment duration. However, the safety of these drugs is not fully explored in patients with decompensated cirrhosis (that is, those with Child-Pugh class C disease), and protease inhibitors should not be used in this group. The optimal use of interferon-free regimes in patients with renal failure or after kidney transplantation is currently being studied. However, new and improved drugs are needed to treat patients infected with HCV genotype 3. Unfortunately, the broad application of new HCV treatments is limited by their high costs. In this Review, I discuss the treatment of patients with hepatitis C with compensated and decompensated cirrhosis, before and after orthotopic liver transplantation and in patients with impaired kidney function. © 2015 Macmillan Publishers Limited.

Aletaha D.,Medical University of Vienna
Current Opinion in Rheumatology | Year: 2015

Purpose of review Disease activity assessment in rheumatoid arthritis (RA) is a rapidly evolving field. Not only are new measures suggested or introduced in the field, but also we continuously learn about the better use of existing ones in the context of managing disease. On that background, we reviewed the literature on disease activity in RA of 2014 and selected interesting or relevant studies for further discussion. Recent findings EULAR Management Criteria suggest that stringent disease activity targets should be used to guide treatment adaptation. Several studies support this, some even claim to change cutpoints for existing composite indices to match this stringency requirement, while others suggest seeking additional guidance by musculoskeletal ultrasound. One study suggests substantial modifications of existing composite measures in order to make them more objective, although the evident patient contribution to treatment decisions from another study would claim the opposite, namely to give more emphasis on the patient's perspective. New measures of disease activity include modification of core set parameters or existing MRI scores, but range up to currently less feasible whole-body MRI scans or sophisticated nuclear medicine methods. Summary Here, we review several new studies on disease activity assessment in the management of RA. On the basis of the studies in 2014, we expect that this specific field will continue to attract scientific attention. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

External organs associated with the male gonopore are described for 29 species covering for the first time all seven currently acknowledged, extant families of the orders Lophogastrida, Stygiomysida, and Mysida, and all ten subfamilies of the Mysidae (Mysida). The gonopores are located throughout on the structures of the coxa of the eighth thoracopods. The three orders are consistently differentiated based on their male genital characteristics. Species of the Stygiomysida genera Stygiomysis (Stygiomysidae) and Spelaeomysis (Lepidomysidae) share a closing apparatus formed by two laminar lobes flanking the genital orifice, an anterior setose lobe, and a posterior bare lobe; no tubular penes are developed. In contrast, the Lophogastrida are characterized by a bare, slot-like orifice without lobes; also, in this taxon, no tubular penes are developed. The gonopore is on the inner wall of the coxa without conspicuous elevation in the species of Eucopia (Eucopiidae) and Lophogaster (Lophogastridae) and on the top of an anvil-like elevation in Paralophogaster (Lophogastridae), or of a dome-shaped elevation in Gnathophausia and Neognathophausia (Gnathophausiidae). In all examined species of the Mysida, the gonopores show a closing apparatus formed by lobes; one or more of these lobes is setose in most species. Within the Mysida, the genus Hansenomysis (Petalophthalmidae) and most subfamilies of the Mysidae have well-developed paired penes with (sub) terminal orifice. Only Rhopalophthalmus (Rhopalophthalminae) lacks penes but has bilobate gonopores located without additional elevation at the inner distal corner of the strongly enlarged coxa of the eighth thoracopods; this coxa contains a large seminal vesicle. Within the variety of external male genitalia in the Eumalacostraca, the structures associated with the gonopores appear to be plesiomorphic in Lophogastrida. In the Mysida, they appear to be apomorphic and support the monophyly of this order with respect to the previously published, competing phylogenetic trees. This requires additional evidence in the case of the Stygiomysida. © 2013 Springer-Verlag Berlin Heidelberg.

Lassmann H.,Medical University of Vienna
Journal of the Neurological Sciences | Year: 2013

In this review the differences in pathology and disease mechanisms between early and late stages of multiple sclerosis are discussed. The data suggest that affection of the brain is different, depending on the location of lesions, on the stage of the disease, when lesions arise, and on inter-individual differences between patients. We suggest that in the early stage of the disease new lesions are formed by new waves of inflammatory cells, entering the central nervous system from the circulation and giving rise to focal demyelinated plaques in the white and gray matter. In contrast, at late stages of the disease inflammation decreases, but the susceptibility of the target tissue for neurodegeneration increases. New data suggest that mitochondrial injury, mediated through oxidative injury, is in the center of the pathogenetic events leading to brain damage in multiple sclerosis patients. © 2013 Elsevier B.V.

Background: For decades, heparins and vitamin K antagonists (VKAs) have been the gold standards in therapy of venous thromboembolism (VTE). The advent of factor IIa and Xa inhibitors provides new therapeutic options. Th e aim of this analysis is to compare the currently available new oral anticoagulants (NOACs) with VKAs and also indirectly the NOACs with each other, as it is unlikely that a head-to-head comparison will ever be available. Patients and methods: In total, 27,024 patients were included in the RE-COVER, RE-COVER II, EINSTEIN DVT and PE, AMPLIFY and HOKUSAI studies with 13,511 in the VKA arm and 13,513 in the NOAC arm. Efficacy and safety endpoints were assessed by relative risks (RR) and absolute risk reductions (ARR) relative to VKA. Th e indirect comparison between the NOACs was performed according to ISPOR guidelines. Results: No differences between NOACs and VKA were found regarding recurrent VTE and death. Bleeding was significantly reduced by NOACs: major bleeding by rivaroxaban (RR 0.55; 0.38-0.81) and apixaban (RR 0.31; 0.17-0.55); major and clinically relevant non-major bleeding by dabigatran (RR 0.63; 0.51-0.77), apixaban (RR 0.44; 0.36-0.55) and edoxaban (RR 0.81; 0.71-0.93). The ARR for major bleeding was 1 % for rivaroxaban and apixaban; and for the composite bleeding endpoint 3.2 % for dabigatran, 5.4 % for apixaban, and 1.9 % for edoxaban. Regarding efficacy, no differences were found between NOACs. Apixaban reduced incidence of major bleeding more than dabigatran and edoxaban. Regarding occurrence of the composite bleeding endpoint, apixaban performed better than all other NOACs and dabigatran better than rivaroxaban and edoxaban. Conclusions: NOACs are as efficient in the treatment of VTE as VKA but with reduced risk of bleeding complications. Indirect comparisons indicate differences in the risk of clinically relevant bleeding events. Important issues such as monitoring and reversal of anticoagulation are still unresolved, but introduction of NOACs increased the therapeutic spectrum and thereby the potential for individualized therapy. © 2014 Hans Huber Publishers, Hogrefe AG, Bern.

Heinze G.,Medical University of Vienna | Juni P.,University of Bern
European Heart Journal | Year: 2011

The assessment of treatment effects from observational studies may be biased with patients not randomly allocated to the experimental or control group. One way to overcome this conceptual shortcoming in the design of such studies is the use of propensity scores to adjust for differences of the characteristics between patients treated with experimental and control interventions. The propensity score is defined as the probability that a patient received the experimental intervention conditional on pre-treatment characteristics at baseline. Here, we review how propensity scores are estimated and how they can help in adjusting the treatment effect for baseline imbalances. We further discuss how to evaluate adequate overlap of baseline characteristics between patient groups, provide guidelines for variable selection and model building in modelling the propensity score, and review different methods of propensity score adjustments. We conclude that propensity analyses may help in evaluating the comparability of patients in observational studies, and may account for more potential confounding factors than conventional covariate adjustment approaches. However, bias due to unmeasured confounding cannot be corrected for. © 2011 The Author.

Trnka H.-J.,Orthopaedic Hospital Speising | Krenn S.,Orthopaedic Hospital Speising | Schuh R.,Medical University of Vienna
International Orthopaedics | Year: 2013

This systematic review aims to illustrate the published results of "minimally invasive" procedures for correction of hallux valgus. Based on former systematic reviews on that topic, the literature search was organised by two independent investigators. MEDLINE was systematically searched for available studies. The keywords used were "hallux valgus", "bunion", "percutaneous surgery", "minimally invasive surgery", "arthroscopy", "Bosch" and "SERI". Studies were assessed using the level of evidence rating. A total of 21 papers were included in this review. These studies described a total of 1,750 patients with 2,195 instances of percutaneous, minimally invasive or arthroscopic hallux valgus surgery. Clinical reports of results after minimally invasive hallux valgus surgery at meetings are common. Published results in peer-reviewed journals are less common and the majority of papers are level IV studies according to the level of evidence ratings. We found one level II and three level III studies. Reported complications seem to be less than one may see in one's own clinical practice. This possible bias may be related to the fact that most studies are published by centres performing primarily minimally invasive hallux valgus surgery. © 2013 Springer-Verlag Berlin Heidelberg.

Kornek B.,Medical University of Vienna
Neuropediatrics | Year: 2013

Multiple sclerosis (MS) in children and adolescents has received increased attention during the past decade. Although not tested in randomized placebo-controlled trials, first-line disease-modifying therapies are widely used in patients with MS who are younger than 18 years. This review summarizes current treatment practices, possible future treatment options, and gives insight into special problems in the treatment of pediatric patients with MS. © 2013 Georg Thieme Verlag KG Stuttgart © 2013 by Thieme Medical Publishers, Inc.

Fuehrer H.-P.,University of Veterinary Medicine Vienna | Noedl H.,Medical University of Vienna
Journal of Clinical Microbiology | Year: 2014

Recent molecular studies indicate that Plasmodium ovale malaria is caused by two closely related species of protozoan parasites, thereby imposing new challenges for detection and species differentiation. This minireview explores the potential value of innovative methods for the molecular diagnosis of malaria with a strong emphasis on the discrimination and genotyping of P. ovale wallikeri and P. ovale curtisi as well as tools for the simultaneous detection of P. ovale sp. An update for the widely used NP-1993 to NP-2005 (SSU rRNA) protocols for all human malaria parasites is discussed. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Gil M.,ETH Zurich | Gil M.,Swiss Institute of Bioinformatics | Gil M.,Medical University of Vienna | Zanetti M.S.,ETH Zurich | And 4 more authors.
Molecular Biology and Evolution | Year: 2013

Markov models of codon substitution naturally incorporate the structure of the genetic code and the selection intensity at the protein level, providing a more realistic representation of protein-coding sequences compared with nucleotide or amino acid models. Thus, for protein-coding genes, phylogenetic inference is expected to be more accurate under codon models. So far, phylogeny reconstruction under codon models has been elusive due to computational difficulties of dealing with high dimension matrices. Here, we present a fast maximum likelihood (ML) package for phylogenetic inference, CodonPhyML offering hundreds of different codon models, the largest variety to date, for phylogeny inference by ML. CodonPhyML is tested on simulated and real data and is shown to offer excellent speed and convergence properties. In addition, CodonPhyML includes most recent fast methods for estimating phylogenetic branch supports and provides an integral framework for models selection, including amino acid and DNA models. © The Author 2013. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Handisurya A.,Medical University of Vienna
British Journal of Cancer | Year: 2016

Background:Mucosal human papillomaviruses (HPV) are a major cause of cancers and papillomas of the anogenital and oropharyngeal tract. HPV-vaccination elicits neutralising antibodies in sera and cervicovaginal secretions and protects uninfected individuals from persistent anogenital infection and associated diseases caused by the vaccine-targeted HPV types. Whether immunisation can prevent oropharyngeal infection and diseases and whether neutralising antibodies represent the correlate of protection, is still unclear.Methods:We determined IgG and neutralising antibodies against low-risk HPV6 and high-risk HPV16/18 in sera and oral fluids from healthy females (n=20) before and after quadrivalent HPV-vaccination and compared the results with non-vaccinated controls.Results:HPV-vaccination induced type-specific antibodies in sera and oral fluids of the vaccinees. Importantly, the antibodies in oral fluids were capable of neutralising HPV pseudovirions in vitro, indicating protection from infection. The increased neutralising antibody levels against HPV16/18 in sera and oral fluids post-vaccination correlated significantly within an individual.Conclusions:We provide experimental proof that HPV-vaccination elicits neutralising antibodies to the vaccine-targeted types in oral fluids. Hence, immunisation may confer direct protection against type-specific HPV infection and associated diseases of the oropharyngeal tract. Measurement of antibodies in oral fluids represents a suitable tool to assess vaccine-induced protection within the mucosal milieu of the orophayrynx.British Journal of Cancer advance online publication 11 February 2016; doi:10.1038/bjc.2015.462 www.bjcancer.com. © 2016 Cancer Research UK

Beuers U.,Tytgat Institute for Liver and Intestinal Research | Trauner M.,Medical University of Vienna | Jansen P.,Tytgat Institute for Liver and Intestinal Research | Poupon R.,French Institute of Health and Medical Research
Journal of Hepatology | Year: 2015

Cholestasis is an impairment of bile formation/flow at the level of the hepatocyte and/or cholangiocyte. The first, and for the moment, most established medical treatment is the natural bile acid (BA) ursodeoxycholic acid (UDCA). This secretagogue improves, e.g. in intrahepatic cholestasis of pregnancy or early stage primary biliary cirrhosis, impaired hepatocellular and cholangiocellular bile formation mainly by complex post-transcriptional mechanisms. The limited efficacy of UDCA in various cholestatic conditions urges for development of novel therapeutic approaches. These include nuclear and membrane receptor agonists and BA derivatives. The nuclear receptors farnesoid X receptor (FXR), retinoid X receptor (RXR), peroxisome proliferator-activated receptor α (PPARα), and pregnane X receptor (PXR) are transcriptional modifiers of bile formation and at present are under investigation as promising targets for therapeutic interventions in cholestatic disorders. The membrane receptors fibroblast growth factor receptor 4 (FGFR4) and apical sodium BA transporter (ASBT) deserve attention as additional therapeutic targets, as does the potential therapeutic agent norUDCA, a 23-C homologue of UDCA. Here, we provide an overview on established and future promising therapeutic agents and their potential molecular mechanisms and sites of action in cholestatic diseases. © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Berlakovich G.A.,Medical University of Vienna
World Journal of Gastroenterology | Year: 2014

Transplantation for the treatment of alcoholic cirrhosis is more controversially discussed than it is for any other indication. The crucial aspect in this setting is abstinence before and after liver transplantation. We established pre-transplant selection criteria for potential transplant candidates. Provided that the underlying disease can be treated, there is no reason to withhold liver transplantation in a patient suffering from alcoholic cirrhosis. Evaluation of the patient by a multidisciplinary team, including an addiction specialist, is considered to be the gold standard. However, several centers demand a specified period of abstinence - usually 6 mo- irrespective of the specialist's assessment. The 6-mo rule is viewed critically because liver transplantation was found to clearly benefit selected patients with acute alcoholic hepatitis; the benefit was similar to that achieved for other acute indications. However, the discussion may well be an academic one because the waiting time for liver transplantation exceeds six months at the majority of centers. The actual challenge in liver transplantation for alcoholic cirrhosis may well be the need for lifelong post-transplant follow-up rather than the patient's pretransplant evaluation. A small number of recipients experience a relapse of alcoholism; these patients are at risk for organ damage and graft-related death. Posttransplant surveillance protocols should demonstrate alcohol relapse at an early stage, thus permitting the initiation of adequate treatment. Patients with alcoholic cirrhosis are at high risk of developing head and neck, esophageal, or lung cancer. The higher risk of malignancies should be considered in the routine assessment of patients suffering from alcoholic cirrhosis. Tumor surveillance protocols for liver transplant recipients, currently being developed, should become a part of standard care; these will improve survival by permitting diagnosis at an early stage. In conclusion, the key factor determining the outcome of transplantation for alcoholic cirrhosis is intensive lifelong medical and psychological care. Post-transplant surveillance might be much more important than pre-transplant selection. © 2014 Baishideng Publishing Group Inc. All rights reserved.

Kovacs G.G.,Medical University of Vienna
Neuropathology and Applied Neurobiology | Year: 2015

Tauopathies are clinically, morphologically and biochemically heterogeneous neurodegenerative diseases characterized by the deposition of abnormal tau protein in the brain. The neuropathological phenotypes are distinguished based on the involvement of different anatomical areas, cell types and presence of distinct isoforms of tau in the pathological deposits. The nomenclature of primary tauopathies overlaps with the modern classification of frontotemporal lobar degeneration. Neuropathological phenotypes comprise Pick's disease, progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, primary age-related tauopathy, formerly called also as neurofibrillary tangle-only dementia, and a recently characterized entity called globular glial tauopathy. Mutations in the gene encoding the microtubule-associated protein tau are associated with frontotemporal dementia and parkinsonism linked to chromosome 17. In addition, further neurodegenerative conditions with diverse aetiologies may be associated with tau pathologies. Thus, the spectrum of tau pathologies and tauopathy entities expands beyond the traditionally discussed disease forms. Detailed multidisciplinary studies are still required to understand their significance. © 2014 British Neuropathological Society.

