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ABSTRACT: Die Atrophie der Skelettmuskulatur ist eine Begleiterscheinung bei einer Vielzahl von akuten und chronischen Erkrankungen,
wie Sepsis, chirurgische Interventionen, Trauma oder Immobilität. Auch während des Alterungsprozesses kommt es zu einem massiven
allgemeinen Muskelabbau. Davon betroffen sind insbesondere die für die Muskelkontraktion notwendigen myofibrillären Proteine
Myosin und Aktin, wodurch ein Verlust an Muskelmasse und Muskelkraft sowie eine beschleunigte Muskelermüdung entsteht. Die
Folgen sind beim kritisch Kranken oder immobilen Patienten erhöhte Infektionsraten, verlangsamte Wundheilung, Komplikationen
bei der Entwöhnung von der Beatmung und erschwerte Mobilisation. Im Alter führt dies zu Stürzen, Knochenbrüchen, Verletzungen
und Mobilitätsverlust. Ausgehend von den primären Stimulatoren – Hormone, Muskeldehnung, Stress, Inflammation, neuronale Aktivität
– konzentriert sich die Wissenschaft auf die Erforschung der Signaltransduktionswege, die zu einer Beeinflussung der Proteinsynthese
und des Proteinabbaus bei Atrophien des Skelettmuskels führen.
Skeletal muscle atrophy is associated with situations of acute and chronical illness, such as sepsis, surgery, trauma and
immobility. Additionally, it is a common problem during the physiological process of aging. The myofibrillar proteins myosin
and actin, which are essential for muscle contraction, are the major targets during the process of protein degradation. This
leads to a general loss of muscle mass, muscle strength and to increased muscle fatigue. In critically ill or immobile patients
skeletal muscle atrophy is accompanied by enhanced inflammation, reduced wound healing, weaning complications and difficulties
in mobilisation. During aging it results in falls, fractures, physical injuries and loss of mobility. Relating to the primary
stimulators – hormones, muscle lengthening, stress, inflammation, neuronal activity – research is now focusing on the investigation
of the signal transduction pathways, which influence protein synthesis and protein degradation during skeletal muscle atrophy.
Wiener klinische Wochenschrift 04/2012; 119(11):337-348. · 0.81 Impact Factor
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Maria Zellner,
Michael Baureder,
Eduard Rappold,
Peter Bugert,
Nicole Kotzailias,
Rita Babeluk,
Roland Baumgartner,
Johannes Attems,
Christopher Gerner,
Kurt Jellinger, Erich Roth,
Rudolf Oehler,
Ellen Umlauf
[show abstract]
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ABSTRACT: Monoamine oxidase-B (Mao-B) catalysing the breakdown of the neurotransmitter dopamine, is known to be involved in the pathophysiology of Parkinson's (PD) and Alzheimer's disease (AD). Increased brain Mao-B activity is associated with AD. This alteration can also be seen in platelets, albeit the cause has hitherto remained elusive. To gain a deeper understanding of the etiology of AD, the platelet proteome was characterised, (2D DIGE pH6-9, including Mao-B) from 150 individuals: 34 AD, 13 vascular dementia, 15 non-demented PD patients, 49 matched controls, 18 oldest old and 21 young individuals. One significant change was noted after applying false discovery rate with the upregulation of the Mao-B expression (30% adjusted P value<0.001; effect size 1.31) in AD compared to age- and sex-matched controls. In contrast, Mao-B levels were unchanged in PD to matched controls. Western blot and mRNA analyses verified these findings. Moreover, Mao-B concentration correlated with age in the cognitive healthy individuals (r=0.53; P<0.001) and PD patients but not in those suffering from AD (r=-0.03; P=0.874). Mao-B activity correlated with the increased Mao-B protein expression in AD (r=0.81; P=0.016). We suggest that Mao-B platelet protein level may serve as a biomarker for age-related dementia, especially AD.
