Thomas Perkmann | Medical University of Vienna (original) (raw)

Papers by Thomas Perkmann

Research paper thumbnail of Physical Exercise Counteracts Genetic Susceptibility to Depression

Neuropsychobiology, Jan 13, 2015

Depression is a highly prevalent disorder in elderly individuals. A genetic variant (rs6265) of t... more Depression is a highly prevalent disorder in elderly individuals. A genetic variant (rs6265) of the brain-derived neurotrophic factor (BDNF) impacting on emotion processing is known to increase the risk for depression. We aim to investigate whether intensive endurance sports might attenuate this genetic susceptibility in a cohort of elderly marathon athletes. Fifty-five athletes and 58 controls were included. rs6265 of the BDNF gene was genotyped by the TaqMan method. Depressive symptoms were assessed by standardized self-rating tests (BDI = Beck Depression Inventory, GDS = Geriatric Depression Scale). In multivariable analysis of BDI and GDS scores, the interaction between group (athletes vs. controls) and genotypes ([C];[C] vs. [C];[T] + [T];[T]) was found to be statistically significant (BDI: p = 0.027, GDS: p = 0.013). Among [C];[C] carriers, merely controls had an increased relative risk of 3.537 (95% CI = 1.276-9.802) of achieving a subclinical depression score ≥10 on the BDI....

Research paper thumbnail of Sepsis in standard care: patients’ characteristics, effectiveness of antimicrobial therapy and patient outcome—a cohort study

Infection, 2015

Fast diagnosis and initiation of appropriate antibiotic therapy is pivotal for the survival of se... more Fast diagnosis and initiation of appropriate antibiotic therapy is pivotal for the survival of sepsis patients. However, most studies on suspected sepsis patients are conducted in the intensive care unit or in the emergency room setting, neglecting the standard care setting. This study evaluated sepsis risk factors, microbiological accurateness of the initial empiric antimicrobial therapy and its effect on hospital mortality in standard care patients. In this prospective observational cohort study, patients with clinically suspected sepsis meeting two or more SIRS criteria were screened on standard care wards. After hospital discharge, occurrence of an infection was assessed according to standardized criteria, and empirical antibiotic therapy was evaluated using antibiograms of recognized pathogens by expert review. Of the 2384 screened patients, 298 fulfilled two or more SIRS criteria. Among these were 28.2 % SIRS patients without infection, 46.3 % non-bacteremic/fungemic sepsis patients and 25.5 % bacteremic/fungemic sepsis patients. Occurrence of a malignant disease and chills were associated with a higher risk of patients having bacteremic/fungemic sepsis, whereas other described risk factors remained insignificant. In total, 91.1 % of suspected sepsis patients received empirical antimicrobial therapy, but 41.1 % of bacteremic sepsis patients received inappropriate therapy. Non-surviving bacteremic sepsis patients received a higher proportion of inappropriate therapy than those who survived (p = 0.022). A significant proportion of bacteremic sepsis patients receive inappropriate empiric antimicrobial therapy. Our results indicate that rapid availability of microbiological results is vital, since inappropriate antimicrobial therapy tended to increase the hospital mortality of sepsis patients.

Research paper thumbnail of RED BLOOD CELL DERIVED MICROPARTICLES ARE THROMBOGENIC IN VITRO AND IN MOUSE MODELS OF ATHEROSCLEROSIS IN VIVO

Atherosclerosis Supplements, 2008

Research paper thumbnail of Interleukin-6 and asymmetric dimethylarginine are associated with platelet activation after percutaneous angioplasty with stent implantation

PloS one, 2015

Data linking in vivo platelet activation with inflammation and cardiovascular risk factors are sc... more Data linking in vivo platelet activation with inflammation and cardiovascular risk factors are scarce. Moreover, the interrelation between endothelial dysfunction as early marker of atherosclerosis and platelet activation has not been studied, so far. We therefore sought to investigate the associations of inflammation, endothelial dysfunction and cardiovascular risk factors with platelet activation and monocyte-platelet aggregate (MPA) formation in 330 patients undergoing angioplasty with stent implantation for atherosclerotic cardiovascular disease. P-selectin expression, activation of glycoprotein IIb/IIIa and MPA formation were determined by flow cytometry. Interleukin (IL)-6, high sensitivity C-reactive protein and asymmetric dimethylarginine (ADMA) were measured by commercially available assays. IL-6 was the only parameter which was independently associated with platelet P-selectin expression and activated GPIIb/IIIa as well as with leukocyte-platelet interaction in multivariat...

Research paper thumbnail of Increased mortality in patients with the lupus anticoagulant: the Vienna Lupus Anticoagulant and Thrombosis Study (LATS)

Blood, Jan 25, 2015

Data on the clinical course of lupus anticoagulant (LA) positive individuals with or without thro... more Data on the clinical course of lupus anticoagulant (LA) positive individuals with or without thrombotic manifestations or pregnancy complications are limited. To investigate mortality rates and factors that might influence mortality, we conducted a prospective observational study of LA positive individuals. In total, 151 patients (82% female) were followed for median of 8.2 years, of whom 30 patients (20%) developed 32 thromboembolic events (15 arterial and 17 venous events) and 20 patients (13%) died. In univariable analysis new onset of thrombosis (HR=8.76, 95%CI 3.46-22.16) was associated with adverse survival. Thrombosis remained a strong adverse prognostic factor after multivariable adjustment for age and hypertension (HR=5.95, 95%CI 2.43-14.95). Concomitant autoimmune diseases, anticoagulant treatment at baseline or positivity for anticardiolipin- or anti-β2-glycoprotein I antibodies were not associated with mortality. In a relative survival analysis, our cohort of LA positive...