Partsch H.,Medical University of Vienna
Phlebology | Year: 2014

Up until today mobile outpatients are put into bed as soon as the diagnosis of deep vein thrombosis (DVT) is made. Fear of pulmonary embolism (PE) is the main rationale for bed-rest; additional arguments are pain and swelling which are expected to resolve faster during leg elevation. Based on previous work it is demonstrated that keeping mobile patients with acute DVT walking under exact anticoagulation does not increase the risk for symptomatic PE in comparison with bed-rest and that there is an immediate reduction of pain and swelling when good compression is applied and the patient is encouraged to walk. Immediate compression and walking seems also to reduce the incidence of a postthrombotic syndrome. One presumed mechanism of action of this adjunct treatment modality is the increase of shear stress in the microcirculation of the vein wall releasing anti-inflammatory and anti-coagulatory mediators. © The Author(s) 2014.

Niederkrotenthaler T.,Medical University of Vienna | Rasmussen F.,Karolinska Institutet | Mittendorfer-Rutz E.,Karolinska Institutet
European Journal of Epidemiology | Year: 2012

Restricted fetal growth and young maternal age have been associated with increased risk of suicidal behaviour later in life. Research investigating the independent and interacting effects of these risk factors with parental mental health and socio-economic status is scarce. A case-control study was effected through record linkage between Swedish registers. Individuals born 1973-1983 who were hospitalized due to a suicide attempt (n = 17,159) or committed suicide (n = 1,407) werematched toB10 controls by sex, month and county of birth. Controlling for parental conditions, significantly increased odds ratios (OR) for suicide attempt were found for low birth weight (OR = 1.12, 95% CI 1.01-1.25), short birth length (OR = 1.15, 95%CI 1.08-1.22), short and light for gestational age (OR = 1.23, 95% CI: 1.10-1.38), short but not light for gestational age (OR = 1.18, 95% CI: 1.09, 1.29), teenage motherhood (OR = 1.66, 95% CI 1.53- 1.80), young fatherhood (OR = 1.33, 95% CI 1.27-1.39) and multiparity (OR = 1.40, 95% CI 1.31-1.50). For completed suicide, increased odds ratios were found for low birth weight (OR = 1.65, 95% CI 1.16-2.35), teenage motherhood (OR = 1.44, 95%CI 1.09-1.90) and young fatherhood (OR = 1.20, 95%CI 1.02-1.41). There was a synergy effect between teenage motherhood and parental psychiatric inpatient care with regard to suicide attempt in offspring [synergy index = 1.53 (95% CI 1.27-1.84)]. Low birth weight and length, and short and light for gestational age may increase the risk of subsequent suicidal behaviour, and more research is needed to investigate underlying mechanisms. Public health implications fromthis study includemeasures to improve preand perinatal parental mental health, particularly in teenage pregnancies. © 2012 Springer Science+Business Media B.V.

Partsch H.,Medical University of Vienna
Phlebology | Year: 2014

Compression therapy is the most important basic treatment modality in venous leg ulcers. The review focusses on the materials which are used: 1. Compression bandages, 2. Compression stockings, 3. Self-adjustable Velcro-devices, 4. Compression pumps, 5. Hybrid devices. Compression bandages, usually applied by trained staff, provide a wide spectrum of materials with different elastic properties. To make bandaging easier, safer and more effective, most modern bandages combine different material components. Self-management of venous ulcers has become feasible by introducing double compression stockings ("ulcer kits") and self-adjustable Velcro devices. Compression pumps can be used as adjunctive measures, especially for patients with restricted mobility. The combination of sustained and intermittent compression ("hybrid device") is a promising new tool.The interface pressure corresponding to the dosage of compression therapy determines the hemodynamic efficacy of each device. In order to reduce ambulatory venous hypertension compression pressures of more than 50 mm Hg in the upright position are desirable. At the same time pressure should be lower in the resting position in order to be tolerated. This prerequisite may be fulfilled by using inelastic, short stretch material including multicomponent bandages and cohesive surfaces, all characterized by high stiffness. Such materials do not give way when calf muscles contract during walking which leads to high peaks of interface pressure ("massaging effect"). © The Author(s) 2014.

Hoftberger R.,Medical University of Vienna
Frontiers in Immunology | Year: 2015

Anti-neuronal autoimmune encephalitis (AIE) comprises a recently characterized group of immune-mediated disorders that result in limbic, multifocal, or diffuse encephalitis due to direct interaction of autoantibodies with neuronal surface or synaptic proteins. The pathological effects of the autoantibodies vary according to the target antigen but when they are removed, neuronal dysfunction is commonly reversed. Ongoing research on AIE constantly increases the number of novel autoantibodies and expands the spectrum of neurological syndromes that are important in the differential diagnosis of psychiatric illness, dementia, or viral encephalitis. This review summarizes recent advances in AIE, focusing on pathogenetic mechanisms and novel associations with other CNS disorders such as neurodegeneration, relapsing symptoms post-herpes simplex virus encephalitis, and demyelinating diseases. In addition, an algorithmic approach to detect and characterize neuronal cell surface autoantibodies is proposed. © 2015 Höftberger.

Seitz C.,Medical University of Vienna
European urology | Year: 2012

Incidence, prevention, and management of complications of percutaneous nephrolitholapaxy (PNL) still lack consensus. To review the epidemiology of complications and their prevention and management. A literature review was performed using the PubMed database between 2001 and May 1, 2011, restricted to human species, adults, and the English language. The Medline search used a strategy including medical subject headings (MeSH) and free-text protocols with the keywords percutaneous, nephrolithotomy, PCNL, PNL, urolithiasis, complications, and Clavien, and the MeSH terms nephrostomy, percutaneous/adverse effects, and intraoperative complications or postoperative complications. Assessing the epidemiology of complications is difficult because definitions of complications and their management still lack consensus. For a reproducible quality assessment, data should be obtained in a standardized manner, allowing for comparison. An approach is the validated Dindo-modified Clavien system, which was originally reported by seven studies. No deviation from the normal postoperative course (Clavien 0) was observed in 76.7% of PNL procedures. Including deviations from the normal postoperative course without the need for pharmacologic treatment or interventions (Clavien 1) would add up to 88.1%. Clavien 2 complications including blood transfusion and parenteral nutrition occurred in 7%; Clavien 3 complications requiring intervention in 4.1.%; Clavien 4, life-threatening complications, in 0.6%; and Clavien 5, mortality, in 0.04%. High-quality data on complication management of rare but potentially debilitating complications are scarce and consist mainly of case reports. Complications after PNL can be kept to a minimum in experienced hands with the development of new techniques and improved technology. A modified procedure-specific Clavien classification should be established that would need to be validated in prospective trials. Copyright © 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Essential thrombocythemia (ET) is currently diagnosed either by the British Committee of Standards in Haematology (BCSH) criteria that are predominantly based on exclusion and not necessarily on bone marrow (BM) morphology, or the World Health Organization (WHO) criteria that require BM examination as essential criterion. We studied the morphological and clinical features in patients diagnosed according either to the BCSH (n=238) or the WHO guidelines (n=232). The BCSH-defined ET cohort was re-evaluated by applying the WHO classification. At presentation, patients of the BCSH group showed significantly higher values of serum lactate dehydrogenase and had palpable splenomegaly more frequently. Following the WHO criteria, the re-evaluation of the BCSH-diagnosed ET cohort displayed a heterogeneous population with 141 (59.2%) ET, 77 (32.4%) prefibrotic primary myelofibrosis (prePMF), 16 (6.7%) polycythemia vera and 4 (1.7%) primary myelofibrosis. Contrasting WHO-confirmed ET, the BCSH cohort revealed a significant worsening of fibrosis-free survival and prognosis. As demonstrated by the clinical data and different outcomes between WHO-diagnosed ET and prePMF, these adverse features were generated by the inadvertent inclusion of prePMF to the BCSH group. Taken together, the diagnosis of ET without a scrutinized examination of BM biopsy specimens will generate a heterogeneous cohort of patients impairing an appropriate clinical management.Leukemia advance online publication, 12 February 2016; doi:10.1038/leu.2015.360. © 2015 Macmillan Publishers Limited

Valent P.,Medical University of Vienna | Dahinden C.A.,University of Bern
Current Opinion in Hematology | Year: 2010

Purpose of review: It is well appreciated that differentiation, growth, and function of basophils are regulated by a network of cytokines, and that these cells express a unique composition of surface receptors including interleukin-binding sites. In the current article, most recent discoveries around cytokine regulation of basophils are discussed and compared with previous data. Recent findings: Confirming previous studies, the most potent growth factor for basophils remains interleukin (IL)-3, followed by granulocyte-macrophage colony-stimulating factor and IL-5. These cytokines also act on mature basophils through specific receptors, thereby mediating adhesion, migration, and releasability. Other molecules regulating basophil function are chemokines such as IL-8 or eotaxin and IL-33. Especially IL-33 has been described as a novel basophil regulator. All cytokines act on basophils via specific receptors and signal transduction pathways. The present article provides a summary of our knowledge on cytokine regulation of basophils and receptor expression, with emphasis on most recent developments in the field. Summary: Basophil regulation by cytokines in health and disease may be a more complex process than has been considered previously. Some of the affected cytokine cascades, receptors, and signal transduction molecules may serve as targets of therapy in 'basophil activation disorders' in the future. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Berry D.,University of Vienna | Reinisch W.,Medical University of Vienna
Best Practice and Research: Clinical Gastroenterology | Year: 2013

The human intestine harbours a complex microbial ecosystem that performs manifold functions important to the nutrition and health of its host. Extensive study has revealed that the composition of the intestinal microbiota is altered in individuals with inflammatory bowel disease (IBD). The IBD associated intestinal microbiota generally has reduced species richness and diversity, lower temporal stability, and disruption of the secreted mucus layer structure. Multiple studies have identified certain bacterial taxa that are enriched or depleted in IBD including Enterobacteriaceae, Ruminococcus gnavus, and Desulfovibrio (enriched) and Faecalibacterium prausnitzii, Lachnospiraceae, and Akkermansia (depleted). Additionally, the relative abundance of some taxa appears to correlate with established markers of disease activity such as Enterobacteriaceae (enriched) and Lachnospiraceae (depleted). Signature shifts in fecal microbial community composition may therefore prove to be valuable as diagnostic biomarkers, particularly for longitudinal monitoring of disease activity and response to treatments. © 2013 Elsevier Ltd. All rights reserved.

Erythropoiesis-stimulating agents (ESAs) have become a hallmark of anaemia therapy in patients with chronic kidney disease (CKD). Although different ESAs are available for the treatment of renal anaemia, each nephrologist should select a single ESA for an individual patient. Epoetin alfa and epoetin beta have been used 1-3 times weekly but extended-interval dosing up to every 4 weeks is also effective in a substantial majority of CKD patients. However, the epoetin dose necessary to achieve or maintain target haemoglobin (Hb) levels increases substantially as the dosing interval increases. Subcutaneous administration of short-acting ESAs is more effective than the intravenous route of administration. Darbepoetin alfa and the continuous erythropoietin receptor activator (CERA) have been developed as a treatment for anaemia with extended administration intervals (every 2 weeks and every 4 weeks, respectively). Dose requirements for these long-acting ESAs are independent of the route of administration. Patents of short-acting ESAs have expired, which has opened the field for biosimilars. Epoetin biosimilars approved by the European Medicines Agency (EMA) or the US Food and Drug Administration (FDA) have been shown to have a comparable efficacy and safety profile to their originators. An alarming increase in pure red cell aplasia (PRCA) in Thailand with follow-on epoetins manufactured in Asia (but also those manufactured in Latin America) indicates that stringent country-specific approval and pharmacovigilance protocols for ESAs manufactured in non-North American and non-EU European countries are urgently needed. Two PRCA cases occurring with subcutaneous HX575 (one certain, one likely) indicate that chances of inducing a more immunogenic product are unpredictable, even with a biosimilar epoetin approved under the EMA biosimilar approval pathway. Phase III clinical trials with peginesatide, a pegylated synthetic peptide-based ESA without any homology to erythropoietin raised safety concerns in non-dialysis CKD patients but not in dialysis patients. © 2013 Springer International Publishing Switzerland.

Villalba-Galea C.A.,Virginia Commonwealth University | Frezza L.,University of Chicago | Sandtner W.,Medical University of Vienna | Bezanilla F.,University of Chicago
Journal of General Physiology | Year: 2013

Voltage control over enzymatic activity in voltage-sensitive phosphatases (VSPs) is conferred by a voltage-sensing domain (VSD) located in the N terminus. These VSDs are constituted by four putative transmembrane segments (S1 to S4) resembling those found in voltage-gated ion channels. The putative fourth segment (S4) of the VSD contains positive residues that likely function as voltage-sensing elements. To study in detail how these residues sense the plasma membrane potential, we have focused on five arginines in the S4 segment of the Ciona intestinalis VSP (Ci-VSP). After implementing a histidine scan, here we show that four arginine-to-histidine mutants, namely R223H to R232H, mediate voltage-dependent proton translocation across the membrane, indicating that these residues transit through the hydrophobic core of Ci-VSP as a function of the membrane potential. These observations indicate that the charges carried by these residues are sensing charges. Furthermore, our results also show that the electrical field in VSPs is focused in a narrow hydrophobic region that separates the extracellular and intracellular space and constitutes the energy barrier for charge crossing. © 2013 Villalba-Galea et al.

Miehsler W.,Medical University of Vienna
Wiener Medizinische Wochenschrift | Year: 2010

Obesity is on the advance in western industrialised countries and is therefore increasingly relevant also to intensive care medicine. In contrast to the common prejudice that obese patients probably have a higher ICU mortality than lean patients, convincing meta-analyses have revealed that this is not the case. Nevertheless, obese ICU patients are challenging. Especially mechanic ventilation has to be addressed: besides obesity-related anatomical problems that may complicate intubation, obstructive sleep apnoea, obesity hypoventilation syndrome and increased intra-abdominal pressure are of major relevance concerning ventilation, weaning and successful extubation. Also the risk of infections is increased in obese ICU patients, although this does not seem to increase the risk of sepsis. Nevertheless, the interplay of obesity and sepsis is a fascinating field in that adipous tissue is not just a passive reservoir of energy but an active endocrine and immunomodulating organ. However, the way of how adipokines interact with inflammation and coagulation in sepsis has yet to be clarified.© Springer-Verlag 2010.

Valent P.,Medical University of Vienna
Blood | Year: 2014

In this issue of Blood, Gallipoli et al show that combined targeting of BCR/ABL1 and Janus kinase 2 (JAK2) by 2 established kinase inhibitors, nilotinib (NI) and the JAK1/2 kinase inhibitor ruxolitinib (RUX), results in synergistic growth inhibition in immature CD34+ stem and progenitor cells obtained from patients with chronic myeloid leukemia (CML). © 2014 by The American Society of Hematology.

Akin C.,Harvard University | Valent P.,Medical University of Vienna
Immunology and Allergy Clinics of North America | Year: 2014

Mastocytosis is characterized by accumulation of pathologic mast cells in tissues. Most patients with mastocytosis experience mast cell activation symptoms in response to various triggers. The diagnosis of mastocytosis should be made from objective pathologic findings. Modern diagnostic criteria and classification of mastocytosis were proposed in 2000 by an international consensus group and formed the basis of the current World Health Organization (WHO) guidelines, which have been validated to correlate with prognosis and help selection of therapy. In this article, the WHO criteria for diagnosis and classification are summarized and practical aspects to avoid common pitfalls in diagnostic workup are discussed. © 2014 Elsevier Inc.

Dunkler D.,Medical University of Vienna
Methods in molecular biology (Clifton, N.J.) | Year: 2011

In Omics experiments, typically thousands of hypotheses are tested simultaneously, each based on very few independent replicates. Traditional tests like the t-test were shown to perform poorly with this new type of data. Furthermore, simultaneous consideration of many hypotheses, each prone to a decision error, requires powerful adjustments for this multiple testing situation. After a general introduction to statistical testing, we present the moderated t-statistic, the SAM statistic, and the RankProduct statistic which have been developed to evaluate hypotheses in typical Omics experiments. We also provide an introduction to the multiple testing problem and discuss some state-of-the-art procedures to address this issue. The presented test statistics are subjected to a comparative analysis of a microarray experiment comparing tissue samples of two groups of tumors. All calculations can be done using the freely available statistical software R. Accompanying, commented code is available at: http://www.meduniwien.ac.at/msi/biometrie/MIMB.