Journal of proteomics 01/2012; 75(7):2080-92. · 5.07 Impact Factor
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ABSTRACT: Studies investigating the impact of high meat intake on cognition have yielded contradictory results as some show improved cognitive performance, whereas others report an increase of risk factors for dementia. However, few studies were designed to directly assess the effect of a high protein (HP) diet on both cognitive performance and corresponding biochemical parameters. A randomised intervention study was conducted with 23 healthy males (aged 19-31 years) to investigate the effects of a usual (UP) versus a HP diet on cognitive function and on the platelet proteome a well-established model for neurons. The study individuals were assigned to either a UP diet (15% energy) or a HP diet (30% energy) for 3 weeks with controlled intake of food and beverages. Blood samples were taken along with measurements of cognitive functions at the beginning and at the end of the intervention period. Among 908 reproducibly studied platelet proteins only the level of monoamine oxidase B (MaoB), a neurotransmitter degrading enzyme, decreased by 26% significantly (adjusted P value < 0.05) due to the HP diet. In addition, we found a correlation (r = 0.477; P < 0.02) between the decrease of MaoB expression and the shortened reaction time (cognitive function) which is in accordance with reports that dementia patients show increased MaoB activity. Plasma vitamin B(12) concentration was increased by the HP diet and correlates inversely with platelet MaoB expression (r = -0.35; P < 0.02). Healthy young males on a HP diet showed improved cognitive function and counteract well-known dementia biomarkers such as platelet MaoB and components of the methylation cycle such as vitamin B(12) and homocysteine.
Acta Neurovegetativa 03/2011; 118(5):653-62. · 2.73 Impact Factor
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ABSTRACT: Recommendations to use other criteria than N-balance for defining protein requirements have been proposed. However, little evidence to support other measures such as physiological functions is available.
To investigate the effects of a usual (UP) versus a high protein (HP) diet on muscle function, cognitive function, quality of life and biochemical regulators of protein metabolism.
A randomised intervention study was conducted with 23 healthy males (aged 19-31 yrs). All subjects consumed a Usual Protein (UP) diet (1.5 g protein/kg BW) for a 1-wk run-in period before the intervention period where they were assigned to either a UP or a High Protein (HP) diet (3.0 g protein/kg BW) for 3-wks with controlled intake of food and beverages. Blood and urine samples were taken along with measurements of physiological functions at baseline and at the end of the intervention period.
The HP group improved their reaction time significantly compared with the UP group. Branched chain amino acids and phenylalanine in plasma were significantly increased following the HP diet, which may explain the improved reaction time.
Healthy young males fed a HP diet improved reaction time. No adverse effects of the HP diet were observed. This trial was registered at www.clinicaltrials.gov as NCT00621231.
Clinical nutrition (Edinburgh, Scotland) 01/2011; 30(3):303-11. · 3.27 Impact Factor
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ABSTRACT: In various diseases amino acid imbalances occur which have been described especially in the 1980s of the last century. It was noted that some of these imbalances may exert specific negative physiological effects. However, mainly because of economic reasons, no real attempts have been made to develop special amino acid solutions for disease processed associated with amino acid imbalances to restore normal amino acid concentrations.
A recent study performed in the fruit-fly Drosophila indicated that modifying the amino acid supply may influence both lifespan and fecundity. It was shown that adding amino acids but not carbohydrates or fat to a restricted diet decreases lifespan. In contrast, administration of certain amino acids especially of methionine increased fecundity without decreasing lifespan. It is known that dietary restriction can decrease fecundity at the cost of a prolonged lifespan.
Recent investigations revealed that amino acids are powerful molecules in mediating cell signalling. Therefore, it can be hypothesized that the severe amino acid imbalances as observed in uraemia or liver failure may exert a relevant impact on various physiologic processes and on organ function. The recent results described in Drosophila should stimulate a new research area on the effect of amino acid supply in various disease processes.
Current opinion in clinical nutrition and metabolic care. 11/2010; 14(1):67-74.