Research paper thumbnail of Urine and serum concentrations of Cytokeratin 19 in preeclampsia

European journal of obstetrics, gynecology, and reproductive biology, 2014

To evaluate the usefulness of Cytokeratin 19 as biomarker for the diagnosis of preeclampsia. Cyto... more To evaluate the usefulness of Cytokeratin 19 as biomarker for the diagnosis of preeclampsia. Cytokeratin 19 protein fragment CYFRA 21-1 was measured by means of electrochemiluminescence immunoassays in urine and serum samples of 32 women with preeclampsia and 32 samples of normotensive healthy singleton pregnancies at random, matched for gestational age, as controls. The median serum concentrations of CYFRA 21-1 in controls and women with preeclampsia were 2.4 (range 1.3-6.6)ng/mL and 4.4 (range 2.1-16.2)ng/mL, respectively (p<0.001). The median urine concentrations of CYFRA 21-1 in controls and women with preeclampsia were 13.7 (range 0.7-441.4)ng/mL and 11.8 (range 1.5-338.6)ng/mL, respectively (p=0.629). Calculation of a ROC curve to study the use of serum CYFRA 21-1 concentration as a predictor of preeclampsia revealed cut-off points with the highest sum of specificity and sensitivity of 3.2ng/mL, leading to specificity of 75% and sensitivity of 84%. A similar curve calculate...

Research paper thumbnail of Efficacy of fosfomycin compared to vancomycin in treatment of implant-associated chronic methicillin-resistant Staphylococcus aureus osteomyelitis in rats

Antimicrobial agents and chemotherapy, 2014

Fosfomycin monotherapy was compared to therapy with vancomycin for the treatment of implant-assoc... more Fosfomycin monotherapy was compared to therapy with vancomycin for the treatment of implant-associated methicillin-resistant Staphylococcus aureus (MRSA) osteomyelitis in an experimental rat model. The proximal tibiae were inoculated with 15 μl of a suspension containing 1×10(8) to 5×10(8) CFU/ml of a clinical isolate of MRSA with simultaneous insertion of a titanium wire. Four weeks later, treatment was started for 28 days with either 50 mg/kg of body weight vancomycin intraperitoneally twice daily (n=11) or 75 mg/kg fosfomycin intraperitoneally once daily (n=10). Eleven animals were left untreated. After treatment, quantitative cultures from bone were found to be positive for MRSA in all animals in the untreated group (median, 3.29×10(6) CFU/g of bone) and the vancomycin group (median, 3.03×10(5) CFU/g of bone). In the fosfomycin group, MRSA was detectable in 2 out of 10 (20%) animals (3.42×10(2) and 1.51×10(3) CFU/g of bone). Vancomycin was superior to the no-drug control (P=0.00...

Research paper thumbnail of Vesicles generated during storage of red cells are rich in the lipid raft marker stomatin

Transfusion, 2008

The release of vesicles by red blood cells (RBCs) occurs in vivo and in vitro under various condi... more The release of vesicles by red blood cells (RBCs) occurs in vivo and in vitro under various conditions. Vesiculation also takes place during RBC storage and results in the accumulation of vesicles in RBC units. The membrane protein composition of the storage-associated vesicles has not been studied in detail. The characterization of the vesicular membrane might hint at the underlying mechanism of the storage-associated changes in general and the vesiculation process in particular. Vesicles from RBCs that had been stored for various periods were isolated and RBCs of the same RBC units were used to generate calcium-induced microvesicles. These two vesicle types were compared with respect to their size with atomic force microscopy, their raft protein content with detergent-resistant membrane (DRM) analysis, and their thrombogenic potential and activity with annexin V binding and thrombin generation, respectively. The storage-associated vesicles and the calcium-induced microvesicles are...

Research paper thumbnail of ID: 284 Phosphatidylserine and oxidized phosphatidylethanolamine interact with Protein C Inhibitor (PCI) and modify its activity

Journal of Thrombosis and Haemostasis, 2006

ABSTRACT

Research paper thumbnail of Long-Term Outcome of Anti-Glomerular Basement Membrane Antibody Disease Treated with Immunoadsorption

PLoS ONE, 2014

Background: Anti-glomerular basement membrane (GBM) antibody disease may lead to acute crescentic... more Background: Anti-glomerular basement membrane (GBM) antibody disease may lead to acute crescentic glomerulonephritis with poor renal prognosis. Current therapy favours plasma exchange (PE) for removal of pathogenic antibodies. Immunoadsorption (IAS) is superior to PE regarding efficiency of antibody-removal and safety. Apart from anecdotal data, there is no systemic analysis of the long-term effects of IAS on anti-GBM-disease and antibody kinetics.

Research paper thumbnail of Additive gene-environment effects on hippocampal structure in healthy humans

Hippocampal volume loss has been related to chronic stress as well as genetic factors. Although g... more Hippocampal volume loss has been related to chronic stress as well as genetic factors. Although genetic and environmental variables affecting hippocampal volume have extensively been studied and related to mental illness, limited evidence is available with respect to G ϫ E interactions on hippocampal volume. The present MRI study investigated interaction effects on hippocampal volume between three well-studied functional genetic variants (COMT Val158Met, BDNF Val66Met, 5-HTTLPR) associated with hippocampal volume and a measure of environmental adversity (life events questionnaire) in a large sample of healthy humans (n ϭ 153). All three variants showed significant interactions with environmental adversity with respect to hippocampal volume. Observed effects were additive by nature and driven by both recent as well as early life events. A consecutive analysis of hippocampal subfields revealed a spatially distinct profile for each genetic variant suggesting a specific role of 5-HTTLPR for the subiculum, BDNF Val66Met for CA4/dentate gyrus, and COMT Val158Met for CA2/3 volume changes. The present study underscores the importance of G ϫ E interactions as determinants of hippocampal volume, which is crucial for the neurobiological understanding of stress-related conditions, such as mood disorders or post-traumatic stress disorder (PTSD).