Lang I.,Medical University of Vienna
British Journal of Haematology | Year: 2010

Chronic thromboembolic pulmonary hypertension (CTEPH) comprises organizing thrombotic obstructions in the pulmonary arteries. While roughly 40% of CTEPH cases are not preceded by a venous thromboembolic event, 0·1-5·1% of acute pulmonary thromboemboli evolve into organized obstructions of the pulmonary artery. In patients with predominantly proximal disease, surgical pulmonary endarterectomy provides a potential cure of the disease. For years, the scientific debate of CTEPH was mainly focused around its thromboembolic nature because of striking dissimilarities to classical venous thromboembolism, for example, the lack of risk factors for venous thrombosis, the lack of clinically apparent pulmonary embolism in many patients, the difficulty to reproduce the disease in animal models of thrombosis, and the nature of the pulmonary vascular obstructions that are dissociated from the degree of hemodynamic compromise. Recent studies have confirmed an association between venous thromboembolism and the evolution of CTEPH, and have shed light on disease-modifying conditions. © 2010 Blackwell Publishing Ltd.

Data regarding the safety and effectiveness of aromatase inhibitors (AIs) as monotherapy or combined with gonadotropin-releasing hormone (GnRH) analogue in male breast cancer are scarce. In this retrospective chart review, cases of male breast cancer patients treated with AIs with or without a GnRH analogue were evaluated. Twenty-three men were included into this case series. Aromatase inhibitors in combination with or without a GnRH analogue were given as first-line therapy in 60.9% and as second-line therapy in 39.1% of patients, respectively. All patients had visceral metastases, whereas in five of them bone lesions coexisted. In all cases AIs were tolerated well, and no case of grade 3 and 4 adverse events was reported. A partial response was observed in 26.1% of patients and stable disease in 56.5%. Median overall survival (OS) was 39 months and median progression-free survival (PFS) was 13 months. Regarding OS and PFS, no significant effects of GnRH analogue co-administration or type of AI were noted. Our study shows that AIs with or without GnRH analogues may represent an effective and safe treatment option for hormone-receptor positive, pretreated, metastatic, male breast cancer patients.

Warren G.,Medical University of Vienna
Nature Reviews Molecular Cell Biology | Year: 2013

The 2013 Nobel Prize in Physiology or Medicine emphasizes the progress made in understanding the molecular mechanisms that underpin the vesicular movement of cargo through the exocytic and endocytic pathways. Attention now focuses on those mechanisms that govern the relative size and position of the many different membrane-bound compartments. These homeostatic mechanisms are discussed in this issue of Nature Reviews Molecular Cell Biology and must be integrated so as to satisfy the needs of the cell and the organism. © 2013 Macmillan Publishers Limited. All rights reserved.

Metabolic diseases dramatically affect life of men and women from infancy up to old age and are a major challenge for clinicians. Health professionals are confronted with different needs of women and men. This article aims at an increase of gender awareness and the implementation of current knowledge of gender medicine in daily clinical practice with regard to pre-diabetes and diabetes. Sex and gender affect screening and diagnosis of metabolic diseases as well as treatment strategies and outcome. Impaired glucose and lipid metabolism, regulation of energy balance and body fat distribution are related to steroid hormones and therefore impose their influence on cardiovascular health in both men and women. Furthermore, education, income and psychosocial factors relate to development of obesity and diabetes differently in men and women. Males appear to be at greater risk of diabetes at younger age and at lower BMI compared to women, but women feature a dramatic increase of their cardiometabolic risk after menopause. The estimated future years of life lost owing to diabetes is somewhat higher in women than men, with higher increase of vascular death in women, but higher increase of cancer death in men. In women pre-diabetes or diabetes are more distinctly associated with a higher number of vascular risk factors, such as inflammatory parameters, unfavourable changes of coagulation and blood pressure. Pre-diabetic and diabetic women are at much higher risk for vascular disease (3-6 times compared to non-diabetic women) than diabetic men (2-3 times compared to healthy males). Women are more often obese and less physically active, but may even have greater benefit from increased physical activity than males. Whereas men predominantly feature impaired fasting glucose, women often show impaired glucose tolerance. A history of gestational diabetes or the presence of a PCOS or increased androgen levels in women, on the other hand the presence of erectile dysfunction (ED) or decreased testosterone levels in men are sex specific risk factors for diabetes development. ED is a common feature of obese men with the Metabolic Syndrome and an important predictor of cardiovascular disease. Several studies showed that diabetic women reach their targets of metabolic control (HbA1c), blood pressure and LDL-cholesterol less often than their male counterparts, although the reasons for worse treatment outcome in diabetic females are not clear. Furthermore, sex differences in action, pharmacokinetics, and side effects of pharmacological therapy have to be taken into account.

Reinisch W.,McMaster University | Smolen J.,Medical University of Vienna
Seminars in arthritis and rheumatism | Year: 2015

OBJECTIVES: This article provides insight into the guidelines issued by the European Medicines Agency (EMA) and the draft guidances issued by the US Food and Drug Administration (FDA) regarding potential safety considerations associated with the development and use of biosimilars.METHODS: EMA and FDA guidelines and the literature were reviewed to identify recommendations and experience of manufacturers regarding the safety of biosimilars.RESULTS: Recent results of phase 3 comparability clinical trials comparing biosimilars with their reference products, and the approval of a biosimilar infliximab by several regulatory agencies, demonstrate the growing importance of biosimilars in inflammatory diseases. The safety profiles of biosimilars developed according to regulatory guidelines appear to be highly similar to the reference product, and postmarketing pharmacovigilance programs are in place. Additional topics related to biosimilars, such as interchangeability, automatic substitution, and nomenclature, are discussed.CONCLUSIONS: Safety considerations in the development of biosimilars are an important focus of regulatory guidelines, although topics such as interchangeability, automatic substitution, and nomenclature are still being debated. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Gnant M.,Medical University of Vienna
Anti-Cancer Agents in Medicinal Chemistry | Year: 2012

Despite progress in surgical and adjuvant therapy, a subset of patients with early stage breast cancer experience disease recurrence and/or distant metastases. Disseminated tumor cells (DTCs) in the bone marrow are believed to be the source of late relapses in bone and other tissues. Bone is the most common site of breast cancer metastasis, and agents that modify the bone microenvironment could therefore affect the disease course. Bisphosphonates are an effective bone-targeted therapeutic option for preventing cancer treatment-induced bone loss (CTIBL) in pre- and postmenopausal women with breast cancer. Bisphosphonates inhibit osteoclast-mediated bone resorption, thereby inhibiting the release of growth factors necessary to promote cancer cell growth, differentiation, and tumor formation in bone. Preclinical and clinical data also suggest anticancer synergy between cytotoxic chemotherapy agents and bisphosphonates. Recent trials of zoledronic acid in the adjuvant setting in breast cancer have demonstrated reduced disease recurrence in bone and other sites. Currently, several ongoing clinical trials are evaluating whether antiresorptives can inhibit disease recurrence and the development of bone metastases from breast cancer. Based on recent data, the role of bisphosphonates in the breast cancer setting is expected to expand in the future. With recent changes to treatment guidelines, routine use of bisphosphonates to prevent bone loss during adjuvant therapy is likely to become standard practice, especially for patients receiving endocrine therapy. Furthermore, the use of zoledronic acid to reduce the risk of recurrence is emerging based on ongoing clinical research. © 2012 Bentham Science Publishers.

Smolen J.S.,Medical University of Vienna | Weinblatt M.E.,Brigham and Womens Hospital | Sheng S.,Janssen Research and Development LLC | Zhuang Y.,Janssen Research and Development LLC | Hsu B.,Janssen Research and Development LLC
Annals of the Rheumatic Diseases | Year: 2014

Objectives: The safety and efficacy of sirukumab, an anti-interleukin-6 (IL-6) monoclonal antibody, were evaluated in a 2-part, placebo-controlled phase II study of patients with active rheumatoid arthritis (RA) despite methotrexate therapy. Methods: In Part A ( proof-of-concept), 36 patients were randomised to placebo or sirukumab 100 mg every 2 weeks (q2w) through week 10, with crossover treatment during weeks 12-22. In Part B (dose finding), 151 patients were randomised to sirukumab (100 mg q2w, 100 mg q4w, 50 mg q4w, or 25 mg q4w) through week 24, or placebo through week 10 with crossover to sirukumab 100 mg q2w (weeks 12-24). The proportion of patients with an American College of Rheumatology 50 (ACR50) response and the change from baseline in the 28-joint count disease activity score using C-reactive protein (DAS28-CRP) were determined. Safety was evaluated through week 38 in both parts. Results: The primary endpoint (ACR50 at week 12 in Part B) was achieved only with sirukumab 100 mg q2w versus placebo (26.7% vs 3.3%; p=0.026). Greater improvements in mean DAS28-CRP at week 12 were observed with sirukumab 100 mg q2w versus placebo in Parts A (2.1 vs 0.6, p<0.001) and B (2.2 vs 1.1; p<0.001). The incidence of adverse events (AEs) was similar for sirukumab-treated and placebo-treated patients through week 12 in Part A (70.6% and 63.2%, respectively) and B (67.8% and 66.7%, respectively). Infections were the most common type of AE; one death occurred (Part B, sirukumab 100 mg q2w, brain aneurysm). Conclusions: Sirukumab-treated patients experienced improvements in the signs/symptoms of RA. Safety results through 38 weeks were consistent with other IL-6 inhibitors. Trial registration number: NCT00718718.

Arock M.,CNRS Laboratory of Biology and Applied Pharmacology | Valent P.,Medical University of Vienna
Expert Review of Hematology | Year: 2010

Mastocytosis is a myeloid neoplasm characterized by abnormal accumulation and frequent activation of mast cells (MCs) in various organs. Organ systems typically involved are the bone marrow, skin, liver and gastrointestinal tract. In most adult patients, the systemic form of mastocytosis (SM) is diagnosed, which includes an indolent subvariant, an aggressive subvariant and a leukemic subvariant, also termed MC leukemia. Whereas in pediatric mastocytosis, which is usually confined to the skin, a number of different KIT mutations and other defects may be detected, the KIT mutation D816V is detectable in most (adult) patients with SM. In a subset of these patients, additional oncogenic factors may lead to enhanced survival and growth of MCs and, thus, to advanced SM. Other factors may lead to MC activation, with consecutive anaphylactic reactions that can be severe or even fatal. Treatment of SM usually focuses on symptom relief by histamine receptor antagonists and other supportive therapy. However, in aggressive and leukemic variants, cytoreductive and targeted drugs must be applied. Unfortunately, the prognosis in these patients remains poor, even when treated with novel KIT-targeting agents, polychemotherapy or stem cell transplantation. This article provides a summary of our knowledge on the pathogenesis and on treatment options in SM. © 2010 Expert Reviews Ltd.

Springer E.,Medical University of Vienna
Investigative Radiology | Year: 2016

OBJECTIVE: The aim of this study was to compare quantitative and semiquantitative parameters (signal-to-noise ratio [SNR] and diagnostic confidence) from a standard knee magnetic resonance imaging (MRI) examination with comparable sequence protocols and acquisition times at 3 T and at 7 T. MATERIALS AND METHODS: Forty patients experiencing knee pain of unknown etiology underwent comparable MR protocols with standard turbo-spin echo and short tau inversion recovery sequences of the knee joint (5 sequences) at 3 T and 7 T. For quantitative analysis, SNR was determined using these 5 sequences and 3 additional morphological sequences. For a semiquantitative assessment of diagnostic confidence, a diagnostic confidence score (DCS) was assigned, using a 10-point scale. Two experienced radiologists who specialized in musculoskeletal imaging and who were blinded to the field-strength independently assessed 22 potential pathological findings, in total, in 4 anatomically defined areas in the knee joint and rated their diagnostic confidence. RESULTS: In quantitative analysis, all sequences provided higher voxel-volume-adjusted SNR values at 7 T compared with that at 3 T. In semiquantitative analysis, summed DCS values for potential pathological findings in each of the 4 anatomically defined areas were higher at 7 T compared with that at 3 T. There was a statistically significant improvement in the DCS for both readers at 7 T for the diagnosis and exclusion of focal or diffuse grade I or II cartilage defects in the patellar cartilage. For 8 potential pathological findings, a statistically significant difference between the 2 field-strengths could be observed for 1 reader only. For the residual 13 potential pathological findings, there was no statistically significant difference observed. The percentage of concordant ratings was 84.6% at 3 T and 85.4% at 7 T. CONCLUSIONS: Ultra-high-field MRI at 7 T improved the overall diagnostic confidence in routine MRI of the knee joint compared with that at 3 T. This is especially true for small joint structures and subtle lesions. Higher spatial resolution was identified as the main reason for this improvement. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

Wober-Bingol C.,Medical University of Vienna
Current Pain and Headache Reports | Year: 2013

Migraine and headache are global disabling conditions causing considerable individual suffering and impaired quality of life in adults as well as in children and adolescents. Therefore, epidemiological studies are essential to assess the scope of the problem. This review covers epidemiological studies on migraine and headache in children and adolescents published in the past 25 years. A total of 64 cross-sectional studies have been identified, published in 32 different countries and including a total of 227,249 subjects. The estimated overall mean prevalence of headache was 54.4 % (95 % CI 43.1-65.8) and the overall mean prevalence of migraine was 9.1 % (95 % CI 7.1-11.1). There is a lack of population-based studies from low and low-middle income countries. In addition, there is very little information about the prevalence of probable migraine and chronic migraine and no information about menstrual migraine in the young. © 2013 Springer Science+Business Media New York.

Lassmann H.,Medical University of Vienna
Experimental Neurology | Year: 2010

Axonal and neuronal injury and loss are of critical importance for permanent clinical disability in multiple sclerosis patients. Axonal injury occurs already early during the disease and accumulates with disease progression. It is not restricted to focal demyelinated lesions in the white matter, but also affects the normal appearing white matter and the grey matter. Experimental studies show that many different immunological mechanisms may lead to axonal and neuronal injury, including antigen-specific destruction by specific T-cells and auto-antibodies as well as injury induced by products of activated macrophages and microglia. They all appear to be relevant for multiple sclerosis pathogensis in different patients and at different stages of the disease. However, in MS lesions a major mechanism of axonal and neuronal damage appears to be related to the action of reactive oxygen and nitrogen species, which may induce neuronal injury through impairment of mitochondrial function and subsequent energy failure. © 2009 Elsevier Inc.

Binder C.J.,Medical University of Vienna | Binder C.J.,Austrian Academy of Sciences
Journal of Clinical Immunology | Year: 2010

Introduction Natural antibodies (NAbs) are mostly antibodies of the IgM isotype with germline or close to germline encoded variable regions that provide them with specificity for both microbial and altered self antigens. Thus, natural IgM possess an important function in the first line defense against invading pathogens and in tissue homeostasis by regulating the clearance of cellular debris. Results Oxidation-specific epitopes represent prominent examples of stress-induced altered self, as they are generated ubiquitously as a consequence of lipid peroxidation during many physiological and pathological situations, and are found on the membranes of apoptotic cells. Importantly, oxidation-specific epitopes are dominant targets of natural IgM antibodies, indicating an important role for natural IgM in their clearance and the neutralization of their proinflammatory properties. Summary and conclusion These findings and the insights they provide into the ability of NAbs in mediating host homeostasis in health and diseases, including atherosclerosis and other chronic inflammatory diseases, will be discussed. © Springer Science+Business Media, LLC 2010.

Schernthaner G.,Rudolfstiftung Hospital | Currie C.J.,University of Cardiff | Schernthaner G.-H.,Medical University of Vienna
Diabetes Care | Year: 2013

An updated algorithm for the initiation and adjustment of therapy for the management of hyperglycemia has been published as a position statement of the American Diabetes Association and European Association for the Study of Diabetes (32). According to this position statement, "pioglitazone appeared to have a modest benefit on CV events as a secondary outcome in one large trial involving patients with overtmacrovascular disease." In the proposed algorithm, pioglitazone monotherapy can be considered an alternative to metformin monotherapy if metformin cannot be used (not tolerated or is contraindicated), as a combination therapy if monotherapy with metformin alone does not achieve/maintain an HbA1c target, or a triple combination therapy, provided that oral agents with complementary mechanisms of action are used. Thus, pioglitazone remains an effective and useful antidiabetes drug with a unique insulin-sensitizing action. However, the clinical use of pioglitazone is currently under scrutiny because of safety issues and because of the availability of newer drugs (DPP-4 inhibitors, glucagonlike peptide-1 receptor agonists, and sodium glucose cotransporter 2 inhibitors). None of these newer drug classes target insulin resistance, however. At the moment, the most insulinresistant patientsdidentifiable by an increased waist circumference, low HDL cholesterol level, and fatty liverdmay be the best candidates for treatment with pioglitazone. In addition, patients with a high risk or history of CVD are also likely to benefit from pioglitazone. It is our belief that pioglitazone represents an important therapeutic option in people with T2DM and that more commonly used regimens are both less effective and more likely to result in worse safety outcomes. So, to answer our original question: yes, we still need pioglitazone for the treatment of T2DM. © 2013 by the American Diabetes Association.