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ABSTRACT: Glutamine depletion in skeletal muscle of severely ill patients is an outstanding metabolic marker related to acute skeletal muscle wasting. To date it is unclear why intracellular glutamine concentrations are lowered in skeletal muscle to such an extent when simultaneously muscular glutamine synthesis and release are stimulated. This essay introduces a hypothesis that intracellular glutamine deficiency is part of a metabolic program maintaining cell integrity. This program seems to resemble short-term hibernation, which can be observed in various mammalian species during periods of starvation. Interestingly, even in septic patients who do not survive, there are no signs of apoptosis or necrosis in affected organs. Therefore, in severe illness evolutionarily conserved energy saving programs may be switched on for protecting the organs in a mode reminiscent of hibernation. This would explain the low energy expenditure as described for septic patients and the limited success of nutrition in avoiding skeletal muscle atrophy in sepsis.
Nutrition 05/2010; 26(5):571-4. · 3.03 Impact Factor
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ABSTRACT: Moderate hyperhomocysteinemia is a well-established coronary risk factor that develops when dietary supply with folate and/or vitamin B(12) is inadequate. Recently, stimulated peripheral blood mononuclear cells were shown to produce homocysteine. Thus, the stimulated immune system may contribute to moderate hyperhomocysteinemia during certain diseases. Because multiple trauma and sepsis are accompanied by often strong inflammatory responses, we investigated whether hyperhomocysteinemia may develop in patients. Total homocysteine and cysteine concentrations were measured in 83 plasma specimens from 18 patients (14 men, 4 women; 15 posttrauma with sepsis and 3 with sepsis alone) every third day of follow-up. Finally results were compared with concentrations of cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-6, the immune activation marker neopterin and the extent of tryptophan degradation as indicated by the kynurenine-to-tryptophan ratio (kyn/trp). Compared with baseline, average total homocysteine (P < 0.05, d 4-d 10) and cysteine (P < 0.05, d 7-d 13) concentrations increased during follow-up of patients. However, only the increase of homocysteine was related to the survival status: total homocysteine was significantly higher in nonsurvivors (P < 0.05, d 4 and d 10) than in survivors, whereas cysteine concentrations increased in both subgroups. Homocysteine correlated with kyn/trp but not with neopterin concentrations. Increase of total homocysteine is common in patients after trauma with unfavorable outcome. Because all patients received standardized enteral nutrition after the end of hypodynamic shock, inconsistent vitamin supply is unlikely to be the reason for hyperhomocysteinemia in some of the patients; rather, it is associated with a stronger proinflammatory response. Certainly, the number of patients in our study is still small and results can only be regarded as preliminary.
Molecular Medicine 03/2010; 16(11-12):498-504. · 3.76 Impact Factor
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ABSTRACT: With the discovery of microRNAs (miRNAs), an exceptional means of regulating gene expression was introduced a few years ago. MiRNAs function to inactivate specific messenger RNA transcripts leading to depletion of the corresponding protein, whereby computational studies have shown that about one third of all animal genes might be miRNA targets. Recent publications highlight the involvement of miRNAs in regulating the immune response. The aim of this review is to provide an overview of miRNA biogenesis and function, to illustrate their impact on both the innate as well as the adaptive immune system, to show the regulation of skeletal muscle plasticity and inflammation, and finally to present their possible role within the field of exercise immunology.