Research paper thumbnail of Myeloperoxidase Levels Predict Executive Function

The main purpose of the study was to investigate whether baseline myeloperoxidase (MPO) levels ar... more The main purpose of the study was to investigate whether baseline myeloperoxidase (MPO) levels are associated with executive cognitive function in individuals with high physical activity. Baseline serum MPO levels of 56 elderly marathon runners and 58 controls were assessed by ELISA. Standardized tests were applied to survey domain-specific cognitive functions. Changes in brain morphology were visualized by magnetic resonance imaging (MRI). High baseline serum MPO levels correlated with worse outcome in tests assessing executive cognitive function in athletes but not in the control group (NAI maze test p&amp;amp;lt;0.05, Trail Making Test ratio p&amp;amp;lt;0.01). In control participants, subcortical white matter hyperintensities were associated with higher scores on the Geriatric Depression Scale (p&amp;amp;lt;0.05), whereas athletes seem to be protected from this effect. During strenuous exercising, MPO as well as its educts may be elevated due to increased oxygen intake and excretion of pro-inflammatory mediators inducing host tissue damage via oxidative stress. This outweighs the potential benefits of physical activity on cognitive function.

Research paper thumbnail of Circulating microparticles carry oxidation-specific epitopes and are recognized by natural IgM antibodies

Journal of lipid research, 2015

Oxidation-specific epitopes (OSEs) present on apoptotic cells and oxidized low density lipoprotei... more Oxidation-specific epitopes (OSEs) present on apoptotic cells and oxidized low density lipoprotein (OxLDL) represent danger-associated molecular patterns that are recognized by different arcs of innate immunity, including natural IgM antibodies. Here, we investigated whether circulating microparticles (MPs), which are small membrane vesicles released by apoptotic or activated cells, are physiological carriers of OSEs. OSEs on circulating MPs isolated from healthy donors and patients with ST-segment elevation myocardial infarction (STE-MI) were characterized by flow cytometry using a panel of OSE-specific monoclonal antibodies. We found that a subset of MPs carry OSEs on their surface, predominantly malondialdehyde (MDA) epitopes. Consistent with this, a majority of IgM antibodies bound on the surface of circulating MPs were found to have specificity for MDA-modified LDL. Moreover, we show that MPs can stimulate THP-1 (human acute monocytic leukemia cell line) and human primary monoc...

Research paper thumbnail of A Risk Prediction Model for Screening Bacteremic Patients: A Cross Sectional Study

PLoS ONE, 2014

Background: Bacteraemia is a frequent and severe condition with a high mortality rate. Despite pr... more Background: Bacteraemia is a frequent and severe condition with a high mortality rate. Despite profound knowledge about the pre-test probability of bacteraemia, blood culture analysis often results in low rates of pathogen detection and therefore increasing diagnostic costs. To improve the cost-effectiveness of blood culture sampling, we computed a risk prediction model based on highly standardizable variables, with the ultimate goal to identify via an automated decision support tool patients with very low risk for bacteraemia.

Research paper thumbnail of B 15-42 Protects against Acid-induced Acute Lung Injury and Secondary Pseudomonas Pneumonia In Vivo

American Journal of Respiratory and Critical Care Medicine, 2009

Rationale: Acute lung injury (ALI) is a serious condition in critically ill patients that predisp... more Rationale: Acute lung injury (ALI) is a serious condition in critically ill patients that predisposes to secondary bacterial pneumonia. Vascular leak is a hallmark in the pathogenesis of ALI. The fibrin-derived peptide Bb 15-42 was shown to preserve endothelial barriers, thereby reducing vascular leak. The potential therapeutic role of Bb 15-42 in ALI has not been addressed so far. Objectives: To investigate the therapeutic potential of Bb 15-42 in ALI and secondary pneumonia induced by Pseudomonas aeruginosa. Methods: The effect of the fibrin-derived peptide Bb 15-42 was studied in models of ALI, induced either by pulmonary administration of LPS or hydrochloric acid. Lung inflammation was analyzed by quantifying cell influx, cytokine levels, and oxidized lipids. Vascular leak was determined by Evans Blue extravasations and alveolar protein content. In subsequent two-hit studies, mice were infected with P. aeruginosa 24 hours after induction of aspiration pneumonitis and effects of Bb 15-42 on inflammation, bacterial clearance, and survival were evaluated. Measurements and Main Results: After LPS or acid inhalation, proinflammatory cytokine levels, neutrophil influx, and vascular leak were found diminished in mice treated with Bb 15-42 . Acid aspiration impaired macrophage functions and rendered mice more susceptible to subsequent P. aeruginosa infection, whereas mice that received Bb 15-42 during acid aspiration and were subsequently challenged with bacteria displayed reduced inflammation, enhanced bacterial clearance, and ultimately improved survival. Conclusions: The fibrin-derived peptide Bb 15-42 exerted protective effects during ALI, resulting in diminished lung injury and preserved antibacterial properties of macrophages, which improved outcome during subsequent P. aeruginosa pneumonia.

Research paper thumbnail of Oppositional COMT Val158Met effects on resting state functional connectivity in adolescents and adults

Brain structure & function, Jan 16, 2014

Prefrontal dopamine levels are relatively increased in adolescence compared to adulthood. Genetic... more Prefrontal dopamine levels are relatively increased in adolescence compared to adulthood. Genetic variation of COMT (COMT Val158Met) results in lower enzymatic activity and higher dopamine availability in Met carriers. Given the dramatic changes of synaptic dopamine during adolescence, it has been suggested that effects of COMT Val158Met genotypes might have oppositional effects in adolescents and adults. The present study aims to identify such oppositional COMT Val158Met effects in adolescents and adults in prefrontal brain networks at rest. Resting state functional connectivity data were collected from cross-sectional and multicenter study sites involving 106 healthy young adults (mean age 24 ± 2.6 years), gender matched to 106 randomly chosen 14-year-olds. We selected the anterior medial prefrontal cortex (amPFC) as seed due to its important role as nexus of the executive control and default mode network. We observed a significant age-dependent reversal of COMT Val158Met effects ...