Baltzer P.A.T.,Medical University of Vienna | Dietzel M.,Friedrich - Alexander - University, Erlangen - Nuremberg
Radiology | Year: 2013

Purpose: To perform a systematic review and meta-analysis to estimate the diagnostic performance of breast proton magnetic resonance (MR) spectroscopy in differentiating benign from malignant lesions and to identify variables that influence the accuracy of MR spectroscopy. Materials and Methods: A comprehensive search of the PubMed database was performed on articles listed until January 6, 2012. The Medical Subject Headings and text words for the terms "breast," "spectroscopy," and "magnetic resonance" were used. Investigations including more than 10 patients at 1.5 T or 3.0 T applying one-dimensional single-voxel MR spectroscopy or spatially resolved MR spectroscopy for differentiation between benign and malignant breast lesions were eligible. A reference standard had to be established either by means of histopathologic examination or imaging follow-up of 12 or more months. Statistical analysis included pooling of diagnostic accuracy, control for data inhomogeneity, and identification of publication bias. Results: Nineteen studies were used for general data pooling. The studies included a total of 1183 patients and 1198 lesions (773 malignant, 452 benign). Pooled sensitivity and specificity were 73% (556 of 761; 95% confidence interval [CI]: 64%, 82%) and 88% (386 of 439; 95% CI: 85%, 91%), respectively. The pooled diagnostic odds ratio (DOR) was 34.30 (95% CI: 16.71, 70.43). For breast cancers versus benign lesions, the area under the symmetric summary receiver operating characteristic curve of MR spectroscopy was 0.88, and the Q*index was 0.81. There was evidence of between-studies heterogeneity regarding sensitivity and DOR (P < .0001). No significant influences of higher field strength, postcontrast acquisition, or qualitative versus quantitative MR spectroscopy measurements were identified. Egger testing confirmed significant publication bias in studies including small numbers of patients (P < .0001). Conclusion: Breast MR spectroscopy shows variable sensitivity and high specificity in the diagnosis of breast lesions, independent from the technical MR spectroscopy approach. Because of significant publication bias, pooled diagnostic measures might be overestimated. © RSNA, 2013.

Mosti G.,Clinica MD Barbantini | Partsch H.,Medical University of Vienna
European Journal of Vascular and Endovascular Surgery | Year: 2014

Background Previous studies have shown that so-called progressive elastic compression stockings (PECS) with a negative pressure gradient have a more pronounced effect on venous pump function than conventional, graduated stockings. The aim of this study was to investigate the effect of higher graduated and non-graduated pressures on the venous calf pump in patients with venous disease. Methods The ejection fraction (EF) of the calf pump was measured by plethysmography under a standardized walking test in 20 patients suffering from chronic venous disease (CEAP C2-C5) without compression, (a) with one and (b) two PECS on top of each other, and (c) with one additional conventional stocking covering only the gaiter area to achieve a graduated high pressure profile. Interface pressure was measured in the gaiter area and on the calf. Results A significant improvement of EF compared with baseline was found with all three compression modalities. The two superimposed PECS, providing median pressures of 33 mmHg in the gaiter area and 46 mmHg at calf level, increased EF significantly up into the normal range. Increasing the gaiter pressure to 56 mmHg without changing the calf pressure did not result in further improvement. Conclusions Two PECS applied on top of each other lead to a maximal improvement of the venous pump function, which cannot be further improved by increasing the pressure in the gaiter area thereby restoring a graduated pressure profile.

Nanoff C.,Medical University of Vienna
Sub-cellular biochemistry | Year: 2012

The polypeptide of a G protein-coupled receptor is inserted into the membrane of the endoplasmic reticulum while being translated and this process by itself may be sufficient to establish the proper receptor fold. X-ray structures reveal a common polypeptide topology with little variation in the alignment and orientation of the seven transmembrane segments, the proximal carboxyl terminus (C-tail) and parts of the extracellular loops. These define a structural core the stability of which probably represents a major criterion for the receptor to pass endoplasmic reticulum (ER) quality control; point mutations affecting the structure of the core have an extraordinary chance of causing receptor retention. In contrast, cytoplasmic loops 2 and 3 and the distal C-tail are poorly ordered at least in the absence of an interaction partner. Similarly, the amino terminal tail of rhodopsin-related receptors (but not of receptor subtypes where ligand binding requires a stable fold of the N-tail) is unlikely to establish a stable fold. These segments can cause ER retention when mutated to inappropriately expose hydrophobic peptide patches; to prevent protein aggregation chaperone molecules attach to them thus initiating selection for ER-associated degradation. It is less clear however if there are additional mechanisms to specifically survey the transmembrane core at the level of the lipid bilayer or if insufficient packing is detected due to misalignment of the cytoplasmic or extracellular face of the receptor.

Karapetian H.,Medical University of Vienna
Methods in Molecular Biology | Year: 2013

The reptilase time is a functional plasma clotting assay, which is based on the enzymatic activity of batroxobin. By specifically cleaving fibrinogen A from fibrinogen, batroxobin leads to the formation of a stable fibrin clot. The time, starting from the addition of batroxobin to the plasma sample, until clot formation is the reptilase time and is given in seconds. Clot formation can be detected manually or on automated coagulation systems. Reference values for healthy adults are 18-22 s. Healthy newborns may have a slightly prolonged reptilase time of up to 24 s. In addition to other coagulation assays, the reptilase time is usually performed to confirm or to exclude the suspicion of dysfibrinogenemias. The reptilase time is independent of thrombin generation disturbances or disturbances in the action of thrombin on fibrinogen. Therefore, it can be used to confirm heparin contamination or to obtain similar information as with the thrombin clotting time in heparinized and hemophiliac patients. © 2013 Springer Science+Business Media New York.

Fonatsch C.,Medical University of Vienna
Genes Chromosomes and Cancer | Year: 2010

Newborns and children with Down syndrome (DS) often present with congenital transient leukemia and have an increased risk of acute myeloid leukemia and acute lymphoblastic leukemia. Thus, constitutional trisomy 21 represents an excellent model to study the origin and progression of leukemia. However, trisomy 21 can also occur as a somatic chromosome aberration leading to sporadic leukemia. During the 50 years, since the discovery of constitutional trisomy 21 in DS, we have also learned that this small chromosome 21, harboring about 300 genes, may be involved in numerous structural aberrations, e.g., translocations, deletions, and amplifications, in leukemias, lymphomas, and solid tumors. Moreover, genes located on chromosome 21 have been identified that play an important role in tumorigenesis. Somatic mutations of several of these genes have been shown to be associated with different solid tumors, but also constitutional mutations of a specific gene on chromosome 21 leading to myelodysplastic syndromes and acute myeloid leukemia have been described. In this review, the specific forms of myeloid leukemia as well as of acute lymphoblastic leukemia in children with DS will be presented and possible explanations for the paucity of solid tumors in DS will be given. Somatic numerical as well as structural chromosome 21 aberrations in association with leukemias will be described. Finally, the nature and function of specific genes, like RUNX1, TMPRSS2, and TFF, located in 21q, and their role in tumorigenesis will be exemplified. © 2010 Wiley-Liss, Inc.

Bieglmayer C.,Medical University of Vienna
Austrian Journal of Clinical Endocrinology and Metabolism | Year: 2010

Neuroendocrine tumors (NET) are rare and account for only about 0.1 % of all neoplasias. Bioactive NETs are capable of hypersecreting hormones, neurotransmitters, and biogenic amines, which cause characteristic afflictions that facilitate early diagnosis. Non-functional NETs do not exhibit endocrine symptoms, the complaints are non-specific and diagnosis is often delayed. Both functional and non-functional tumors express specific proteins, like somatostatin receptors and granins. Granins are involved in selecting hormones for the regulated pathway of secretion and are co-stored with hormones, neurotransmitters, and biogenic amines in the secretory granula prior to exocytosis. Chromogranin A (CGA) is the most important and abundant granin in NET, thus clinically it serves as a marker for NET. It is involved in hormone processing and secretion and is disassembled to biologically active peptides. CGA is heterogeneous due to metabolic modifications and tissue- and tumor-specific cleavage sites. Commercial immunoassays for CGA differ in standardization and units, in origin and specificity of antibodies as well as in label and assay format. Data from method comparison studies are reported. Clinical applications of CGA as a marker for NET as well as conditions which interfere with CGA results are reviewed.

Gruber R.,Medical University of Vienna
Wiener Medizinische Wochenschrift | Year: 2010

Osteoimmunology is defined as the research area focusing on the crosstalk between the immune system and the muskoskeletal system. After nearly a decade of research, we are now beginning to understand the basic principles of this crosstalk. It seems that almost all immune cells are capable of communicating with osteoblasts, osteoclasts, and their respective progenitors - and vice versa. Diseases that fall into the category of osteoimmunology including osteoporosis, rheumatoid arthritis, and periodontal disease are of particular significance considering their implications in quality of life, their increased incidence in the population, and socioeconomic issues. To better understand the underlying pathogenesis, the main pathways of the crosstalk between the immune system and the muskoskeletal system need to be uncovered. Our current understanding has already provided the scientific basis for the development of targeted therapies. However, the challenge of future studies is to further decipher this crosstalk at cellular and molecular levels. © 2010 Springer-Verlag.

Blachier M.,University Paris Est Creteil | Leleu H.,University Paris Est Creteil | Peck-Radosavljevic M.,Medical University of Vienna | Valla D.-C.,French Institute of Health and Medical Research | Roudot-Thoraval F.,University Paris Est Creteil
Journal of Hepatology | Year: 2013

To survey the burden of liver disease in Europe and its causes 260 epidemiological studies published in the last five years were reviewed. The incidence and prevalence of cirrhosis and primary liver cancer are key to understand the burden of liver disease. They represent the end-stage of liver pathology and thus are indicative of the associated mortality. About 0.1% of Hungarian males will die of cirrhosis every year compared with 0.001% of Greek females. WHO estimate that liver cancer is responsible for around 47,000 deaths per year in the EU. Harmful alcohol consumption, viral hepatitis B and C and metabolic syndromes related to overweight and obesity are the leading causes of cirrhosis and primary liver cancer in Europe. Chronic hepatitis B affects 0.5-0.7% of the European population. In the last decade the prevalence of chronic hepatitis C was 0.13-3.26%. It is of great concern that about 90% of people in Europe infected by viral hepatitis are unaware of their status. Available data suggest the prevalence rate of NAFLD is 2-44% in the general European population (including obese children) and 42.6-69.5% in people with type 2 diabetes. Each of these four major causes of liver disease is amenable to prevention and treatment, reducing the burden of liver disease in Europe and saving lives. Further surveys are urgently needed to implement cost-effective prevention programmes and novel treatments to tackle this problem.

Gnant M.,Medical University of Vienna | Clezardin P.,University of Lyon
Cancer Treatment Reviews | Year: 2012

The bone marrow microenvironment provides a site for cancer cells to evade systemic anticancer therapy. Dormant tumor micrometastases are believed to be the source of disease persistence and relapse; however, the exact characteristics of cancer stem cells vs. cancer cells with limited metastatic potential have yet to be elucidated. Bisphosphonates inhibit osteoclast-mediated bone resorption, are approved for treating malignant bone disease from advanced cancers, and have shown efficacy for preventing cancer treatment-induced bone loss. Altering the bone marrow microenvironment to make it less conducive to cancer cell survival is now emerging as an important means to prevent cancer recurrence. This review aims to distill the diverse literature and provide a brief overview of the numerous preclinical and early clinical studies of bisphosphonates demonstrating a variety of direct and indirect anticancer activities that affect both the tumor cell (the "seed") and surrounding microenvironment (the "soil"). Recently, zoledronic acid was found to improve disease-free survival and overall survival in some adjuvant breast cancer settings and prolonged survival in patients with multiple myeloma and other advanced cancers. In the prostate cancer setting, antiresorptive therapy was reported to delay the development of overt bone metastases. Ongoing studies will provide further insight regarding the anticancer potential of bisphosphonates and other antiresorptive agents. © 2011 Elsevier Ltd.

Mannhalter C.,Medical University of Vienna
Hamostaseologie | Year: 2014

The haemostatic system maintains the blood in a fluid state, but allows rapid clot formation at sites of vascular injury to prevent excessive bleeding. Unbalances within the haemostatic system can lead to thrombosis. Inspite of successful research our understanding of the disease pathogenesis is still incomplete. There is great hope that genetic, genomic, and epigenetic discoveries will enhance the diagnostic capability, and improve the treatment options. During the preceding 20 years, the identification of polymorphisms and the elucidation of their role in arterial and venous thromboses became an important area of research. Today, a large body of data is available regarding associations of single nucleotide polymorphisms (SNPs) in candidate genes with plasma concentrations and e. g. the risk of ischaemic stroke or myocardial infarction. However, the results for individual polymorphisms and genes are often controversial. It is now well established that besides acquired also hereditary risk factors influence the occurrence of thrombotic events, and environmental factors may add to this risk. Currently available statistical methods are only able to identify combined risk genotypes if very large patient collectives (>10 000 cases) are tested, and appropriate algorithms to evaluate the data have yet to be developed. Further research is needed to understand the functional effects of genetic variants in genes of blood coagulation proteins that are critical to the pathogenesis of arterial and venous thrombotic disorders. In this review genetic variants in selected genes of the haemo static system and their relevance for arterial and venous thrombosis will be discussed. © Schattauer 2014.

Buttgereit F.,Charite - Medical University of Berlin | Smolen J.S.,Medical University of Vienna | Coogan A.N.,National University of Ireland, Maynooth | Cajochen C.,University of Basel
Nature Reviews Rheumatology | Year: 2015

Circadian rhythms are of crucial importance for cellular and physiological functions of the brain and body. Chronobiology has a prominent role in rheumatoid arthritis (RA), with major symptoms such as joint pain and stiffness being most pronounced in the morning, possibly mediated by circadian rhythms of cytokine and hormone levels. Chronobiological principles imply that tailoring the timing of treatments to the circadian rhythm of individual patients (chronotherapy) could optimize results. Trials of NSAID or methotrexate chronotherapy for patients with RA suggest such an approach can improve outcomes and reduce adverse effects. The most compelling evidence for RA chronotherapy, however, is that coordinating the timing of glucocorticoid therapy to coincide with the nocturnal increase in blood IL-6 levels results in reduced morning stiffness and pain compared with the same glucocorticoid dose taken in the morning. Aside from optimizing relief of the core symptoms of RA, chronotherapy might also relieve important comorbid conditions such as depression and sleep disturbances. Surprisingly, chronobiology is not mentioned in official guidelines for conducting RA drug registration trials. Given the imperative to achieve the best value with approved drugs and health budgets, the time is ripe to translate the 'circadian concept' in rheumatology from bench to bedside. © 2015 Macmillan Publishers Limited. All rights reserved.

Silva B.C.,Columbia University | Leslie W.D.,University of Manitoba | Resch H.,Medical University of Vienna | Lamy O.,University of Lausanne | And 5 more authors.
Journal of Bone and Mineral Research | Year: 2014

The trabecular bone score (TBS) is a gray-level textural metric that can be extracted from the two-dimensional lumbar spine dual-energy X-ray absorptiometry (DXA) image. TBS is related to bone microarchitecture and provides skeletal information that is not captured from the standard bone mineral density (BMD) measurement. Based on experimental variograms of the projected DXA image, TBS has the potential to discern differences between DXA scans that show similar BMD measurements. An elevated TBS value correlates with better skeletal microstructure; a low TBS value correlates with weaker skeletal microstructure. Lumbar spine TBS has been evaluated in cross-sectional and longitudinal studies. The following conclusions are based upon publications reviewed in this article: 1) TBS gives lower values in postmenopausal women and in men with previous fragility fractures than their nonfractured counterparts; 2) TBS is complementary to data available by lumbar spine DXA measurements; 3) TBS results are lower in women who have sustained a fragility fracture but in whom DXA does not indicate osteoporosis or even osteopenia; 4) TBS predicts fracture risk as well as lumbar spine BMD measurements in postmenopausal women; 5) efficacious therapies for osteoporosis differ in the extent to which they influence the TBS; 6) TBS is associated with fracture risk in individuals with conditions related to reduced bone mass or bone quality. Based on these data, lumbar spine TBS holds promise as an emerging technology that could well become a valuable clinical tool in the diagnosis of osteoporosis and in fracture risk assessment. © 2014 American Society for Bone and Mineral Research.