Exercise immunology review 01/2010; 16:22-39. · 2.79 Impact Factor
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ABSTRACT: Immune system activation and inflammation accompanies immune dysfunction in trauma and sepsis patients. Immunodeficiency may develop in such patients as one consequence of an activated chronic pro-inflammatory response. According to recent data, degradation of L-tryptophan (TRP) via the kynurenine (KYN) pathway by the cytokine-inducible enzyme indoleamine 2,3-dioxygenase (IDO) could represent an important contributor to the deficient responsiveness of immunocompetent cells. Compared to healthy controls, patients post trauma or with sepsis had increasing KYN concentrations and KYN to TRP ratios (KYN/TRP) whereas TRP concentrations decreased. Likewise, concentrations of cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) and of immune activation marker neopterin increased in patients (all p < 0.001). Furthermore in patients KYN/TRP, KYN and neopterin concentrations were further increasing (all p < 0.001), whereas the changes of TRP, TNF-α and IL-6 concentrations were not significant. Compared to the survivors, the non-survivors had a higher concentration of KYN, neopterin, TNF-α and IL-6 as well as a higher KYN/TRP ratio. KYN/TRP correlated with neopterin (p < 0.001) and also with TNF-α (p < 0.01) and IL-6 concentrations (p < 0.05) and inversely with the in vitro response of stimulated monocytes. We conclude that increased TRP degradation in patients post trauma is closely associated with immune activation. Cytokines released during the pro-inflammatory response may induce the activity of IDO and thus accelerate TRP degradation. Thus, increased IDO activity most likely represents a result of host response to pro-inflammation in patients. Data support a possible role of inflammation-induced IDO in the diminished immunoresponsiveness in patients.
International Journal of Tryptophan Research 01/2010; 3:61-7.
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Eva Maria Strasser,
Stefan Stättner,
Josef Karner,
Martin Klimpfinger,
Matthias Freynhofer,
Vera Zaller,
Alexandra Graf,
Barbara Wessner,
Norbert Bachl, Erich Roth,
Michael Quittan
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ABSTRACT: To investigate the effect of neuromuscular electrical stimulation (NMES) on skeletal muscle metabolism after major abdominal surgery.
Protein catabolism associated with surgical interventions leads to reduced muscle strength, increased clinical complications and prolonged convalescence. Immobilization is suggested as a major stimulus for muscle wasting. This study investigates the potency of NMES on skeletal muscle growth factors and degradation processes in surgical patients.
This observer blind study included 26 patients after major abdominal surgery mainly due to cancer aged 60 +/- 10 years. Starting on the first postoperative day, 1 randomly assigned thigh of each patient was treated on 4 consecutive days with NMES, whereas the other leg was used as sham-stimulated control. Thereafter, muscle biopsies from both legs were performed. Differences in mRNA level, protein expression, and enzyme activity between legs were analyzed by cross-over analysis of variance (Clinical Trial Registration Number: NCT00635440).
NMES significantly increased total RNA content and total sarcoplasmatic protein content. NMES significantly reduced ubiquitin-conjugated sarcoplasmatic proteins and proteasome activity. The mechano growth factor mRNA level correlated positively with the applied current and negatively with the body mass index of the patients. The increase in insulin like growth factor-1Ea mRNA after NMES correlated negatively with the age of the patients.
This study shows that NMES significantly increases total RNA content and reduces protein degradation in postoperative patients. Moreover, the induction of growth factors by NMES reveals dependency on body mass index, age, and applied current. We conclude that NMES is a useful clinical tool to reduce protein catabolism in postoperative patients.
Annals of surgery 05/2009; 249(5):738-43. · 7.90 Impact Factor
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ABSTRACT: Recently we showed that the polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA) sensitizes arsenic trioxide (As2O3)-resistant tumor cells to a clinically achievable concentration (1 microM) of As2O3 via a reactive oxygen species (ROS)-dependent mechanism. The aim of the present study was to evaluate, whether this combined effect of As2O3 and DHA is also applicable to other PUFAs [i.e., eicospentaenoic acid (EPA), arachidonic acid (AA), and gamma-linolenic acid (GLA)]. Fourteen tumor cell lines were incubated with As2O3 (1 microM), PUFA (25-100 microM), or the combination thereof (+/- vitamin E). Cell viability (colorimetric), apoptosis (bivariate annexin V/propidium iodide staining, detection of hypodiploid DNA), and thiobarbituric acid reactive substances (TBARS) were evaluated. Twelve of 14 As2O3-resistant cell lines tested were resistant to PUFA monotherapy. However, combined treatment with As2O3 and either PUFA significantly reduced cell viability in a dose-dependent manner with AA being the most potent As2O3 enhancer. The combined cytotoxic effect of As2O3/AA treatment was due to induction of apoptosis, preceded by increased intracellular TBARS and was abolished by the antioxidant vitamin E. Importantly, the combined effect of As2O3 and AA was selectively toxic for malignant cells because no cytotoxic effect was observed in normal skin fibroblasts and human microvascular endothelial cells. In conclusion, our study shows that also other PUFAs than DHA-and in particular the omega-6-PUFA AA--can be used as effective modulators of tumor cell chemosensitivity to clinically achievable concentrations of As2O3. Enhanced lipid peroxidation most likely constitutes the key mechanism for the combined effect.
Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics 01/2009; 18(2-3):83-94. · 1.30 Impact Factor
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ABSTRACT: Immune system activation and inflammation accompanies immune dysfunction in trauma and sepsis patients. Tryptophan degradation via the kynurenine pathway by the cytokine-inducible enzyme indoleamine 2,3-dioxy-genase (IDO) could contribute to the deficient responsiveness of immunocompetent cells. Activated IDO in patients after trauma and with sepsis is indicated by an increased kynurenine to tryptophan ratio (kyn/trp), which was found to be associated with poor outcome of patients. In this study, tryptophan and kynurenine concentra-tions in 18 patients post trauma or with sepsis during 12-14 days of follow up (up to 84 specimens were avail-able) were compared to concentrations of neopterin and cytokines tumor necrosis factor-α (TNF-α) and inter-leukin-6 (IL-6) and the in vitro response of lipopolysaccharide-stimulated monocytes. Compared to healthy con-trols, average kyn/trp and kynurenine, TNF-α, IL-6 and neopterin concentrations were increased in patients, and tryptophan concentrations were decreased. During follow-up, only kyn/trp, kynurenine and neopterin concentra-tions (all p <0.001) were increasing, whereas the changes of tryptophan, TNF-α and IL-6 concentrations were not significant. Non-survivors presented not only with higher kyn/trp and with higher kynurenine and neopterin con-centrations than survivors, but also TNF-α and IL-6 concentrations were higher. Kyn/trp correlated with neopterin (r s = 0.590; p <0.001) and also with TNF-α (r s = 0.374; p <0.01) and IL-6 concentrations (r s = 0.262; p <0.05) and inversely with the in vitro response of stimulated monocytes. Data imply that increased tryptophan degradation in patients post trauma is due to IDO activation. Increased IDO activity most likely represents a result of host defence response in patients, and data support a possible role of IDO to diminish immunoresponsiveness in such patients.
PTERIDINES 01/2009; 20:54-61. · 0.44 Impact Factor
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[show abstract]
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ABSTRACT: Immune dysfunction in trauma patients is associated with immune system activation and inflammation. The cytokine-inducible enzyme IDO (indoleamine 2,3-dioxygenase) initiates the degradation of the essential aromatic amino acid tryptophan via the kynurenine pathway and could contribute to deficient immune responsiveness. Activated IDO is indicated by an increased kyn/trp (kynurenine/tryptophan) ratio. The aim of the present study was to investigate whether tryptophan degradation is associated with outcome in patients post-trauma. Tryptophan and kynurenine concentrations were measured by HPLC in serum specimens of 15 patients post-trauma during 12-14 days of follow-up. Up to five samples within this observation period from each patient were included in this analysis, and a total a 69 samples were available. For further comparisons, concentrations of the immune activation marker neopterin were measured. Compared with healthy controls, the average kyn/trp ratio and kynurenine concentrations were increased in patients, whereas tryptophan concentrations were decreased. During follow-up, increased kyn/trp ratio and kynurenine concentrations (all P<0.001) were observed, whereas the changes in tryptophan concentrations were not significant. Non-survivors had higher kyn/trp ratios and kynurenine concentrations compared with survivors. The kyn/trp ratio correlated with neopterin concentrations (r(s)=0.590, P<0.001). In conclusion, these results imply that increased tryptophan degradation in patients is due to activated IDO, which most probably is a consequence of a host defence response. These findings support a possible role for IDO in the development of immunodeficiency and death in patients.