Research paper thumbnail of Supplemental Data Identification of Oxidative Stress and Toll-like Receptor 4 Signaling as a Key Pathway of Acute Lung Injury

Research paper thumbnail of Coagulation factor VIII levels are associated with long-term survival – interactions with gender in a large hospital-based cohort

Wiener klinische Wochenschrift, 2010

Elevated coagulation factor VIII activity has been associated with increased risk for both venous... more Elevated coagulation factor VIII activity has been associated with increased risk for both venous and arterial thrombosis. The current study evaluated the influence of Factor VIII levels and interactions with gender on all cause mortality in a large Austrian cohort. During 1991 and 2003, 11203 individuals, first ever request for laboratory analyses of FVIII: C, age &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; or =18 years, were included in this study. The median observation period was 5 years covering a total of 46000 person-years. The death rate was 17.1%. Compared to individuals within the reference category (FVIII: C &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;94%) hazard ratios gradually increased from 1.4 (95% CI: 1.1-1.8) in the 152-170% category (5th decile) to finally 4.4 (95% CI: 3.5-5.5) in the &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;313% category (highest decile, all p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05). The association between FVIII: C levels and mortality remained essentially unchanged when considering non-cancer mortality, all cause vascular mortality or mortality due to ischemic heart disease. Compared to males females with elevated FVIII: C had a worse outcome resulting in higher hazard ratios reaching 6.8 (95% CI: 4.6-9.9) within the highest decile compared to males (HR: 3.4 (95% CI: 2.6-4.5)). In our large patient cohort we might be able to demonstrate for the first time that FVIII: C plasma activity is strongly associated with all cause mortality. Additionally, FVIII: C appears to interact with gender. Especially in women FVIII: C might help identifying high-risk cohorts, which might benefit from individualized prevention strategies.

Research paper thumbnail of The EGF 61A/G polymorphism – a predictive marker for recurrence of liver metastases from colorectal cancer

Wiener klinische Wochenschrift, 2009

Epidermal growth factor (EGF) plays an important role in tumorigenesis. Variations in the DNA seq... more Epidermal growth factor (EGF) plays an important role in tumorigenesis. Variations in the DNA sequence of the gene EGF can lead to alterations in EGF activity, which is suspected to influence tumor progression. This retrospective study aimed to investigate the influence of EGF 61A/G polymorphism on the recurrence of liver metastases after hepatic surgery in patients with colorectal cancer. EGF 61A/G polymorphism was determined in 268 consecutive patients (175 [65%] men and 93 [35%] women, mean age 62 +/- 10.3 years) who had liver metastases at primary diagnosis and were treated by surgery with curative intent (R0) for liver metastases from colorectal cancer. Overall, 81 of 268 (30%) patients exhibited wild-type EGF 61 A/A, 137 (51%) were heterozygous EGF 61 A/G and 50 (19%) were homozygous EGF 61 G/G. After adjusting for age, sex, UICC stage and tumor location, we observed a trend-wise 1.6-fold increased risk for hepatic recurrence (HR 1.6; 95% CI 1.0-2.5, P = 0.06) in individuals with the G/G genotype compared with carriers of the A-allele. The effect was much more pronounced in younger patients (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;or= 65 years), who showed a 2.0-fold increased risk of hepatic recurrence (HR 2.0; 95% CI 1.1-3.5, P = 0.021). No effect was observed in older patients (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;or= 65 years). Interestingly, male patients with EGF G/G had a 1.6-fold higher risk of recurrence (HR 1.6; 95% CI 1.0-2.5, P = 0.07). A significant correlation (P = 0.033) was detected between Dukes classification and the homozygous 61 G/G genotype. Despite the limitations of our study, the retrospective results indicate that carriers of the EGF polymorphism might be at higher risk of developing liver recurrences. If confirmed in subsequent studies, genotyping for the EGF A/G variant might help in identification of patients at high risk of recurrence of liver metastases.

Research paper thumbnail of Cognitive function in elderly marathon runners: Cross-sectional data from the marathon trial (apsoem)

Wiener klinische Wochenschrift, 2010

Background: Cognitive impairment of the elderly contributes to morbidity, loss of quality of life... more Background: Cognitive impairment of the elderly contributes to morbidity, loss of quality of life and impairment of work ability in aging western societies. Thus strategies to maintain cognitive function at an advanced age imply a great challenge to Occupational Medicine. Aim: To study whether intensive endurance exercise training is associated with better cognitive performance and increases brain-derived neurotrophic factor (BDNF) and insulin-like growth factor (IGF). Methods: Active elderly marathon runners or bicyclists older than 60 years were recruited and matched with an inactive control group according to age, sex, and education years. After exclusion of various diseases according to the study protocol 56 athletes and 58 controls could be selected for follow-up studies. The influence of endurance training on cognitive function was assessed by the use of the Vienna Neuropsychological Test Battery and the CERAD test battery. Other relevant outcomes were the levels of BDNF, IGF-1, Apo e4 carrier state and self ratings. Results: The elderly marathon group performed better only in one specific cognitive task (the Five Point Test, p=0.04) and almost significantly better in one additional test (the NAI Stroop Test, p=0.08). Neither BDNF nor IGF-1 was related to the duration of daily exercise and no differences in the basal levels of these humoral growth factors in the exercise and the control cohort were found. Interestingly, we also found significantly decreased BDNF levels in subjects with Alzheimer´s disease in the family in spite of the maintained normal cognitive performance (p=0.01).