Although epicardial blood flow can be restored by an early intervention in most cases, a lack of adequate reperfusion at the microvascular level is often a limiting prognostic factor of acute myocardial infarction (AMI). Our group has recently found that paracrine factors secreted from apoptotic peripheral blood mononuclear cells (APOSEC) attenuate the extent of myocardial injury. The aim of this study was to determine the influence of APOSEC on microvascular obstruction (MVO) in a porcine AMI model. A single dose of APOSEC was intravenously injected in a closed chest reperfused infarction model. MVO was determined by magnetic resonance imaging and cardiac catheterization. Role of platelet function and vasodilation were monitored by means of ELISA, flow cytometry, aggregometry, western blot and myographic experiments in vitro and in vivo. Treatment of AMI with APOSEC resulted in a significant reduction of MVO. Platelet activation markers were reduced in plasma samples obtained during AMI, suggesting an anti-aggregatory capacity of APOSEC. This finding was confirmed by in vitro tests showing that activation and aggregation of both porcine and human platelets were significantly impaired by co-incubation with APOSEC, paralleled by vasodilator-stimulated phosphoprotein (VASP)-mediated inhibition of platelets. In addition, APOSEC evidenced a significant vasodilatory capacity on coronary arteries via p-eNOS and iNOS activation. Our data give first evidence that APOSEC reduces the extent of MVO during AMI, and suggest that modulation of platelet activation and vasodilation in the initial phase after myocardial infarction contributes to the improved long-term outcome in APOSEC treated animals.

Gutnick T.,Hebrew University of Jerusalem | Byrne R.A.,Medical University of Vienna | Hochner B.,Hebrew University of Jerusalem | Kuba M.,Hebrew University of Jerusalem
Current Biology | Year: 2011

Octopuses are intelligent, soft-bodied animals with keen senses that perform reliably in a variety of visual and tactile learning tasks [1-6]. However, researchers have found them disappointing in that they consistently fail in operant tasks that require them to combine central nervous system reward information with visual and peripheral knowledge of the location of their arms [6-8]. Wells [6] claimed that in order to filter and integrate an abundance of multisensory inputs that might inform the animal of the position of a single arm, octopuses would need an exceptional computing mechanism, and "There is no evidence that such a system exists in Octopus, or in any other soft bodied animal." Recent electrophysiological experiments, which found no clear somatotopic organization in the higher motor centers, support this claim [9]. We developed a three-choice maze that required an octopus to use a single arm to reach a visually marked goal compartment. Using this operant task, we show for the first time that Octopus vulgaris is capable of guiding a single arm in a complex movement to a location. Thus, we claim that octopuses can combine peripheral arm location information with visual input to control goal-directed complex movements. Video Abstract: © 2011 Elsevier Ltd All rights reserved.

Pirker R.,Medical University of Vienna
Current Opinion in Oncology | Year: 2015

PURPOSE OF REVIEW: The epidermal growth factor receptor (EGFR) is overexpressed in many nonsmall cell lung cancers (NSCLCs). Blockade of EGFR by monoclonal antibodies has been studied as a strategy to improve the outcome of first-line chemotherapy in patients with NSCLC. The present review updates the findings from phase III trials. RECENT FINDINGS: Cetuximab improved survival when combined with first-line chemotherapy and this benefit was limited to patients with high EGFR expression in their tumors. A Southwest Oncology Group study currently prospectively evaluates the predictive biomarkers for cetuximab. In the SQUIRE phase III trial, necitumumab added to cisplatin and gemcitabine increased the survival in patients with advanced squamous cell NSCLC. The INSPIRE trial studied chemotherapy with and without necitumumab in patients with nonsquamous NSCLC but was prematurely halted because of increased thromboembolic events with chemotherapy and necitumumab. SUMMARY: EGFR monoclonal antibodies improved the outcome including survival in selected patients with advanced NSCLC. Prospective validation of predictive biomarkers is ongoing. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Honigsmann H.,Medical University of Vienna
Photochemical and Photobiological Sciences | Year: 2013

Over many centuries, treatment with sunlight or "heliotherapy" was used in the treatment of skin diseases. More than 3500 years ago, ancient Egyptian and Indian healers used the ingestion of plant extracts or seeds in addition to sunlight for treating "leucoderma". Modern phototherapy began with Nobel Prize winner Niels Finsen who developed a "chemical rays" lamp with which he treated patients with skin tuberculosis. However, it took several decades until phototherapy was introduced anew into the dermatological armamentarium. It was the development of photochemotherapy (PUVA) in 1974 that marked the beginning of a huge upsurge in photodermatology. The subsequent development of high intensity UV sources with defined spectra facilitated an optimized therapy for psoriasis and led to an expansion of indications for photo(chemo)therapy also in combination with topical and systemic agents. The introduction of extracorporeal photopheresis in 1987 for cutaneous T-cell lymphoma and of topical photodynamic therapy widely expanded the therapeutic possibilities in dermato-oncology. This journal is © 2013 The Royal Society of Chemistry and Owner Societies.

Fellinger J.,11 Health | Fellinger J.,Medical University of Vienna | Holzinger D.,11 Health | Holzinger D.,University of Graz | Pollard R.,University of Rochester
The Lancet | Year: 2012

Deafness is a heterogeneous condition with far-reaching effects on social, emotional, and cognitive development. Onset before language has been established happens in about seven per 10 000 people. Increased rates of mental health problems are reported in deaf people. Many regard themselves as members of a cultural minority who use sign language. In this Review, we describe discrepancies between a high burden of common mental health disorders and barriers to health care. About a quarter of deaf individuals have additional disabilities and a high probability of complex mental health needs. Research into factors affecting mental health of deaf children shows that early access to effective communication with family members and peers is desirable. Improved access to health and mental health care can be achieved by provision of specialist services with professionals trained to directly communicate with deaf people and with sign-language interpreters. © 2012 Elsevier Ltd.

Regele H.,Medical University of Vienna
Kidney International | Year: 2011

Mostly indirect evidence suggests an important pathogenic role for non-HLA anti-endothelial cell antibodies (AECAs) in both acute and chronic rejection. The lack of standardized screening assays for AECAs unfortunately hampers the systematic collection of data in multicenter trials. Diagnostic tests based on commercially available platforms could pave the way for testing larger patient cohorts, but they still suffer from some important limitations. © 2011 International Society of Nephrology.

Ravaud A.,Bordeaux University Hospital Center | Ravaud A.,French Institute of Health and Medical Research | Schmidinger M.,Medical University of Vienna
Annals of Oncology | Year: 2013

There are now a range of effective targeted agents available for the first-and second-line treatment of advanced renal cell carcinoma (RCC). However, patients with advanced RCC have varied responses to therapy; some experience long-term responses while others may not respond, or even progress rapidly. Characteristics or markers that could be used to determine which patients will benefit most from which agent may enable us to select the optimal treatment of each individual patient, thereby improving efficacy and avoiding unnecessary toxic effects. These characteristics may be at the cellular or genetic level. Alternatively, the occurrence of adverse events may act as surrogate markers of a drug's on treatment activity, enabling prediction of outcomes during treatment. Recently, it has been suggested that during some targeted therapy for advanced RCC, the occurrence of specific adverse events, such as hypertension, hypothyroidism, hand-foot syndrome or fatigue/asthenia, may be associated with improved efficacy. This article reviews the evidence supporting clinical biomarkers in patients with advanced RCC receiving targeted agents. We also consider how these clinical biomarkers may affect the future management of patients with advanced RCC. © The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Marsche G.,Medical University of Graz | Saemann M.D.,Medical University of Vienna | Heinemann A.,Medical University of Graz | Holzer M.,Medical University of Graz
Pharmacology and Therapeutics | Year: 2013

There is clear epidemiological evidence that plasma levels of high-density lipoprotein (HDL)-cholesterol are inverse and independent predictors of cardiovascular disease risk, fuelling interest in novel therapies capable of raising HDL-cholesterol. However, the relevance of HDL-cholesterol as a surrogate marker for HDL-related risk has been questioned. Latest failures of HDL-cholesterol raising drugs and a recent study that showed no causal association between risk for myocardial infarction and genetically raised plasma HDL-cholesterol indicate that steady-state HDL-cholesterol concentrations may provide limited information regarding the potential antiatherogenic functions of HDL. There is accumulating evidence that HDL composition determines its functional properties, rather than the levels of circulating HDL-cholesterol. Therefore, assessing HDL composition and function might provide more relevant information than steady-state HDL-cholesterol levels. Recent mass spectrometric analyses revealed that protein composition of HDL is complex, expanding our understanding of the functions and structures of lipoproteins. Significant alterations were identified in the composition and function of circulating HDL of patients with high cardiovascular risk, as well as in HDL isolated from atherosclerotic tissue. These novel insights may help to develop therapies that target the functionality of HDL and further enable the identification of patients at increased cardiovascular risk. © 2012 Elsevier Inc.

Wiedermann U.,Medical University of Vienna
Travel Medicine and Infectious Disease | Year: 2010

The increase of TBE cases in Europe has become a problem of international public health and travel medicine, because it is not only of concern for endemic areas, but also for visitors from non-endemic countries. Although highly effective modern vaccines are on the market in 28 European countries, there are still 7, mainly Eastern European, countries with no or an uncertain number of cases and without licensed modern vaccines. The prevailing danger for travellers, however, lies in underestimation and not awareness of the disease by public authorities, travel agencies and by the travellers themselves, a lack of mandatory notifications and sometimes a lack of financial resources. Outside Europe TBE has mostly not been recognized as a travel associated disease. Recommendation for travellers to endemic countries and suggestions to extra-European travellers and health authorities as well as vaccination advices are summarized in this paper. © 2010 Elsevier Ltd. All rights reserved.

van Duijn E.,Medical University of Vienna | van Duijn E.,University of Oslo | van Duijn E.,University of Ulm
Journal of neurology, neurosurgery, and psychiatry | Year: 2014

BACKGROUND: The majority of Huntington's disease (HD) mutation carriers experience some psychopathology during their lifetime, varying from irritability to psychosis, but prevalences of particular symptoms vary widely due to diverse study populations in different stages of HD and the use of different assessment methods.METHODS: The study population consisted of 1993 HD mutation carriers from 15 European countries, all participating in the observational REGISTRY study. The behavioural section of the Unified HD Rating Scale was used to examine the prevalence and correlates of five neuropsychiatric features: depression, irritability/aggression, obsessive/compulsive behaviours, apathy and psychosis.RESULTS: Twenty-seven per cent of the participants did not have any neuropsychiatric symptom in the last month. Moderate to severe apathy occurred in 28.1% of the participants, whereas moderate to severe depression was found in 12.7%. Irritable/aggressive symptoms were present in 13.9% of the participants, and 13.2% showed obsessive/compulsive behaviours. Moderate to severe psychotic symptoms were found in only 1.2%. Only 54.9% of all participants with moderate to severe depression used antidepressants, suggesting undertreatment of depression. Obsessive/compulsive behaviours and irritability/aggression were inversely correlated with the Total Functional Capacity score, but with apathy showing the strongest inverse association.CONCLUSIONS: A variety of neuropsychiatric symptoms are highly prevalent in different stages of HD in this European HD population, with apathy as the most frequent symptom. Depression, irritability/aggression and OCBs are prevalent in all stages of HD. Apathy was the key neuropsychiatric symptom occurring most often in advanced HD stages. Due to possible selection of relatively healthy participants, prevalences reported in this study might be an underestimation of prevalence in the entire HD population. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Gnant M.,Medical University of Vienna
Expert Review of Anticancer Therapy | Year: 2012

Approaches to treatment for many patients with advanced breast cancer are based on the expression of specific receptors. Treatments targeting the hormone receptor (typically the estrogen receptor) are used to reduce signaling through these receptors and thereby inhibit proliferation of breast cancer cells expressing these receptors. Although these treatments are effective for many patients, resistance to treatment is common. Recent clinical trials suggest that using multiple agents targeting the same pathway is not sufficient to overcome resistance. New treatment approaches are needed for these patients. Inhibition of the mTOR signaling pathway, a key point of confluence for multiple signaling cascades, offers a promising approach to restoring sensitivity to endocrine therapy in breast cancer. This article reviews the current data from studies of mTOR inhibitors everolimus and temsirolimus in combination with endocrine therapies to overcome treatment resistance in patients with advanced breast cancer. © 2012 2012 Expert Reviews Ltd.

Becattini C.,University of Perugia | Agnelli G.,University of Perugia | Schenone A.,Galliera Hospital | Eichinger S.,Medical University of Vienna | And 7 more authors.
New England Journal of Medicine | Year: 2012

BACKGROUND: About 20% of patients with unprovoked venous thromboembolism have a recurrence within 2 years after the withdrawal of oral anticoagulant therapy. Extending anticoagulation prevents recurrences but is associated with increased bleeding. The benefit of aspirin for the prevention of recurrent venous thromboembolism is unknown. METHODS:In this multicenter, investigator-initiated, double-blind study, patients with first-ever unprovoked venous thromboembolism who had completed 6 to 18 months of oral anticoagulant treatment were randomly assigned to aspirin, 100 mg daily, or placebo for 2 years, with the option of extending the study treatment. The primary efficacy outcome was recurrence of venous thromboembolism, and major bleeding was the primary safety outcome. RESULTS:Venous thromboembolism recurred in 28 of the 205 patients who received aspirin and in 43 of the 197 patients who received placebo (6.6% vs. 11.2% per year; hazard ratio, 0.58; 95% confidence interval [CI], 0.36 to 0.93) (median study period, 24.6 months). During a median treatment period of 23.9 months, 23 patients taking aspirin and 39 taking placebo had a recurrence (5.9% vs. 11.0% per year; hazard ratio, 0.55; 95% CI, 0.33 to 0.92). One patient in each treatment group had a major bleeding episode. Adverse events were similar in the two groups. CONCLUSIONS: Aspirin reduced the risk of recurrence when given to patients with unprovoked venous thromboembolism who had discontinued anticoagulant treatment, with no apparent increase in the risk of major bleeding. (Funded by the University of Perugia and others; WARFASA ClinicalTrials.gov number, NCT00222677.) Copyright © 2012 Massachusetts Medical Society.

Aringer M.,TU Dresden | Smolen J.S.,Medical University of Vienna
Autoimmunity Reviews | Year: 2012

TNF is an important mediator of inflammation, but is also involved in the control of autoimmunity. The latter has been demonstrated in a murine model of SLE (NZB/W) and by the occurrence of autoantibodies to nuclear antigens as well as occasional, transient lupus-like syndromes in patients under TNF blockade. In contrast, data on increased TNF levels in serum, kidney and skin samples of SLE patients as well as results in other mouse models of the disease point to an inflammatory role of TNF in SLE organ disease. Despite all due caution, given these two sides of the cytokine, TNF blockade has by now been employed for several years in single cases and open label studies; data on more than fifty patients have meanwhile been published, for the vast majority of which infliximab was employed. These clinical data have to be very cautiously interpreted, as always with data on single cases or open label trials. However, some consistent pieces of information emerge and may inform controlled clinical trials: (i) While antibodies to double-stranded DNA commonly showed transient increases, lupus flares have not been seen so far and thus apparently are at least not the rule; (ii) in contrast, increases in anti-phospholipid antibodies may be associated with vascular adverse events; (iii) bacterial infections, pneumonia and urinary tract infections in particular, have been observed; (iv) short term induction therapy appears relatively safe, while long-term TNF blockade may confer significant risks in SLE; (v) TNF blocker induction therapy may lead to long-term remission in patients with lupus nephritis, hemophagocytic syndrome, and interstitial lung disease; (vi) patients with lupus arthritis often respond to TNF-blockade but symptoms recur after cessation of therapy, necessitating longer term therapy, which is more risky than short term treatment. © 2011.

Schoder D.,Medical University of Vienna
Journal of Food Protection | Year: 2010

This is the first study proving the existence of melamine in milk powder and infant formula exported to the African market. A total of 49 milk powder batches were collected in Dar-es-Salaam (Tanzania, East Africa), the center of international trade in East Africa, which serves as a commercial bottleneck and shipment hub for sub-Saharan, Central, and East Africa. Two categories of samples were collected between October and December 2008, immediately after the melamine contamination of Chinese products became public: (i) market brands of all international companies supplying the East African market and (ii) illegally sold products from informal channels. Melamine concentration was determined with the AgraQuant Melamine Sensitive Assay. Despite the national import prohibition of Chinese milk products and unlabeled milk powder in Tanzania, 11% (22 of 200) of inspected microretailers sold milk powder on the local black market. Manufacturers could be identified for only 55% (27) of the 49 investigated batches. Six percent (3 of 49) of all samples and 11% (3 of 27) of all international brand name products tested revealed melamine concentrations up to 5.5 mg/kg of milk powder. This amount represents about twice the tolerable daily intake as suggested by the U.S Food and Drug Administration. Based on our study, we can assume that the number of affected children in Africa is substantial. Copyright © International Association for Food Protection.