Clinical Science 12/2008; 116(7):593-8. · 4.61 Impact Factor
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Erich Roth
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ABSTRACT: Glutamine is the most abundant free amino acid of the human body. Besides its role as a constituent of proteins and its importance in amino acid transamination, glutamine has regulatory capacity in immune and cell modulation. Glutamine deprivation reduces proliferation of lymphocytes, influences expression of surface activation markers on lymphocytes and monocytes, affects the production of cytokines, and stimulates apoptosis. Moreover, glutamine administration seems to have a positive effect on glucose metabolism in the state of insulin resistance. Glutamine influences a variety of different molecular pathways. Glutamine stimulates the formation of heat shock protein 70 in monocytes by enhancing the stability of mRNA, influences the redox potential of the cell by enhancing the formation of glutathione, induces cellular anabolic effects by increasing the cell volume, activates mitogen-activated protein kinases, and interacts with particular aminoacyl-transfer RNA synthetases in specific glutamine-sensing metabolism. Glutamine is applied under clinical conditions as an oral, parenteral, or enteral supplement either as the single amino acid or in the form of glutamine-containing dipeptides for preventing mucositis/stomatitis and for preventing glutamine-deficiency in critically ill patients. Because of the high turnover rate of glutamine, even high amounts of glutamine up to a daily administration of 30 g can be given without any important side effects.
Journal of Nutrition 11/2008; 138(10):2025S-2031S. · 3.92 Impact Factor
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Daniela Kandioler,
Georgios Stamatis,
Wilfried Eberhardt,
Sonja Kappel,
Sabine Zöchbauer-Müller,
Irene Kührer,
Martina Mittlböck,
Ronald Zwrtek,
Clemens Aigner,
Christoph Bichler,
Victoria Tichy,
Marcus Hudec,
Thomas Bachleitner,
Adelheid End,
Michael Rolf Müller, Erich Roth,
Walter Klepetko
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ABSTRACT: The objective of this study is to establish clinical evidence that the p53 genotype can serve as a predictive marker for response to cisplatin-based induction therapy.
Patients with advanced non-small cell lung cancer who had received neoadjuvant chemotherapy in the context of a prospective phase II trial were analyzed for the p53 genotype of their tumors. Response to induction therapy was then correlated to the p53 genotype as assessed by complete direct DNA sequencing. Patients had received 3 cycles of cisplatin and etoposide, and 1 cycle of simultaneous radiochemotherapy. All 3 treatment components mediate their cytotoxic effect through induction of apoptosis, which is suggested to require an intact p53 gene. In addition, the results from a previously published hypothesis-finding study are updated to demonstrate the consistency of clinical results and summarize currently available clinical evidence.
In the phase II trial, 35 patients underwent resection after induction chemotherapy, allowing a pathohistologic response assessment. The presence of a mutant p53 genotype was highly indicative of resistance to induction chemotherapy (P < .002). The sensitivity of a mutant p53 genotype to identify nonresponders was 94% (71.3-99.9 confidence interval). A normal p53 gene was significantly associated with radical resection (P < .004) and survival advantage (P = .02).
This is the second clinical evaluation demonstrating a significant relation between p53 genotype and response to induction therapy in non-small cell lung cancer. We conclude that the p53 genotype should be evaluated as a predictive marker for response to induction therapy in prospective randomized protocols.
The Journal of thoracic and cardiovascular surgery 05/2008; 135(5):1036-41. · 3.41 Impact Factor
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ABSTRACT: Although accurate assessment of liver function in liver transplant recipients is of crucial importance for optimal timing of the procedure and for determining graft viability, none of the many available methods has proven reliable in the clinical routine. Thus, a novel non-isotopic assay of tyrosine kinetics using the tyrosine-containing dipeptide L-alanyl-L-tyrosine (Ala-Tyr) was tested for its clinical feasibility in patients undergoing orthotopic liver transplantation (OLT).