Research paper thumbnail of Physical Exercise Counteracts Genetic Susceptibility to Depression

Neuropsychobiology, Jan 13, 2015

Depression is a highly prevalent disorder in elderly individuals. A genetic variant (rs6265) of t... more Depression is a highly prevalent disorder in elderly individuals. A genetic variant (rs6265) of the brain-derived neurotrophic factor (BDNF) impacting on emotion processing is known to increase the risk for depression. We aim to investigate whether intensive endurance sports might attenuate this genetic susceptibility in a cohort of elderly marathon athletes. Fifty-five athletes and 58 controls were included. rs6265 of the BDNF gene was genotyped by the TaqMan method. Depressive symptoms were assessed by standardized self-rating tests (BDI = Beck Depression Inventory, GDS = Geriatric Depression Scale). In multivariable analysis of BDI and GDS scores, the interaction between group (athletes vs. controls) and genotypes ([C];[C] vs. [C];[T] + [T];[T]) was found to be statistically significant (BDI: p = 0.027, GDS: p = 0.013). Among [C];[C] carriers, merely controls had an increased relative risk of 3.537 (95% CI = 1.276-9.802) of achieving a subclinical depression score ≥10 on the BDI....

Research paper thumbnail of Sepsis in standard care: patients’ characteristics, effectiveness of antimicrobial therapy and patient outcome—a cohort study

Infection, 2015

Fast diagnosis and initiation of appropriate antibiotic therapy is pivotal for the survival of se... more Fast diagnosis and initiation of appropriate antibiotic therapy is pivotal for the survival of sepsis patients. However, most studies on suspected sepsis patients are conducted in the intensive care unit or in the emergency room setting, neglecting the standard care setting. This study evaluated sepsis risk factors, microbiological accurateness of the initial empiric antimicrobial therapy and its effect on hospital mortality in standard care patients. In this prospective observational cohort study, patients with clinically suspected sepsis meeting two or more SIRS criteria were screened on standard care wards. After hospital discharge, occurrence of an infection was assessed according to standardized criteria, and empirical antibiotic therapy was evaluated using antibiograms of recognized pathogens by expert review. Of the 2384 screened patients, 298 fulfilled two or more SIRS criteria. Among these were 28.2 % SIRS patients without infection, 46.3 % non-bacteremic/fungemic sepsis patients and 25.5 % bacteremic/fungemic sepsis patients. Occurrence of a malignant disease and chills were associated with a higher risk of patients having bacteremic/fungemic sepsis, whereas other described risk factors remained insignificant. In total, 91.1 % of suspected sepsis patients received empirical antimicrobial therapy, but 41.1 % of bacteremic sepsis patients received inappropriate therapy. Non-surviving bacteremic sepsis patients received a higher proportion of inappropriate therapy than those who survived (p = 0.022). A significant proportion of bacteremic sepsis patients receive inappropriate empiric antimicrobial therapy. Our results indicate that rapid availability of microbiological results is vital, since inappropriate antimicrobial therapy tended to increase the hospital mortality of sepsis patients.

Research paper thumbnail of RED BLOOD CELL DERIVED MICROPARTICLES ARE THROMBOGENIC IN VITRO AND IN MOUSE MODELS OF ATHEROSCLEROSIS IN VIVO

Atherosclerosis Supplements, 2008

Research paper thumbnail of Interleukin-6 and asymmetric dimethylarginine are associated with platelet activation after percutaneous angioplasty with stent implantation

PloS one, 2015

Data linking in vivo platelet activation with inflammation and cardiovascular risk factors are sc... more Data linking in vivo platelet activation with inflammation and cardiovascular risk factors are scarce. Moreover, the interrelation between endothelial dysfunction as early marker of atherosclerosis and platelet activation has not been studied, so far. We therefore sought to investigate the associations of inflammation, endothelial dysfunction and cardiovascular risk factors with platelet activation and monocyte-platelet aggregate (MPA) formation in 330 patients undergoing angioplasty with stent implantation for atherosclerotic cardiovascular disease. P-selectin expression, activation of glycoprotein IIb/IIIa and MPA formation were determined by flow cytometry. Interleukin (IL)-6, high sensitivity C-reactive protein and asymmetric dimethylarginine (ADMA) were measured by commercially available assays. IL-6 was the only parameter which was independently associated with platelet P-selectin expression and activated GPIIb/IIIa as well as with leukocyte-platelet interaction in multivariat...

Research paper thumbnail of Increased mortality in patients with the lupus anticoagulant: the Vienna Lupus Anticoagulant and Thrombosis Study (LATS)

Blood, Jan 25, 2015

Data on the clinical course of lupus anticoagulant (LA) positive individuals with or without thro... more Data on the clinical course of lupus anticoagulant (LA) positive individuals with or without thrombotic manifestations or pregnancy complications are limited. To investigate mortality rates and factors that might influence mortality, we conducted a prospective observational study of LA positive individuals. In total, 151 patients (82% female) were followed for median of 8.2 years, of whom 30 patients (20%) developed 32 thromboembolic events (15 arterial and 17 venous events) and 20 patients (13%) died. In univariable analysis new onset of thrombosis (HR=8.76, 95%CI 3.46-22.16) was associated with adverse survival. Thrombosis remained a strong adverse prognostic factor after multivariable adjustment for age and hypertension (HR=5.95, 95%CI 2.43-14.95). Concomitant autoimmune diseases, anticoagulant treatment at baseline or positivity for anticardiolipin- or anti-β2-glycoprotein I antibodies were not associated with mortality. In a relative survival analysis, our cohort of LA positive...