Objectives: Recently, 'unresponsive wakefulness syndrome' (UWS) was coined for challenging conditions previously termed vegetative state or apallic syndrome. Materials and methods: In a post-mortem series of 630 patients who sustained a blunt traumatic brain injury, 100 (59 men and 41 women, aged 5-86 years; 77% traffic accidents, 23% falls and others) showed various disorders of consciousness which were compared with neuropathology with focus on brainstem lesions. Results: In the total autopsy series (n=630), the incidence of cortical contusions, diffuse axonal injury (DAI) and intracranial haemorrhages was 41, 55 and 73%, respectively, of diencephalic, hypothalamic and hippocampal lesions 62% each, brainstem lesions 92%. Clinical prognosis was related to the location and extent of brainstem damage. Lesions in central parts of the rostral brainstem, frequently associated with extensive DAI, allowed no recovery from coma or UWS (n=67), which occurred only with damage to the dorso-lateral brainstem tegmentum or pontine basis (n=33). Only two of 11 patients with minimally conscious state (MCS), in addition to haemorrhages (n=4), contusions (n=10) and DAI (n=7), showed small lesions in dorsolateral pontine tegmentum or diffuse pontine gliosis. Conclusions: These and other data confirm the importance of the pattern and extent of brainstem damage for the prognosis of UWS, only small peripheral lesions in pontine tegmentum allowing progressive remission. © 2013 Informa UK Ltd.

Marosi C.,Medical University of Vienna
Handbook of Clinical Neurology | Year: 2012

The persisting reservation against the use of chemotherapy in patients with malignant glioma was finally overcome by the breakthrough achieved with the use of the oral alkylating agent temozolomide (TMZ) as concomitant and adjuvant chemotherapy in patients with newly diagnosed glioblastoma multiforme (GBM). The basic condition for an effective systemic drug therapy against malignant glioma is that the drug be able to cross the blood-brain barrier (BBB) and the brain-tumor barrier. Drugs crossing the BBB have to be nonpolar, small molecules with a molecular weight of less than 500. Da, to bear no electrical charge, or to be able to use active transport mechanisms, as the BBB is functional in the peripheral growing areas of GBM. The prerequisite of liposolubility is best achieved by a group of drugs termed alkylating agents; nitrosoureas were the agents used most historically, until the now most widely used drug, TMZ, became available. All alkylating agents share a common molecular mechanism of action, which is by nature cytotoxic, mutagenic, and carcinogenic. They differ greatly in their pharmacokinetic features and liposolubility, and thus also in the pattern of toxicities observed, such as myelosuppression, induction of secondary tumors, impact on fertility in both sexes, and induction of nausea and vomiting. The effectiveness of alkylating chemotherapy in tumors of glial origin depends on the DNA repair capacity of the individual tumor - most precisely on the intracellular presence of the DNA repair enzyme MGMT (O 6-methylguanine-DNA methyltransferase). The promoter of the gene encoding for MGMT may be silenced by epigenetic methylation; in this case, the tumor responds to alkylating therapy. At the time of writing, it is not clear whether prolonged exposure to alkylating chemotherapy succeeds in depleting MGMT in tumor cells and might thus produce a response in patients whose tumor cells have an unmethylated MGMT promoter sequence. The most prominent clinically relevant side-effect is myelosuppression, most pronounced for white blood cells and platelets, less for red blood cells. ACNU (nimustine), BCNU (carmustine), and CCNU (lomustine) are nitrosourea drugs that have been used for the treatment of brain tumors for more than 40 years. Their most prominent side-effect is delayed myelosuppression, with the nadir occurring 5-6 weeks after drug administration. This long delay to the occurrence of the dose-limiting side-effects of leukocytopenia and thrombocytopenia demands special attention for controls and complicates the use of drug combinations. For TMZ, the risk of severe myelosuppression in the standard dosage is around 7% for thrombocytopenia and for leukocytopenia. With increasing duration of TMZ use, the rate of lymphopenia, selective for CD4 lymphocytes, increases, with up to 47% encountered in the 21/28 schedule. When the CD4 count drops below 200/mm 3 or the total lymphocytes decrease to less than 400/mm 3, there is a significant risk of opportunistic infection, such as Pneumocystis carinii pneumonia, herpes zoster, Kaposi sarcoma, or reactivation of herpes or hepatitis B infection. In analogy to patients with HIV/AIDS, P. carinii prophylaxis with trimethoprim or monthly pentamidine inhalations is strongly recommended during concomitant chemotherapy and/or for patients with lymphocyte counts below 400/mm 3.Other drugs used in neuro-oncology include the platinum compounds cisplatin and carboplatin, which act like alkylating agents and are sometimes used in low doses in combination with alkylating agents, the topoisomerase inhibitors derived from camptothecins, irinotecan and, for brain metastases, topotecan; and the podophyllum toxins etoposide and VM26, pegylated and/or liposomal anthracyclines, and, although it does not penetrate the BBB, the vinca alkaloid vincristine. The toxicity profiles of these drugs are reviewed briefly. © 2012 Elsevier B.V.

Neubauer A.,National Research Council Canada | Wolfsberger S.,Medical University of Vienna | Wolfsberger S.,University of Calgary
Neurosurgery | Year: 2013

Virtual endoscopy is the computerized creation of images depicting the inside of patient anatomy reconstructed in a virtual reality environment. It permits interactive, noninvasive, 3-dimensional visual inspection of anatomical cavities or vessels. This can aid in diagnostics, potentially replacing an actual endoscopic procedure, and help in the preparation of a surgical intervention by bridging the gap between plain 2-dimensional radiologic images and the 3-dimensional depiction of anatomy during actual endoscopy. If not only the endoscopic vision but also endoscopic handling, including realistic haptic feedback, is simulated, virtual endoscopy can be an effective training tool for novice surgeons. In neurosurgery, the main fields of the application of virtual endoscopy are third ventriculostomy, endonasal surgery, and the evaluation of pathologies in cerebral blood vessels. Progress in this very active field of research is achieved through cooperation between the technical and the medical communities. While the technology advances and new methods for modeling, reconstruction, and simulation are being developed, clinicians evaluate existing simulators, steer the development of new ones, and explore new fields of application. This review introduces some of the most interesting virtual reality systems for endoscopic neurosurgery developed in recent years and presents clinical studies conducted either on areas of application or specific systems. In addition, benefits and limitations of single products and simulated neuroendoscopy in general are pointed out. Copyright © 2012 by the Congress of Neurological Surgeons.

Kasper S.,Medical University of Vienna
International Psychogeriatrics | Year: 2012

Research into early intervention for Alzheimer's disease (AD) and dementia has involved cohort data from large epidemiological studies and data from specifically designed intervention trials. Cohort data indicate that use of nootropics and Ginkgo biloba extract may be associated with a reduced incidence of dementia and death. Data from large trials have often been inconclusive due to issues with poor medication adherence. However, such trials do indicate potential benefits with Gingko biloba extract in terms of reduced incidence of dementia of the AD type, vascular dementia and mixed pathology, reduced progression in terms of the clinical dementia rating and improvements in attention and memory. Furthermore, Gingko biloba extract EGb 761® is a useful option for long-term intervention on the basis of decades of previous experience and an excellent safety record. However, benefits can be expected only with sufficient medication adherence and treatment duration, so clear evidence of a disease-modifying benefit of this extract is needed from adequately designed trials using modern methods to ensure high levels of adherence. © 2012 International Psychogeriatric Association.

Pirker R.,Medical University of Vienna
Current Opinion in Oncology | Year: 2016

Purpose of review Patients with epidermal growth factor receptor (EGFR) mutation-positive nonsmall cell lung cancer (NSCLC) develop resistance during therapy with EGFR tyrosine kinase inhibitors (TKIs). In about half of the patients, this resistance is because of the emergence of the T790M mutation. Third-generation TKIs are active against EGFR-activating mutations and the T790M resistance mutation and have only limited efficacy against wild-type EGFR. Here we review the current status of the clinical development of these novel TKIs. Recent findings Third-generation TKIs in clinical development include osimertinib, rociletinib, and HM61713. Osimertinib and rociletinib have shown clinical efficacy in phase I/II trials in patients who had acquired resistance to first- or second-generation TKIs. Both TKIs are currently further evaluated in phase III trials as first-line or second-line therapy in patients with advanced EGFR mutation-positive NSCLC. HM61713 is in early clinical development. Summary Third-generation EGFR TKIs have shown activity in patients with acquired resistance to first- and second-generation EGFR TKIs and may further improve clinical outcome in patients with advanced EGFR mutation-positive NSCLC. © Copyright 2016 Wolters Kluwer Health, Inc. All rights reserved.

Wekerle T.,Medical University of Vienna | Grinyo J.M.,University of Barcelona
Transplant International | Year: 2012

Gradually improved immunosuppression has contributed significantly to the progress achieved in transplantation medicine so far. Nevertheless, current drug regimens are associated with late graft loss - in particular as a result of immunologic damage or drug toxicity - and substantial morbidity. Recently, the costimulation blocker belatacept (marketed under the name Nulojix") has been approved for immunosuppression in renal transplantation. Belatacept (a mutated version of CTLA4Ig) is a fusion protein rationally designed to block CD28, a critical activating receptor on T cells, by binding and saturating its ligands B7-1 and B7-2. In phase II and III trials, belatacept was compared with cyclosporine (in combination with basiliximab, MMF, and steroids). Advantages observed with belatacept include superior graft function, preservation of renal structure and improved cardiovascular risk profile. Concerns associated with belatacept are a higher frequency of cellular rejection episodes and more post-transplant lymphoproliferative disorder (PTLD) cases especially in EBV seronegative patients, who should be excluded from belatacept-based regimens. Thus, after almost three decades of calcineurin inhibitors as mainstay of immunosuppression, belatacept offers a potential alternative. In this article, we will provide an overview of belatacept's preclinical development and will discuss the available evidence from clinical trials. © 2011 European Society for Organ Transplantation.

Haditsch M.,Austria and Labor Hanover MVZ GmbH | Kunze U.,Medical University of Vienna
Travel Medicine and Infectious Disease | Year: 2013

Tick-borne encephalitis (TBE) is a vector-borne disease that is primarily transmitted to humans by infected ticks and causes infection of the central nervous system. Clinical presentations range from meningitis to encephalitis with or without myelitis, and infection may result in death or long-term neurological sequelae. TBE is endemic in regions of at least 27 European as well as in some Asian countries. Infection and disease, however, can be averted successfully by tick-bite prevention and active vaccination. The risk of infection has shifted from daily life and occupational exposure to leisure-time activities, including travelling. Outdoor activities during the tick season with contact with nature increase the risk of tick bites. Although the number of travel-associated cases is unknown, it is certainly under-estimated because there is hardly any awareness of TBE in non-endemic countries. Therefore, the majority of cases remain undiagnosed, also because of the lack of diagnostic serology, as there is no routine screening for TBE in non-endemic regions. Because of the increasing number of travellers from TBE non-endemic to endemic regions, and in view of the fact that TBE was included in the list of notifiable diseases in the European Union in September 2012, this disease needs to become an important issue in travel medicine. © 2013 Elsevier Ltd. All rights reserved.

Kyrle P.A.,Medical University of Vienna
Thrombosis Research | Year: 2014

The association between cancer and venous thromboembolism (VTE) is well-established. Many clinical and laboratory risk factors of a first cancer-associated VTE have been identified. In contrast, the pathogenesis of recurrent VTE in cancer patients is less well studied. There is only very limited information on the importance of clinical risk factors and the role of biomarkers in this context has never been studied. Patients with cancer-associated VTE usually receive low-molecular-weight heparin for at least 3 to 6 months. Nevertheless, the recurrence risk during anticoagulation is as high as 10% and treatment-related major bleeding is more common in cancer-patient than in non-cancer patients. Thus improvement of current treatment concepts is warranted. One important step to achieve this task is developing strategies that allow distinguishing patients with a high risk of recurrent VTE (who may benefit from prolonged or even intensified anticoagulation) from those with a low risk (i.e. patients in whom a shorter period of anticoagulant treatment at lower dose may be sufficient). Recently, a risk assessment model (RAM) for predicting recurrent VTE has been presented. By combining 4 clinical patient characteristics (sex, cancer type and stage, history of VTE), the Ottawa score allows stratification of cancer patients according to their VTE recurrence risk. The prediction tool was successfully validated in more than 800 patients from 2 prospective VTE treatment studies. Before this RAM can be introduced into routine clinical practice, however, management studies and impact analyses are required. © 2014 Elsevier Ltd. All rights reserved. © 2014 Elsevier Ltd.

Hoerth C.,Medical University of Vienna
VASA. Zeitschrift für Gefässkrankheiten. Journal for vascular diseases | Year: 2012

Nailfold capillaroscopy (NVC) is a diagnostic tool particularly useful in the differential diagnosis of rheumatic and connective tissue diseases. Although successfully applied since many years, little is known about prevalence and distribution of NVC changes in healthy individuals. NVC was performed in 120 individuals (57 men and 63 women; age 18 to 70 years) randomly selected according to predefined age and sex strata. Diseases associated with NVC changes were excluded. The nailfolds of eight fingers were assessed according to standardized procedures. A scoring system was developed based on the distribution of the number of morphologically deviating capillaries, microhaemorrhages, and capillary density. Only 18 individuals (15 %) had no deviation in morphology, haemorrhages, or capillary density on any finger. Overall 67 % had morphological changes, 48 % had microhaemorrhages, and 40 % of volunteers below 40 years of age and 18 % above age 40 had less than 8 capillaries/mm. Among morphological changes tortous (43 %), ramified (47 %), and bushy capillaries (27 %) were the most frequently altered capillary types. A semiquantitative scoring system was developed in such a way that a score above 1 indicates an extreme position (above the 90th percentile) in the distribution of scores among healthy individuals. Altered capillaries occur frequently among healthy individuals and should be interpreted as normal unless a suspicious increase in their frequency is determined by reference to the scoring system. Megacapillaries and diffuse loss of capillaries were not found and seem to be of specific diagnostic value.

Deregulated Rho GTPases Rac1 and Cdc42 have been discovered in various tumors, including prostate and Rac protein expression significantly increases in prostate cancer. The Rac and Cdc42 pathways promote the uncontrolled proliferation, invasion and metastatic properties of human cancer cells. We synthesized the novel compound AZA1 based on structural information of the known Rac1 inhibitor NSC23766. In the current study we investigated the effects of inhibition of these pathways by AZA1 on prostate tumorigenicity by performing preclinical studies using a xenograft mouse model of prostate cancer. In androgen-independent prostate cancer cells, AZA1 inhibited both Rac1 and Cdc42 but not RhoA GTPase activity in a dose-dependent manner and blocked cellular migration and proliferation. Cyclin D1 expression significantly decreased following Rac1/Cdc42 inhibition in prostate cancer cells. AZA1 treatment also down-regulated PAK and AKT activity in prostate cancer cells, associated with induction of the pro-apoptotic function of BAD by suppression of serine-112 phosphorylation. Daily systemic administration of AZA1 for 2 weeks reduced growth of human 22Rv1 prostate tumor xenografts in mice and improved the survival of tumor-bearing animals significantly. These data suggest a role of AZA1 in blocking Rac1/Cdc42-dependent cell cycle progression, cancer cell migration and increase of cancer cell apoptosis involving down-regulation of the AKT and PAK signaling pathway in prostate cancer cells. We therefore propose that a small-molecule inhibitor therapy targeting Rac1/Cdc42 Rho GTPase signaling pathways may be used as a novel treatment for patients with advanced prostate cancer.

Fish is among the most important allergen sources causing IgE-mediated food hypersensitivities. In sensitized individuals contact with and consumption of fish can lead to a variety of symptoms affecting the skin, the gastrointestinal tract, and the respiratory system and can, at worst, also provoke severe anaphylactic reactions. Fish allergies are predominantly mediated by one major allergen, the small, calcium-binding muscle protein, parvalbumin. Owing to this feature, fish allergies hold a special position among food allergies and might serve as a model system, since developments in diagnosis and treatment can be focused on one single molecule. This paper illustrates how the recent application of recombinant DNA technology led to the development of novel strategies for improvement of diagnosis and therapy of fish allergy. © 2011 Dustri-Verlag Dr. Karl Feistle.