Plasma levels of tyrosine and clearance of tyrosine released after infusion of the dipetide Ala-Tyr were assessed before and one day after OLT in 10 liver transplant recipients with normal graft function, also in three organ donors and in three recipients showing poor graft function. Standard laboratory parameters (e.g. aminotransferases) and the plasma disappearance rate of indocyanine green were also measured.
Following uneventful OLT, tyrosine plasma levels (before 127 +/- 15 micromol/vs. post-OLT 52 +/- 6 micromol/l, P < 0.05) and kinetics (tyrosine clearance: before 206 +/- 77 ml/min vs. post-OLT 371 +/- 109 ml/min, P < 0.05) were normalized. In cases of severe graft dysfunction, tyrosine kinetics (tyrosine clearance: 238 +/- 61 ml/min) resembled the situation in end-stage liver disease, whereas no such correlation was seen with conventional markers of liver function. Organ preservation had only a minor impact on tyrosine kinetics (n.s.).
OLT rapidly normalizes both the plasma levels and the kinetics of tyrosine. Graft failure is associated with an immediate rise in plasma tyrosine levels and a delay in tyrosine elimination. Our results show that tyrosine clearance using the dipetide Ala-Tyr is a suitable non-isotopic, non-invasive indicator of graft viability in the early postoperative course following OLT.
Wiener klinische Wochenschrift 02/2008; 120(1-2):19-24. · 0.81 Impact Factor
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Wolfgang Winkler,
Maria Zellner,
Michael Diestinger,
Rita Babeluk,
Martina Marchetti,
Alexandra Goll,
Sonja Zehetmayer,
Peter Bauer,
Eduard Rappold,
Ingrid Miller, Erich Roth,
Günter Allmaier,
Rudolf Oehler
[show abstract]
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ABSTRACT: Knowledge about the extent of total variation experienced between samples from different individuals is of great importance for the design of not only proteomics but every clinical study. This variation defines the smallest statistically significant detectable signal difference when comparing two groups of individuals. We isolated platelets from 20 healthy human volunteers aged 56-100 years because this age group is most commonly encountered in the clinics. We determined the technical and total variation experienced in a proteome analysis using two-dimensional DIGE with IPGs in the pI ranges 4-7 and 6-9. Only spots that were reproducibly detectable in at least 90% of all gels (n = 908) were included in the study. All spots had a similar technical variation with a median coefficient of variation (cv) of about 7%. In contrast, spots showed a more diverse total variation between individuals with a surprisingly low median cv of only 18%. Because most known biomarkers show an effect size in a 1-2-fold range of their cv, any future clinical proteomics study with platelets will require an analytical method that is able to detect such small quantitative differences. In addition, we calculated the minimal number of samples (sample size) needed to detect given protein expression differences with statistical significance.
Molecular & Cellular Proteomics 02/2008; 7(1):193-203. · 7.40 Impact Factor
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Erich Roth
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ABSTRACT: Sir David Cuthbertson was the first to define metabolic alterations in post-aggression syndrome (PAS). From basic measurements of nitrogen loss and total protein synthesis/degradation, the current research has moved to genomics, proteomics and metabolomics. In this respect, first evidence was accumulated for the influence of acute catabolism, immobilisation by bed rest and sarcopenia of old age on the muscle-cell genome and proteome. Moreover, in post-aggression syndrome specific amino acids such as glutamine, arginine, glycine, taurine, tryptophan and cysteine are used for cell and immune modulation. Our laboratory has focused on the regulative capacity of glutamine. Glutamine deficiency as found in post-aggression syndrome reduces lymphocyte proliferation, alters monocyte/macrophage activity, decreases the formation of heat-shock proteins, stimulates cell apoptosis, shifts the cellular redox potential by altering the glutathione synthesis and increases the activity of the AMPK system. Investigating the molecular effect of glutamine on Hsp 70 induction, we tested the glutamine dependence on the formation of transfer-RNA and of heat-shock factor 1 (HSF 1), and on transcription and translation of Hsp 70. We could demonstrate that glutamine stabilises the mRNA of Hsp 70 thereby prolonging its half-life. The lecture also discusses the principal molecular targets of administered arginine, glycine, cysteine, taurine and tryptophan.