Research paper thumbnail of Urine and serum concentrations of Cytokeratin 19 in preeclampsia

European journal of obstetrics, gynecology, and reproductive biology, 2014

To evaluate the usefulness of Cytokeratin 19 as biomarker for the diagnosis of preeclampsia. Cyto... more To evaluate the usefulness of Cytokeratin 19 as biomarker for the diagnosis of preeclampsia. Cytokeratin 19 protein fragment CYFRA 21-1 was measured by means of electrochemiluminescence immunoassays in urine and serum samples of 32 women with preeclampsia and 32 samples of normotensive healthy singleton pregnancies at random, matched for gestational age, as controls. The median serum concentrations of CYFRA 21-1 in controls and women with preeclampsia were 2.4 (range 1.3-6.6)ng/mL and 4.4 (range 2.1-16.2)ng/mL, respectively (p<0.001). The median urine concentrations of CYFRA 21-1 in controls and women with preeclampsia were 13.7 (range 0.7-441.4)ng/mL and 11.8 (range 1.5-338.6)ng/mL, respectively (p=0.629). Calculation of a ROC curve to study the use of serum CYFRA 21-1 concentration as a predictor of preeclampsia revealed cut-off points with the highest sum of specificity and sensitivity of 3.2ng/mL, leading to specificity of 75% and sensitivity of 84%. A similar curve calculate...

Research paper thumbnail of Efficacy of fosfomycin compared to vancomycin in treatment of implant-associated chronic methicillin-resistant Staphylococcus aureus osteomyelitis in rats

Antimicrobial agents and chemotherapy, 2014

Fosfomycin monotherapy was compared to therapy with vancomycin for the treatment of implant-assoc... more Fosfomycin monotherapy was compared to therapy with vancomycin for the treatment of implant-associated methicillin-resistant Staphylococcus aureus (MRSA) osteomyelitis in an experimental rat model. The proximal tibiae were inoculated with 15 μl of a suspension containing 1×10(8) to 5×10(8) CFU/ml of a clinical isolate of MRSA with simultaneous insertion of a titanium wire. Four weeks later, treatment was started for 28 days with either 50 mg/kg of body weight vancomycin intraperitoneally twice daily (n=11) or 75 mg/kg fosfomycin intraperitoneally once daily (n=10). Eleven animals were left untreated. After treatment, quantitative cultures from bone were found to be positive for MRSA in all animals in the untreated group (median, 3.29×10(6) CFU/g of bone) and the vancomycin group (median, 3.03×10(5) CFU/g of bone). In the fosfomycin group, MRSA was detectable in 2 out of 10 (20%) animals (3.42×10(2) and 1.51×10(3) CFU/g of bone). Vancomycin was superior to the no-drug control (P=0.00...

Research paper thumbnail of Vesicles generated during storage of red cells are rich in the lipid raft marker stomatin

Transfusion, 2008

The release of vesicles by red blood cells (RBCs) occurs in vivo and in vitro under various condi... more The release of vesicles by red blood cells (RBCs) occurs in vivo and in vitro under various conditions. Vesiculation also takes place during RBC storage and results in the accumulation of vesicles in RBC units. The membrane protein composition of the storage-associated vesicles has not been studied in detail. The characterization of the vesicular membrane might hint at the underlying mechanism of the storage-associated changes in general and the vesiculation process in particular. Vesicles from RBCs that had been stored for various periods were isolated and RBCs of the same RBC units were used to generate calcium-induced microvesicles. These two vesicle types were compared with respect to their size with atomic force microscopy, their raft protein content with detergent-resistant membrane (DRM) analysis, and their thrombogenic potential and activity with annexin V binding and thrombin generation, respectively. The storage-associated vesicles and the calcium-induced microvesicles are...

Research paper thumbnail of ID: 284 Phosphatidylserine and oxidized phosphatidylethanolamine interact with Protein C Inhibitor (PCI) and modify its activity

Journal of Thrombosis and Haemostasis, 2006

ABSTRACT

Research paper thumbnail of Long-Term Outcome of Anti-Glomerular Basement Membrane Antibody Disease Treated with Immunoadsorption

PLoS ONE, 2014

Background: Anti-glomerular basement membrane (GBM) antibody disease may lead to acute crescentic... more Background: Anti-glomerular basement membrane (GBM) antibody disease may lead to acute crescentic glomerulonephritis with poor renal prognosis. Current therapy favours plasma exchange (PE) for removal of pathogenic antibodies. Immunoadsorption (IAS) is superior to PE regarding efficiency of antibody-removal and safety. Apart from anecdotal data, there is no systemic analysis of the long-term effects of IAS on anti-GBM-disease and antibody kinetics.

Research paper thumbnail of Additive gene-environment effects on hippocampal structure in healthy humans

Hippocampal volume loss has been related to chronic stress as well as genetic factors. Although g... more Hippocampal volume loss has been related to chronic stress as well as genetic factors. Although genetic and environmental variables affecting hippocampal volume have extensively been studied and related to mental illness, limited evidence is available with respect to G ϫ E interactions on hippocampal volume. The present MRI study investigated interaction effects on hippocampal volume between three well-studied functional genetic variants (COMT Val158Met, BDNF Val66Met, 5-HTTLPR) associated with hippocampal volume and a measure of environmental adversity (life events questionnaire) in a large sample of healthy humans (n ϭ 153). All three variants showed significant interactions with environmental adversity with respect to hippocampal volume. Observed effects were additive by nature and driven by both recent as well as early life events. A consecutive analysis of hippocampal subfields revealed a spatially distinct profile for each genetic variant suggesting a specific role of 5-HTTLPR for the subiculum, BDNF Val66Met for CA4/dentate gyrus, and COMT Val158Met for CA2/3 volume changes. The present study underscores the importance of G ϫ E interactions as determinants of hippocampal volume, which is crucial for the neurobiological understanding of stress-related conditions, such as mood disorders or post-traumatic stress disorder (PTSD).