Brodowicz T.,Medical University of Vienna | O'byrne K.,St Jamess Hospital | Manegold C.,University of Mannheim
Annals of Oncology | Year: 2012

Background: Bone metastases are a significant and undertreated clinical problem in patients with advanced lung cancer. Design: We reviewed the incidence of bone metastases and skeletal-related events (SREs) in patients with lung cancer and examined the burden on patients' lives and on health care systems. Available therapies to improve survival and lessen the impact of SREs on quality of life (QoL) were also investigated. Results: Bone metastases are common in lung cancer; however, owing to short survival times, data on the incidences of SREs are limited. As with other cancers, the costs associated with treating SREs in lung cancer are substantial. Bisphosphonates reduce the frequency of SREs and improve measures of pain and QoL in patients with lung cancer; however, nephrotoxicity is a common complication of therapy. Denosumab, a recently approved bone-targeted therapy, is superior to zoledronic acid in increasing the time to first on-study SRE in patients with solid tumours, including lung cancer. Additional roles of bone-targeted therapies beyond the prevention of SREs are under investigation. Conclusions: With increasing awareness of the consequences of SREs, bone-targeted therapies may play a greater role in the management of patients with lung cancer, with the aim of delaying disease progression and preserving QoL. © The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

Preceding studies on the mode of action of non-genotoxic hepatocarcinogens (NGCs) have concentrated on alterations induced in hepatocytes (HCs). A potential role of non-parenchymal liver cells (NPCs) in NGC-driven hepatocarcinogenesis has been largely neglected so far. The aim of this study is to characterize NGC-induced alterations in the proteome profiles of HCs as well as NPCs. We chose the prototypic NGC phenobarbital (PB) which was applied to male rats for a period of 14 days. The livers of PB-treated rats were perfused by collagenase and the cell suspensions obtained were subjected to density gradient centrifugation to separate HCs from NPCs. In addition, HCs and NPC isolated from untreated animals were treated with PB in vitro. Proteome profiling was done by CHIP-HPLC and ion trap mass spectrometry. Proteome analyses of the in vivo experiments showed many of the PB effects previously described in HCs by other methods, e.g. induction of phase I and phase II drug metabolising enzymes. In NPCs proteins related to inflammation and immune regulation such as PAI-1 and S100-A10, ADP-ribosyl cyclase 1 and to cell migration such as kinesin-1 heavy chain, myosin regulatory light chain RLC-A and dihydropyrimidinase-related protein 1 were found to be induced, indicating major PB effects on these cells. Remarkably, in vitro treatment of HCs and NPCs with PB hardly reproduced the proteome alterations observed in vivo, indicating differences of NGC induced responses of cells at culture conditions compared to the intact organism. To conclude, the present study clearly demonstrated that PB induces proteome alterations not only in HCs but also in NPCs. Thus, any profound molecular understanding on the mode of action of NGCs has to consider effects on cells of the hepatic mesenchyme.

MacHold K.P.,Medical University of Vienna
Best Practice and Research: Clinical Rheumatology | Year: 2010

Advances in treatment of rheumatoid arthritis have made it possible to profoundly influence signs and symptoms as well as the course of joint destruction in inflammatory arthritis. Earlier and more efficient treatment appears to significantly improve the prognosis of this disease. Despite these advances, cure (the absence of signs and symptoms without further treatment) is still relatively rare, observable in, at most, 20% of the patients. Remission (or a state of very low disease activity), however, has been observed with intense and individually tailored treatment in up to 75% of patients. The use of structured assessments followed by individual modification of the intensity of treatment aiming for remission leads to better clinical responses and radiological outcomes. It remains to be seen whether earlier and more aggressive treatment of patients with not yet 'fully established' rheumatoid arthritis may succeed in preventing at least some of them from progressing to destructive arthritis. © 2009 Elsevier Ltd. All rights reserved.

Kaye W.H.,University of California at San Diego | Wierenga C.E.,University of California at San Diego | Bailer U.F.,University of California at San Diego | Bailer U.F.,Medical University of Vienna | And 3 more authors.
Trends in Neurosciences | Year: 2013

Individuals with anorexia nervosa (AN) engage in relentless restrictive eating and often become severely emaciated. Because there are no proven treatments, AN has high rates of relapse, chronicity, and death. Those with AN tend to have childhood temperament and personality traits, such as anxiety, obsessions, and perfectionism, which may reflect neurobiological risk factors for developing AN. Restricted eating may be a means of reducing negative mood caused by skewed interactions between serotonin aversive or inhibitory and dopamine reward systems. Brain imaging studies suggest that altered eating is a consequence of dysregulated reward and/or awareness of homeostatic needs, perhaps related to enhanced executive ability to inhibit incentive motivational drives. An understanding of the neurobiology of this disorder is likely to be important for developing more effective treatments. © 2013.

Smolen J.S.,Medical University of Vienna
Current Opinion in Rheumatology | Year: 2016

Purpose of review Treat-to-target (T2T) is a new paradigm in the treatment of rheumatoid arthritis (RA). This review is timely, because the evidence is compelling and the world's major organizations have included it in their management recommendations. Recent findings T2T involves regular disease activity monitoring, ideally using the most recently described composite measures and remission criteria. The findings in the literature fully support previous notions on prevention of damage, maintenance of physical function and reduction of comorbidity risks using this strategy in early RA and have expanded these insights to established RA, elderly patients and work capacity. T2T has now even been advocated for psoriatic arthritis and is suggested of value also for ankylosing spondylitis and systemic lupus erythematosus. Summary This paradigm is independent of the availability of particular drugs, as the strategy in itself will maximize the benefit for the patient, irrespective of specific medications. Adhering to this strategy in clinical practice will optimize the outcomes in patients with RA. © 2016 Wolters Kluwer Health, Inc. All rights reserved.

Fischer G.,Medical University of Vienna | Stover H.,Frankfurt University of Applied Sciences
Heroin Addiction and Related Clinical Problems | Year: 2012

Opioid-dependence treatment varies between countries despite the underlying condition being similar. The European Quality Audit of Opioid Treatment (EQUATOR) project utilised a survey design in 10 European countries to characterise the treatment of opioid dependence from the perspective of treating physicians, patients in treatment, and opioid users currently outside the medication-assisted treatment system. The survey covered topics including treatment goals; knowledge about and experience of treatment; drug use, misuse and diversion; employment; and prison experience. EQUATOR provides the opportunity to generate important new insights to guide treatment policy and practice. This article presents a detailed overview of the study methodology. © Icro Maremmani.

Lassmann H.,Medical University of Vienna | van Horssen J.,VU University Amsterdam
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2016

Oxidative injury plays amajor role in brain damage inmany age-related human brain diseases and is particularly pronounced in the progressive stage of multiple sclerosis. In the latter it is related to the chronic inflammatory process and is amplified by brain changes due to aging and accumulation of disease burden. It induces demyelination and neurodegeneration by direct oxidation of lipids, proteins and DNA as well as by the induction of mitochondrial injury, which results in energy deficiency and further amplification of oxygen radical production. It affects neurons and all types of glia cells, but neurons and oligodendrocytes are most vulnerable. Difference in the susceptibility for oxidative injury between different cellular components of the central nervous system appears to be due to cell type specific differences in anti-oxidant defense mechanisms, iron loading, cellular susceptibility to apoptosis induction and energy demand. This article is part of a Special Issue entitled: Neuro Inflammation edited by Helga E. de Vries and Markus Schwaninger. © 2015 Elsevier B.V.

Arrich J.,Medical University of Vienna
Cochrane database of systematic reviews (Online) | Year: 2012

Good neurologic outcome after cardiac arrest is hard to achieve. Interventions during the resuscitation phase and treatment within the first hours after the event are critical. Experimental evidence suggests that therapeutic hypothermia is beneficial, and a number of clinical studies on this subject have been published. This review was originally published in 2009. We performed a systematic review and meta-analysis to assess the effectiveness of therapeutic hypothermia in patients after cardiac arrest. Neurologic outcome, survival and adverse events were our main outcomes. We aimed to perform individual patient data analysis, if data were available, and to form subgroups according to the cardiac arrest situation. We searched the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2001, Issue 7); MEDLINE (1971 to July 2011); EMBASE (1987 to July 2011); CINAHL (1988 to July 2011); PASCAL (2000 to July 2011); and BIOSIS (1989 to July 2011). The original search was performed in January 2007. We included all randomized controlled trials assessing the effectiveness of therapeutic hypothermia in patients after cardiac arrest, without language restrictions. Studies were restricted to adult populations cooled with any cooling method, applied within six hours of cardiac arrest. Validity measures, the intervention, outcomes and additional baseline variables were entered into a database. Meta-analysis was only done for a subset of comparable studies with negligible heterogeneity. For these studies, individual patient data were available. We included four trials and one abstract reporting on 481 patients in the systematic review. The updated search resulted in no new studies to include. Quality of the included studies was good in three out of five studies. For the three comparable studies on conventional cooling methods all authors provided individual patient data. With conventional cooling methods, patients in the hypothermia group were more likely to reach a best cerebral performance categories (CPC) score of one or two (five point scale: 1 = good cerebral performance, to 5 = brain death) during the hospital stay (individual patient data; RR 1.55; 95% CI 1.22 to 1.96) and were more likely to survive to hospital discharge (individual patient data; RR 1.35; 95% CI 1.10 to 1.65) compared to standard post-resuscitation care. Across all studies, there was no significant difference in reported adverse events between hypothermia and control. Conventional cooling methods to induce mild therapeutic hypothermia seem to improve survival and neurologic outcome after cardiac arrest. Our review supports the current best medical practice as recommended by the International Resuscitation Guidelines.

Kaye W.H.,University of California at San Diego | Wierenga C.E.,University of California at San Diego | Bailer U.F.,University of California at San Diego | Bailer U.F.,Medical University of Vienna | And 4 more authors.
Biological Psychiatry | Year: 2013

Is starvation in anorexia nervosa (AN) or overeating in bulimia nervosa (BN) a form of addiction? Alternatively, why are individuals with BN more vulnerable and individuals with AN protected from substance abuse? Such questions have been generated by recent studies suggesting that there are overlapping neural circuits for foods and drugs of abuse. To determine whether a shared neurobiology contributes to eating disorders and substance abuse, this review focused on imaging studies that investigated response to tastes of food and tasks designed to characterize reward and behavioral inhibition in AN and BN. BN and those with substance abuse disorders may share dopamine D2 receptor-related vulnerabilities, and opposite findings may contribute to protection from substance abuse in AN. Moreover, imaging studies provide insights into executive corticostriatal processes related to extraordinary inhibition and self-control in AN and diminished inhibitory self-control in BN that may influence the rewarding aspect of palatable foods and likely other consummatory behaviors. AN and BN tend to have premorbid traits, such as perfectionism and anxiety that make them vulnerable to using extremes of food ingestion, which serve to reduce negative mood states. Dysregulation within and/or between limbic and executive corticostriatal circuits contributes to such symptoms. Limited data support the hypothesis that reward and inhibitory processes may contribute to symptoms in eating disorders and addictive disorders, but little is known about the molecular biology of such mechanisms in terms of shared or independent processes. © 2013 Society of Biological Psychiatry.

Eichler H.-G.,European Medicines Agency | Bloechl-Daum B.,Medical University of Vienna | Abadie E.,Agence Francaise de Securite Sanitaire des Produits de Sante astr temp 143 147 | Barnett D.,University of Leicester | And 2 more authors.
Nature Reviews Drug Discovery | Year: 2010

Drug regulatory agencies have traditionally assessed the quality, safety and efficacy of drugs, and the current paradigm dictates that a new drug should be licensed when the benefits outweigh the risks. By contrast, third-party payers base their reimbursement decisions predominantly on the health benefits of the drug relative to existing treatment options (termed relative efficacy; RE). Over the past decade, the role of payers has become more prominent, and time-to-market no longer means time-to-licensing but time-to-reimbursement. Companies now have to satisfy the sometimes divergent needs of both regulators and payers, and to address RE during the pre-marketing stages. This article describes the current political background to the RE debate and presents the scientific and methodological challenges as they relate to RE assessment. In addition, we explain the impact of RE on drug development, and speculate on future developments and actions that are likely to be required from key players. © 2010 Macmillan Publishers Limited. All rights reserved.

Eder-Czembirek C.,Medical University of Vienna
Strahlentherapie und Onkologie : Organ der Deutschen Röntgengesellschaft ... [et al] | Year: 2010

Betulinic acid, a pentacyclic triterpene, is a new cytotoxic compound active on melanoma, neuroblastoma, glioblastoma and head and neck squamous cell carcinoma (HNSCC) cells. In combination with irradiation it has been shown to have an additive effect on growth inhibition in melanoma cells. In this study, the radiosensitizing effect of betulinic acid on sequential irradiation was investigated in HNSCC cell lines. Two HNSCC cell lines, SCC9 and SCC25, were treated with increasing doses of betulinic acid and sequentially irradiated with a single boost of 4 Gy from a conventional radiation source. The cells were counted, the surviving fraction was determined, and colony-forming assays were performed. It could be shown that betulinic acid alone inhibits cell survival, affects cell survival additively in combination with irradiation and decreases clonogenic survival in both cell lines when applied alone. Betulinic acid could be a promising treatment agent in radioresistant head and neck cancer. A combination of betulinic acid with radiotherapy seems to be beneficial.

Peck-Radosavljevic M.,Medical University of Vienna
Therapeutic Advances in Gastroenterology | Year: 2010

Medical therapies have entered center stage in the treatment of hepatocellular carcinoma (HCC) little more than a year after the positive results of a large phase III trial of sorafenib showed a clear survival benefit with sorafenib, a targeted agent, in this setting. Even though this marks a breakthrough in the treatment of HCC, the narrow patient profile necessary for the study to be successful has generated a number of questions regarding the efficacy of this approach in other clinical settings. New studies aiming to define the role of sorafenib from in the adjuvant setting, through patients with more advanced liver disease, all the way to combination treatments of HCC have been initiated. The success of one targeted drug has stimulated enormously the efforts of competitors to develop additional and better drugs, either in a first-line or a second-line setting. These are exciting times for the treatment of HCC, both for physicians and patients. In the years to come we will see an extension of treatment options in different clinical situations in patients with HCC, and survival will be improved in many stages of the disease, except for the most advanced. The rapid increase in knowledge about the molecular mechanisms underlying the development and progression of HCC will lead to a more tailored approach to treatment depending on the molecular characteristics of the tumor and the disease stage. © The Author(s), 2010.

Gruenberger T.,Medical University of Vienna | Arnold D.,University of Hamburg | Rubbia-Brandt L.,University of Geneva
Surgical Oncology | Year: 2012

For patients with colorectal liver metastases (CLM), hepatic resection currently offers the best chance for long-term survival. Preoperative chemotherapy is now integral to the management of these patients, conferring a disease-free survival advantage over surgery alone in patients with 'upfront' resectable disease and enabling some initially unresectable CLM to become resectable. However, although surgery may improve long-term survival, up to 65.0% of patients will experience disease recurrence at 5 years and reliable prognostic factors are needed to predict those patients who are more likely to experience recurrence after resection. Recently, pathologic tumor response, defined as the 'objective measurement of residual cancer cells in resected tissue,' has been identified as a reliable prognostic factor in patients with colorectal cancer (CRC) receiving preoperative chemotherapy and has been shown to correlate with improved survival after resection of CLM. Addition of the targeted biologic agent bevacizumab to preoperative chemotherapy is associated with an increase in pathologic response rate and an increase in survival compared with chemotherapy alone in patients undergoing hepatic resection. This review discusses the data in support of pathologic response rate as an important new outcome endpoint after hepatic resection of CLM and considers the evidence to date on pathologic response to bevacizumab-containing chemotherapy in metastatic CRC and its correlation with survival. © 2012 Elsevier Ltd. All rights reserved.

Tricoire F.,University of Vienna | Tricoire F.,NICTA | Graf A.,Medical University of Vienna | Gutjahr W.J.,University of Vienna
Computers and Operations Research | Year: 2012

We formulate a bi-objective covering tour model with stochastic demand where the two objectives are given by (i) cost (opening cost for distribution centers plus routing cost for a fleet of vehicles) and (ii) expected uncovered demand. In the model, it is assumed that depending on the distance, a certain percentage of clients go from their homes to the nearest distribution center. An application in humanitarian logistics is envisaged. For the computational solution of the resulting bi-objective two-stage stochastic program with recourse, a branch-and-cut technique, applied to a sample-average version of the problem obtained from a fixed random sample of demand vectors, is used within an epsilon-constraint algorithm. Computational results on real-world data for rural communities in Senegal show the viability of the approach. © 2011 Elsevier Ltd. All rights reserved.

Schmitt J.,TU Dresden | Langan S.,University of Pennsylvania | Stamm T.,Medical University of Vienna | Williams H.C.,University of Nottingham
Journal of Investigative Dermatology | Year: 2011

There is wide variation in the use of outcome measures for eczema. We performed a three-stage web-based international Delphi exercise to develop consensus-based sets of core outcome domains for eczema for controlled trials and clinical recordkeeping. A total of 57 individuals from four stakeholder groups (consumers, clinical experts, regulatory agency representatives, and journal editors) representing 13 countries were asked to rate the importance of 19 outcome domains for eczema and to choose which domains should be included in two core sets of outcomes. Forty-six individuals (81%) participated. Participants received standardized feedback, including the group median, interquartile range, and previous responses, and the assessment was repeated in two subsequent rounds. We defined consensus a priori if at least 60% of the members of at least three stakeholder groups, including consumers, recommended domain inclusion in the core set. Consensus was achieved for inclusion of symptoms, physician-assessed clinical signs, and a measurement for long-term control of flares in the core set of outcome domains for eczema trials. We recommend including these three core outcomes in future eczema trials in order to enhance clinical interpretability and to enable meta-analyses across different studies. For recordkeeping, consensus was reached to regularly monitor eczema symptoms in clinical practice. Future work is needed to select which existing or new scales should be used to measure the domains identified as relevant for the core set. © 2011 The Society for Investigative Dermatology.