Clinical Nutrition 11/2007; 26(5):535-44. · 3.73 Impact Factor
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Michael Krebs,
Barbara Brunmair,
Attila Brehm,
Michaela Artwohl,
Julia Szendroedi,
Peter Nowotny, Erich Roth,
Clemens Fürnsinn,
Miriam Promintzer,
Christian Anderwald,
Martin Bischof,
Michael Roden
[show abstract]
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ABSTRACT: The nutrient-sensitive kinase mammalian target of rapamycin (mTOR) and its downstream target S6 kinase (S6K) are involved in amino acid-induced insulin resistance. Whether the mTOR/S6K pathway directly modulates glucose metabolism in humans is unknown. We studied 11 healthy men (29 years old, BMI 23 kg/m(2)) twice in random order after oral administration of 6 mg rapamycin, a specific mTOR inhibitor, or placebo. An amino acid mixture was infused to activate mTOR, and somatostatin-insulin-glucose clamps created conditions of low peripheral hyperinsulinemia (approximately 100 pmol/l, 0-180 min) and prandial-like peripheral hyperinsulinemia (approximately 450 pmol/l, 180-360 min). Glucose turnover was assessed using d-[6,6-(2)H(2)]glucose infusion (n = 8). Skeletal muscle biopsies were performed at baseline and during prandial-like peripheral hyperinsulinemia (n = 3). At low peripheral hyperinsulinemia, whole-body glucose uptake was not affected by rapamycin. During prandial-like peripheral hyperinsulinemia, rapamycin increased glucose uptake compared with placebo by 17% (R(d 300-360 min), 75 +/- 5 vs. 64 +/- 5 micromol x kg(-1) x min(-1), P = 0.0008). Rapamycin affected endogenous glucose production neither at baseline nor during low or prandial-like peripheral hyperinsulinemia. Combined hyperaminoacidemia and prandial-like hyperinsulinemia increased S6K phosphorylation and inhibitory insulin receptor substrate-1 (IRS-1) phosphorylation at Ser312 and Ser636 in the placebo group. Rapamycin partially inhibited this increase in mTOR-mediated S6K phosphorylation and IRS-1 Ser312 and Ser636 phosphorylation. In conclusion, rapamycin stimulates insulin-mediated glucose uptake in man under conditions known to activate the mTOR/S6K pathway.
Diabetes 07/2007; 56(6):1600-7. · 8.29 Impact Factor
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[show abstract]
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ABSTRACT: Reports regarding the pro- or anti-inflammatory effects of lipid emulsion used in parenteral nutrition are conflicting. Aim was to assess the effect of different intravenous lipid emulsions on immunological function in humans.
We performed a computerized bibliographic search, searched reference lists in trial reports, hand-searched journals and contacted experts in the field. Randomized clinical trials evaluating the immunological effects of different parenteral lipid emulsions were included. Three authors independently performed data extraction, statistical processes were performed by two experts. Immunological parameters were classified by two immunologists as marker of improved or worsened immune function. A meta-analysis with standardized effect size estimation was performed for the comparison between long-chain triglycerides vs. glucose or other fat emulsions.
Of 682 assessed studies, 120 compared the immunological effects of intravenously applied lipid emulsions. Of 30 randomized trials, 14 were included in the meta-analysis. None of the lipid regimens showed any clear effect on the evolution of the immunological status or mortality in humans. Length of hospital stay and stay in the intensive care unit could not be evaluated.
We found no evidence that lipid emulsions and in particular those containing long-chain triglycerides have an unfavorable effect on immune function.
Clinical Nutrition 06/2007; 26(3):302-13. · 3.73 Impact Factor