Research paper thumbnail of Myeloperoxidase Levels Predict Executive Function

The main purpose of the study was to investigate whether baseline myeloperoxidase (MPO) levels ar... more The main purpose of the study was to investigate whether baseline myeloperoxidase (MPO) levels are associated with executive cognitive function in individuals with high physical activity. Baseline serum MPO levels of 56 elderly marathon runners and 58 controls were assessed by ELISA. Standardized tests were applied to survey domain-specific cognitive functions. Changes in brain morphology were visualized by magnetic resonance imaging (MRI). High baseline serum MPO levels correlated with worse outcome in tests assessing executive cognitive function in athletes but not in the control group (NAI maze test p&amp;amp;lt;0.05, Trail Making Test ratio p&amp;amp;lt;0.01). In control participants, subcortical white matter hyperintensities were associated with higher scores on the Geriatric Depression Scale (p&amp;amp;lt;0.05), whereas athletes seem to be protected from this effect. During strenuous exercising, MPO as well as its educts may be elevated due to increased oxygen intake and excretion of pro-inflammatory mediators inducing host tissue damage via oxidative stress. This outweighs the potential benefits of physical activity on cognitive function.

Research paper thumbnail of Circulating microparticles carry oxidation-specific epitopes and are recognized by natural IgM antibodies

Journal of lipid research, 2015

Oxidation-specific epitopes (OSEs) present on apoptotic cells and oxidized low density lipoprotei... more Oxidation-specific epitopes (OSEs) present on apoptotic cells and oxidized low density lipoprotein (OxLDL) represent danger-associated molecular patterns that are recognized by different arcs of innate immunity, including natural IgM antibodies. Here, we investigated whether circulating microparticles (MPs), which are small membrane vesicles released by apoptotic or activated cells, are physiological carriers of OSEs. OSEs on circulating MPs isolated from healthy donors and patients with ST-segment elevation myocardial infarction (STE-MI) were characterized by flow cytometry using a panel of OSE-specific monoclonal antibodies. We found that a subset of MPs carry OSEs on their surface, predominantly malondialdehyde (MDA) epitopes. Consistent with this, a majority of IgM antibodies bound on the surface of circulating MPs were found to have specificity for MDA-modified LDL. Moreover, we show that MPs can stimulate THP-1 (human acute monocytic leukemia cell line) and human primary monoc...

Research paper thumbnail of A Risk Prediction Model for Screening Bacteremic Patients: A Cross Sectional Study

PLoS ONE, 2014

Background: Bacteraemia is a frequent and severe condition with a high mortality rate. Despite pr... more Background: Bacteraemia is a frequent and severe condition with a high mortality rate. Despite profound knowledge about the pre-test probability of bacteraemia, blood culture analysis often results in low rates of pathogen detection and therefore increasing diagnostic costs. To improve the cost-effectiveness of blood culture sampling, we computed a risk prediction model based on highly standardizable variables, with the ultimate goal to identify via an automated decision support tool patients with very low risk for bacteraemia.

Research paper thumbnail of B 15-42 Protects against Acid-induced Acute Lung Injury and Secondary Pseudomonas Pneumonia In Vivo

American Journal of Respiratory and Critical Care Medicine, 2009

Rationale: Acute lung injury (ALI) is a serious condition in critically ill patients that predisp... more Rationale: Acute lung injury (ALI) is a serious condition in critically ill patients that predisposes to secondary bacterial pneumonia. Vascular leak is a hallmark in the pathogenesis of ALI. The fibrin-derived peptide Bb 15-42 was shown to preserve endothelial barriers, thereby reducing vascular leak. The potential therapeutic role of Bb 15-42 in ALI has not been addressed so far. Objectives: To investigate the therapeutic potential of Bb 15-42 in ALI and secondary pneumonia induced by Pseudomonas aeruginosa. Methods: The effect of the fibrin-derived peptide Bb 15-42 was studied in models of ALI, induced either by pulmonary administration of LPS or hydrochloric acid. Lung inflammation was analyzed by quantifying cell influx, cytokine levels, and oxidized lipids. Vascular leak was determined by Evans Blue extravasations and alveolar protein content. In subsequent two-hit studies, mice were infected with P. aeruginosa 24 hours after induction of aspiration pneumonitis and effects of Bb 15-42 on inflammation, bacterial clearance, and survival were evaluated. Measurements and Main Results: After LPS or acid inhalation, proinflammatory cytokine levels, neutrophil influx, and vascular leak were found diminished in mice treated with Bb 15-42 . Acid aspiration impaired macrophage functions and rendered mice more susceptible to subsequent P. aeruginosa infection, whereas mice that received Bb 15-42 during acid aspiration and were subsequently challenged with bacteria displayed reduced inflammation, enhanced bacterial clearance, and ultimately improved survival. Conclusions: The fibrin-derived peptide Bb 15-42 exerted protective effects during ALI, resulting in diminished lung injury and preserved antibacterial properties of macrophages, which improved outcome during subsequent P. aeruginosa pneumonia.

Research paper thumbnail of Oppositional COMT Val158Met effects on resting state functional connectivity in adolescents and adults

Brain structure & function, Jan 16, 2014

Prefrontal dopamine levels are relatively increased in adolescence compared to adulthood. Genetic... more Prefrontal dopamine levels are relatively increased in adolescence compared to adulthood. Genetic variation of COMT (COMT Val158Met) results in lower enzymatic activity and higher dopamine availability in Met carriers. Given the dramatic changes of synaptic dopamine during adolescence, it has been suggested that effects of COMT Val158Met genotypes might have oppositional effects in adolescents and adults. The present study aims to identify such oppositional COMT Val158Met effects in adolescents and adults in prefrontal brain networks at rest. Resting state functional connectivity data were collected from cross-sectional and multicenter study sites involving 106 healthy young adults (mean age 24 ± 2.6 years), gender matched to 106 randomly chosen 14-year-olds. We selected the anterior medial prefrontal cortex (amPFC) as seed due to its important role as nexus of the executive control and default mode network. We observed a significant age-dependent reversal of COMT Val158Met effects ...