Kessler J.,University of Heidelberg | Marhofer P.,Medical University of Vienna | Hopkins P.M.,University of Leeds | Hollmann M.W.,Academic Medical Center Amsterdam
British Journal of Anaesthesia | Year: 2015

Background: Our aim was to review the recent evidence for the efficacy of peripheral regional anaesthesia. Methods: Following a systematic literature search and selection of publications based on prospectively agreed upon criteria, we produced a narrative review of the most commonly performed peripheral regional anaesthetic blocks for surgery on the upper limb, the lower limb, and the trunk. We considered short-term and longer-term benefits and complications among the outcomes of interest. Results: Where good quality evidence exists, the great majority of the blocks reviewed were associated with one or any combination of reduced postoperative pain, reduced opioid consumption, or increased patient satisfaction. For selected surgical procedures, the use of blocks avoided general anaesthesia and was associated with increased efficiency of the surgical pathway. The exceptions were supraclavicular block, where there was insufficient evidence, and transversus abdominis plane block, where the evidence for efficacy was conflicting. The evidence for the impact of the blocks on longer-term outcomes was, in general, inadequate to inform clinical decision making. Permanent complications are rare.Conclusions: The majority of peripheral regional anaesthetic techniques have been shown to produce benefits for patients and hospital efficiency. Further interventional trials are required to clarify such benefits for supraclavicular block and transversus abdominis plane block and to ascertain any longer-term benefits for almost all of the blocks reviewed. Permanent complications of peripheral regional anaesthetic blocks are rare but accurate estimates of their incidence are yet to be determined. © The Author 2014. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.

Baltzer P.A.T.,Medical University of Vienna | Dietzel M.,Friedrich - Alexander - University, Erlangen - Nuremberg | Kaiser W.A.,University Hospital Jena
European Radiology | Year: 2013

Objectives: In the face of multiple available diagnostic criteria in MR-mammography (MRM), a practical algorithm for lesion classification is needed. Such an algorithm should be as simple as possible and include only important independent lesion features to differentiate benign from malignant lesions. This investigation aimed to develop a simple classification tree for differential diagnosis in MRM. Methods: A total of 1,084 lesions in standardised MRM with subsequent histological verification (648 malignant, 436 benign) were investigated. Seventeen lesion criteria were assessed by 2 readers in consensus. Classification analysis was performed using the chi-squared automatic interaction detection (CHAID) method. Results include the probability for malignancy for every descriptor combination in the classification tree. Results: A classification tree incorporating 5 lesion descriptors with a depth of 3 ramifications (1, root sign; 2, delayed enhancement pattern; 3, border, internal enhancement and oedema) was calculated. Of all 1,084 lesions, 262 (40.4 %) and 106 (24.3 %) could be classified as malignant and benign with an accuracy above 95 %, respectively. Overall diagnostic accuracy was 88.4 %. Conclusions: The classification algorithm reduced the number of categorical descriptors from 17 to 5 (29.4 %), resulting in a high classification accuracy. More than one third of all lesions could be classified with accuracy above 95 %. Key Points: • A practical algorithm has been developed to classify lesions found in MR-mammography. • A simple decision tree consisting of five criteria reaches high accuracy of 88.4 %. • Unique to this approach, each classification is associated with a diagnostic certainty. • Diagnostic certainty of greater than 95 % is achieved in 34 % of all cases. © 2013 European Society of Radiology.

Gruber C.W.,Medical University of Vienna
Experimental Physiology | Year: 2014

Neuropeptides and regulatory peptide hormones control many developmental, physiological and behavioural processes in animals, including humans. The nonapeptides oxytocin and arginine vasopressin are produced and released by the pituitary gland and have actions on many organs and tissues. Receptive cells possess particular receptors to which the peptides bind as ligands, leading to activation of G-protein-coupled receptors, hence cellular responses. In humans and other mammalian species, oxytocin and vasopressin mediate a range of peripheral and central physiological functions that are important for osmoregulation, reproduction, complex social behaviours, memory and learning. The origin of the oxytocin/vasopressin signalling system is thought to date back more than 600 million years. All vertebrate oxytocin- and vasopressin-like peptides have presumably evolved from the ancestral nonapeptide vasotocin by gene duplication and today are present in vertebrates, including mammals, birds, reptiles, amphibians and fish. Oxytocin- and vasopressin-like peptides have been identified in several invertebrate species, including molluscs, annelids, nematodes and arthropods. Members of this peptide family share high sequence similarity, and it is possible that they are functionally related across the entire animal kingdom. However, it is evident that not all animals express oxytocin/vasopressin neuropeptides and that there is little information available about the biology and physiology of this signalling system of invertebrates and, in particular, of insects, which represent more than half of all known living organisms. This report describes the discovery of novel oxytocin- and vasopressin-like peptides in arthropods and summarizes the status quo of the functional relevance of this neuropeptide signalling system in invertebrates, which will have beneficial implications for the design of selective and potent ligands to human oxytocin and vasopressin receptors. © 2013 The Author.

Lassmann H.,Medical University of Vienna
Experimental Neurology | Year: 2014

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system, which leads to widespread focal lesions of primary demyelination with variable axonal, neuronal and astroglia injury. The mechanisms responsible for tissue injury in the MS brain and spinal cord are only incompletely understood. In this review we discuss that the formation of confluent subpial cortical lesions is the most specific type of tissue damage, which is exclusively present in MS patients. Current data suggest that subpial demyelination is triggered by a soluble factor, which is produced in meningeal inflammatory infiltrates and diffuses into the cortical parenchyma, where it destroys myelin either directly or indirectly through microglia activation. The presence of demyelinating activity in sera and cerebrospinal fluid of MS patients is known for decades, but the molecular nature of the possibly underlying demyelinating factor is still unclear. Destruction of myelin sheaths and oligodendrocytes as well as neurodegeneration in MS are associated with massive oxidative stress and mitochondrial injury. Oxidative stress appears to be driven in early MS by activated microglia and oxidative burst and is, in the progressive stage of the disease, amplified by additional factors related to the age of patients and accumulation of pre-existing brain damage. Thus, the demyelinating factor in MS patients may either be a currently unknown cytokine or an inflammatory mediator or, alternatively, a mixture of cytokines. It may activate microglia towards uncontrolled oxygen radical production. Alternatively, the demyelinating factor may by itself trigger demyelination, which is then amplified by oxidative injury. The molecular characterization of the demyelinating factor may provide an important clue for the understanding of MS pathogenesis in the future. © 2013 Elsevier Inc.

De Wit M.P.T.,Medical Center | Smolen J.S.,Medical University of Vienna | Gossec L.,University of Paris Descartes | Van Der Heijde D.M.F.M.,Leiden University
Annals of the Rheumatic Diseases | Year: 2011

To transcribe the treat-to-target (T2T) recommendations into a version that can be easily understood by patients. A core group of physicians and patients involved in the elaboration of the T2T recommendations produced a draft version of the T2T recommendations in lay language. This version was discussed, changed and reworded during a 1-day meeting with nine patients with rheumatoid arthritis (RA) from nine different European countries. Finally, the level of agreement with the translation and with the content of the recommendations was assessed by the patient participants. The project resulted in a patient version of the T2T recommendations. The level of agreement with the translation and the content was high. The group discussion revealed a number of potentialbarriers for the implementation of the recommendations in clinical practice, such as inequalities in arthritis healthcare provision across Europe. An accurate version of the T2T recommendations that can be easily understood by patients is available and can improve the shared decision process in the management of RA.

Holzer L.A.,Medical University of Graz | Holzer G.,Medical University of Vienna
Journal of Arthroplasty | Year: 2014

The 50 highest cited articles related to hip and knee arthroplasty were searched in Thomson ISI Web of Science®. The 50 highest cited articles had up to 2495 citations. The top 10 papers according to absolute number were cited 580 times at least. Most papers were published in the Journal of Bone and Joint Surgery American Volume (n= 22). Eight countries contributed to the list with most contributions from the United States (n= 30). The majority of papers were published since 1990 (n= 27). Studies focusing on the clinical outcome of hip arthroplasty dominate the literature in orthopedic arthroplasty in respect to absolute citations numbers. In the last decade however, papers on perioperative management have been published that show a high citation frequency. © 2014 Elsevier Inc.

BACKGROUND: In lung transplant recipients (LTRs), human cytomegalovirus (HCMV) DNA detection in the bronchoalveolar lavage fluid (BALF) indicates HCMV replication in the pulmonary compartment. Such local HCMV replication episodes may remain asymptomatic or may lead to symptomatic HCMV disease. Here, we investigated LTRs with intrapulmonary HCMV replication for the chemokines CCL-18 and CCL-20. In particular, we analyzed whether these chemokines rise in the allograft and/or the blood and are associated with HCMV disease. METHODS: CCL-18 and CCL-20 levels were quantitated by ELISA in BALF and serum samples from 60 LTRs. During the posttransplant follow-up, these LTRs displayed HCMV DNA detection in the BALF by PCR, whereas other infectious agents were undetectable. Furthermore, we investigated samples from 10 controls who did not display any HCMV replication episode during the follow-up. RESULTS: HCMV replication in the allograft was associated with a significant increase of CCL-18 and CCL-20 BALF levels (P < 0.001, Wilcoxon signed-rank test) and a significant rise of CCL-20 (P < 0.0001, Wilcoxon signed-rank test) but not of CCL-18 in the blood. In controls, no such chemokine increase was observed. Furthermore, CCL-18 BALF levels were significantly higher in 8 LTRs who additionally developed HCMV disease, as compared with the other 52 patients in whom HCMV replication remained asymptomatic (P < 0.001, Mann–Whitney U test). CONCLUSIONS: HCMV replication in the allograft causes an intrapulmonary increase of CCL-18 and CCL-20 and a systemic rise of CCL-20 serum levels. Strong intrapulmonary CCL-18 responses are associated with symptomatic HCMV disease, proposing that CCL-18 BALF levels could serve as a marker. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

Schabbauer G.,Medical University of Vienna
Drug Discovery Today: Disease Models | Year: 2012

Sepsis is a disease syndrome covering many different aspects of the host immune system. Our understanding of sepsis is still incomplete. Several animal models of sepsis have been developed and much of our current knowledge on the molecular basis of the disease has originated from these models. Two of the most reliable and clinically relevant rodent models to mimic human sepsis in the animal model are cecal ligation and puncture (CLP) and colon ascendens stent peritonitis (CASP). © 2011 Elsevier Ltd. All rights reserved.

Watanabe H.,University of Heidelberg | Schmidt H.A.,Medical University of Vienna | Kuhn A.,University of Heidelberg | Hoger S.K.,University of Heidelberg | And 4 more authors.
Nature | Year: 2014

In bilaterians, three orthogonal body axes define the animal form, with distinct anterior-posterior, dorsal-ventral and left-right asymmetries. The key signalling factors are Wnt family proteins for the anterior-posterior axis, Bmp family proteins for the dorsal-ventral axis and Nodal for the left-right axis. Cnidarians, the sister group to bilaterians, are characterized by one oral-aboral body axis, which exhibits a distinct biradiality of unknown molecular nature. Here we analysed the biradial growth pattern in the radially symmetrical cnidarian polyp Hydra, and we report evidence of Nodal in a pre-bilaterian clade. We identified a Nodal-related gene (Ndr) in Hydra magnipapillata, and this gene is essential for setting up an axial asymmetry along the main body axis. This asymmetry defines a lateral signalling centre, inducing a new body axis of a budding polyp orthogonal to the mother polyp's axis. Ndr is expressed exclusively in the lateral bud anlage and induces Pitx, which encodes an evolutionarily conserved transcription factor that functions downstream of Nodal. Reminiscent of its function in vertebrates, Nodal acts downstream of β-Catenin signalling. Our data support an evolutionary scenario in which a 'core-signalling cassette' consisting of β-Catenin, Nodal and Pitx pre-dated the cnidarian-bilaterian split. We presume that this cassette was co-opted for various modes of axial patterning: for example, for lateral branching in cnidarians and left-right patterning in bilaterians. © 2014 Macmillan Publishers Limited. All rights reserved.

Melatonin, the popular hormone of the darkness, is primarily synthesized in the pineal gland, and acts classically through the G-protein coupled plasma membrane melatonin receptors MT1 and MT2, respectively. Although some of the receptor mediated functions of melatonin, especially those on the (central) circadian system, have been more or less clarified, the functional meaning of MT-receptors in various peripheral organs are still not sufficiently investigated yet. There is, however, accumulating evidence for oncostatic effects of melatonin with both, antioxidative and MT-receptor mediated mechanisms possibly playing a role. This review briefly summarizes the physiology of melatonin and MT-receptors, and discusses the expression and function of MT-receptors in human cancer cells and tissues. © 2014, Springer-Verlag Wien.

Amering M.,Medical University of Vienna
Psychiatria Danubina | Year: 2012

Context: Advocacy for Recovery has been joined by research offering new perspectives on mental health policy, treatment, rehabilitation and anti-discrimination efforts. Objectives: Chances and challenges of a Recovery model for the mental health field will be presented and discussed. Key messages: Recovery is currently widely endorsed as a guiding principle of mental health policy. New rules for services, e.g. user involvement and person-centred care, as well as new tools for clinical collaborations, e.g. shared decision making and psychiatric advance directives, are being complemented by new proposals regarding more ethically consistent anti-discrimination and involuntary treatment legislation as well as participatory approaches to evidence-based medicine and policy. Recovery advocacy has been joined by research on recovery and resilience resulting in new data on the long-term perspectives of people experiencing common as well as severe mental health problems. Definitions of remission and recovery as well as the concept of chronicity are under debate. Research questions regarding recovery as a process as well as an outcome warrant scientific efforts enabling the integration of different perspectives as well as different methodologies. Conclusions: Consequences and challenges of the Recovery model need to be tackled from different perspectives by clinicians, researchers, policy makers and-essentially - users and carers and their representatives in order to be fully explored and brought to life.

Beyer T.,Cmi experts GmbH | Moser E.,Medical University of Vienna
Magnetic Resonance Materials in Physics, Biology and Medicine | Year: 2013

After the very successful clinical introduction of combined PET/CT imaging a decade ago, a hardware combination of PET and MR is following suit. Today, three different approaches towards integrated PET/MR have been proposed: (1) a triple-modality system with a 3T MRI and a time-of-flight PET/CT installed in adjacent rooms, (2) a tandem system with a 3T MRI and a time-of-flight PET/CT in a co-planar installation with a joint patient handling system, and (3) a fully-integrated system with a whole-body PET system mounted inside a 3T MRI system. This special issue of MAGMA brings together contributions from key experts in the field of PET/MR, PET/CT and CT. The various papers share the author's perspectives on the state-of-the-art PET/MR imaging with any of the three approaches mentioned above. In addition to several reviews discussing advantages and challenges of combining PET and MRI for clinical diagnostics, first clinical data are also presented. We expect this special issue to nurture future improvements in hardware, clinical protocols, and efficient post-processing strategies to further assess the diagnostic value of combined PET/MR imaging. It remains to be seen whether a so-called "killer application" for PET/MRI will surface. In that case PET/MR is likely to excel in pre-clinical and selected research applications for now. This special issue helps the readers to stay on track of this exciting development. © 2013 ESMRMB.

Duranton F.,RD Nephrologie | Cohen G.,Medical University of Vienna | De Smet R.,Ghent University | Rodriguez M.,University of Cordoba, Spain | And 3 more authors.
Journal of the American Society of Nephrology | Year: 2012

An updated review of the existing knowledge regarding uremic toxins facilitates the design of experimental studies. We performed a literature search and found 621 articles about uremic toxicity published after a 2003 review of this topic. Eighty-seven records provided serum or blood measurements of one or more solutes in patients with CKD. These records described 32 previously known uremic toxins and 56 newly reported solutes. The articlesmost frequently reported concentrations of β2-microglobulin, indoxyl sulfate, homocysteine, uric acid, and parathyroid hormone. We found most solutes (59%) in only one report. Compared with previous results, more recent articles reported higher uremic concentrations of many solutes, including carboxymethyllysine, cystatin C, and parathyroid hormone. However, five solutes had uremic concentrations less than 10% of the originally reported values. Furthermore, the uremic concentrations of four solutes did not exceed their respective normal concentrations, although they had been previously described as uremic retention solutes. In summary, this review extends the classification of uremic retention solutes and their normal and uremic concentrations, and it should aid the design of experiments to study the biologic effects of these solutes in CKD. Copyright © 2012 by the American Society of Nephrology.