Research paper thumbnail of Supplemental Data Identification of Oxidative Stress and Toll-like Receptor 4 Signaling as a Key Pathway of Acute Lung Injury

Research paper thumbnail of Coagulation factor VIII levels are associated with long-term survival – interactions with gender in a large hospital-based cohort

Wiener klinische Wochenschrift, 2010

Elevated coagulation factor VIII activity has been associated with increased risk for both venous... more Elevated coagulation factor VIII activity has been associated with increased risk for both venous and arterial thrombosis. The current study evaluated the influence of Factor VIII levels and interactions with gender on all cause mortality in a large Austrian cohort. During 1991 and 2003, 11203 individuals, first ever request for laboratory analyses of FVIII: C, age &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; or =18 years, were included in this study. The median observation period was 5 years covering a total of 46000 person-years. The death rate was 17.1%. Compared to individuals within the reference category (FVIII: C &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;94%) hazard ratios gradually increased from 1.4 (95% CI: 1.1-1.8) in the 152-170% category (5th decile) to finally 4.4 (95% CI: 3.5-5.5) in the &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;313% category (highest decile, all p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05). The association between FVIII: C levels and mortality remained essentially unchanged when considering non-cancer mortality, all cause vascular mortality or mortality due to ischemic heart disease. Compared to males females with elevated FVIII: C had a worse outcome resulting in higher hazard ratios reaching 6.8 (95% CI: 4.6-9.9) within the highest decile compared to males (HR: 3.4 (95% CI: 2.6-4.5)). In our large patient cohort we might be able to demonstrate for the first time that FVIII: C plasma activity is strongly associated with all cause mortality. Additionally, FVIII: C appears to interact with gender. Especially in women FVIII: C might help identifying high-risk cohorts, which might benefit from individualized prevention strategies.

Research paper thumbnail of The EGF 61A/G polymorphism – a predictive marker for recurrence of liver metastases from colorectal cancer

Wiener klinische Wochenschrift, 2009

Epidermal growth factor (EGF) plays an important role in tumorigenesis. Variations in the DNA seq... more Epidermal growth factor (EGF) plays an important role in tumorigenesis. Variations in the DNA sequence of the gene EGF can lead to alterations in EGF activity, which is suspected to influence tumor progression. This retrospective study aimed to investigate the influence of EGF 61A/G polymorphism on the recurrence of liver metastases after hepatic surgery in patients with colorectal cancer. EGF 61A/G polymorphism was determined in 268 consecutive patients (175 [65%] men and 93 [35%] women, mean age 62 +/- 10.3 years) who had liver metastases at primary diagnosis and were treated by surgery with curative intent (R0) for liver metastases from colorectal cancer. Overall, 81 of 268 (30%) patients exhibited wild-type EGF 61 A/A, 137 (51%) were heterozygous EGF 61 A/G and 50 (19%) were homozygous EGF 61 G/G. After adjusting for age, sex, UICC stage and tumor location, we observed a trend-wise 1.6-fold increased risk for hepatic recurrence (HR 1.6; 95% CI 1.0-2.5, P = 0.06) in individuals with the G/G genotype compared with carriers of the A-allele. The effect was much more pronounced in younger patients (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;or= 65 years), who showed a 2.0-fold increased risk of hepatic recurrence (HR 2.0; 95% CI 1.1-3.5, P = 0.021). No effect was observed in older patients (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;or= 65 years). Interestingly, male patients with EGF G/G had a 1.6-fold higher risk of recurrence (HR 1.6; 95% CI 1.0-2.5, P = 0.07). A significant correlation (P = 0.033) was detected between Dukes classification and the homozygous 61 G/G genotype. Despite the limitations of our study, the retrospective results indicate that carriers of the EGF polymorphism might be at higher risk of developing liver recurrences. If confirmed in subsequent studies, genotyping for the EGF A/G variant might help in identification of patients at high risk of recurrence of liver metastases.

Research paper thumbnail of Cognitive function in elderly marathon runners: Cross-sectional data from the marathon trial (apsoem)

Wiener klinische Wochenschrift, 2010

Background: Cognitive impairment of the elderly contributes to morbidity, loss of quality of life... more Background: Cognitive impairment of the elderly contributes to morbidity, loss of quality of life and impairment of work ability in aging western societies. Thus strategies to maintain cognitive function at an advanced age imply a great challenge to Occupational Medicine. Aim: To study whether intensive endurance exercise training is associated with better cognitive performance and increases brain-derived neurotrophic factor (BDNF) and insulin-like growth factor (IGF). Methods: Active elderly marathon runners or bicyclists older than 60 years were recruited and matched with an inactive control group according to age, sex, and education years. After exclusion of various diseases according to the study protocol 56 athletes and 58 controls could be selected for follow-up studies. The influence of endurance training on cognitive function was assessed by the use of the Vienna Neuropsychological Test Battery and the CERAD test battery. Other relevant outcomes were the levels of BDNF, IGF-1, Apo e4 carrier state and self ratings. Results: The elderly marathon group performed better only in one specific cognitive task (the Five Point Test, p=0.04) and almost significantly better in one additional test (the NAI Stroop Test, p=0.08). Neither BDNF nor IGF-1 was related to the duration of daily exercise and no differences in the basal levels of these humoral growth factors in the exercise and the control cohort were found. Interestingly, we also found significantly decreased BDNF levels in subjects with Alzheimer´s disease in the family in spite of the maintained normal cognitive performance (p=0.01).