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    Keywords: brain ; RECEPTOR ; CELL ; Germany ; KINASE ; EXPOSURE ; NEW-YORK ; PATIENT ; INDEX ; treatment ; cell culture ; culture ; TRIAL ; PLASMA ; DECREASE ; ATP ; SKELETAL-MUSCLE ; GLUCOSE ; DOUBLE-BLIND ; OXIDATIVE STRESS ; SMOKERS ; OXYGEN ; insulin ; INSULIN-RECEPTOR ; 3T3-L1 ADIPOCYTES ; CREATINE SUPPLEMENTATION ; HYDROGEN-PEROXIDE PRODUCTION ; LOW-CARBOHYDRATE ; obesity,hyperlipidemia,body fat,insulin reactivity,thiol antioxidant treatment ; REDOX STATE ; REVERSES ENDOTHELIAL DYSFUNCTION ; STRESS IMPAIRS INSULIN ; SUPPLEMENTATION ; TYROSINE KINASE DOMAIN
    Abstract: Insulin signaling is enhanced by moderate concentrations of reactive oxygen species (ROS) and suppressed by persistent exposure to ROS. Diabetic patients show abnormally high ROS levels and a decrease in insulin reactivity which is ameliorated by antioxidants, such as N-acetylcysteine (NAC). A similar effect of NAC has not been reported for non-diabetic subjects. We now show that the insulin receptor (IR) kinase is inhibited in cell culture by physiologic concentrations of cysteine. In two double-blind trials involving a total of 140 non-diabetic subjects we found furthermore that NAC increased the HOMA-R index (derived from the fasting insulin and glucose concentrations) in smokers and obese patients, but not in nonobese non-smokers. In obese patients NAC also caused a decrease in glucose tolerance and body fat mass. Simultaneous treatment with creatine, a metabolite utilized by skeletal muscle and brain for the interconversion of ADP and ATP, reversed the NAC-mediated increase in HOMA-R index and the decrease in glucose tolerance without preventing the decrease in body fat. As the obese and hyperlipidemic patients had lower plasma thiol concentrations than the normolipidemic subjects, our results suggest that low thiol levels facilitate the development of obesity. Supplementation of thiols plus creatine may reduce body fat without compromising glucose tolerance
    Type of Publication: Journal article published
    PubMed ID: 15007512
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  • 3
    Keywords: EXPRESSION ; SURVIVAL ; CELL ; Germany ; KINASE ; imaging ; NEW-YORK ; PATIENT ; ACTIVATION ; MARKER ; prognosis ; QUALITY ; TYPE-1 ; MAGNETIC-RESONANCE ; magnetic resonance imaging ; FIBER COMPOSITION ; BREAST-CANCER ; NO ; PERFORMANCE ; PLASMA ; AGE ; genetics ; FIBER ; MUSCLE ; PARAMETERS ; MORPHOLOGY ; SKELETAL-MUSCLE ; PREDICTION ; BODY ; POOR-PROGNOSIS ; heredity ; OXYGEN ; BIOPSY ; exercise ; MASSES ; BODIES ; REGRESSION ; INCREASE ; WEIGHT ; LIFE ; PHYSICAL-ACTIVITY ; HEIGHT ; QUALITY-OF-LIFE ; LEVEL ; MYOPATHY ; PLASMA-LEVELS ; technique ; USA ; LOSSES ; uptake ; correlation ; cachexia ; myopathies ; PREDICT ; BIOPSIES ; INCREASES ; - ; RESONANCE ; CANCER DIAGNOSIS ; TRACK ; FOXO TRANSCRIPTION FACTORS ; cancer cachexia ; muscle biopsy ; muscle morphology ; muscle wasting
    Abstract: Progressive muscle wasting is a central feature of cancer-related cachexia and has been recognized as a determinant of poor prognosis and quality of life. However, until now, no easily assessable clinical marker exists that allows to predict or to track muscle wasting. The present study evaluated the potential of myoglobin (MG) plasma levels to indicate wasting of large locomotor muscles and, moreover, to reflect the loss of MG-rich fiber types, which are most relevant for daily performance. In 17 cancer-cachectic patients (weight loss 22%) and 27 age- and gender-matched healthy controls, we determined plasma levels of MG and creatine kinase (CK), maximal quadriceps muscle cross-sectional area (CSA) by magnetic resonance imaging, muscle morphology and fiber composition in biopsies from the vastus lateralis muscle, body cell mass (BCM) by impedance technique as well as maximal oxygen uptake (VO(2)max). In cachectic patients, plasma MG, muscle CSA, BCM, and VO(2)max were 30-35% below control levels. MG showed a significant positive correlation to total muscle CSA (r=0.65, p 〈 0.001) and to the CSA fraction formed by type 1 and 2a fibers (r=0.80, p 〈 0.001). However, when adjusted for body height and age by multiple regression, MG yielded a largely improved prediction of total CSA (multiple r=0.83, p 〈 0.001) and of fiber type 1 and 2a CSA (multiple r=0.89, p 〈 0.001). The correlations between CK and these muscle parameters were weaker, and elevated CK values were observed in 20% of control subjects despite a prior abstinence from exercise for 5 days. In conclusion, plasma MG, when adjusted for anthropometric parameters unaffected by weight, may be considered as a novel marker of muscle mass (CSA) indicating best the mass of MG-rich type 1 and 2a fibers as well as VO(2)max as an important functional readout. CK plasma levels appear to be less reliable because prolonged increases are observed in even subclinical myopathies or after exercise. Notably, cancer-related muscle wasting was not associated with increases in plasma MG or CK in this study
    Type of Publication: Journal article published
    PubMed ID: 17605115
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  • 4
    Keywords: AEROBIC CAPACITY, analysis, BIOPSIES, BIOPSY, BLOOD, blood volume, BLOOD-FLOW, BODIES, BODY, body we
    Abstract: PURPOSE To assess metabolism and microcirculation of healthy skeletal muscle by magnetic resonance (MR) and ultrasound techniques and to compare these data with muscle histology, and anthropometric and blood parameters. METHODS Thirty-four healthy volunteers were selected such that their measured aerobic capacity (VO(2)max) per body weight ranged between 23 and 66 mL/minute/kg to render a large variability of skeletal muscle capillarization as a result of their different physical activity. We analyzed body composition, blood parameters, and skeletal muscle fiber size and capillarization in biopsies of the vastus lateralis muscle. These data were compared with knee extensor cross-sectional area (CSA) obtained by MR imaging, microcirculation of the vastus lateralis muscle by contrast-enhanced ultrasound (CEUS), and its energy and lipid metabolism measured with P-31 and H-1 MR spectroscopy. Statistical analysis was performed using Pearson's correlation coefficient and significance was tested at a level of .5%. RESULTS The variable physical activity was reflected in a large variability of vastus lateralis muscle perfusion and metabolism at rest with highest histologic capillarization and CEUS-perfusion values observed in the best-trained volunteers. Levels of high-energy phosphates, such as phosphocreatine, were positively correlated with CSA (r = .5) and histologic fiber size (r = .6 for type IIA and IIX fibers), while phosphocreatine concentration was significantly negatively correlated to myocellular lipids (r = -.6) and trimethyl ammonium containing compounds (r = -.8). Local blood volume measured in vivo with CEUS was positively correlated with several histologic capillarization parameters. CONCLUSIONS Dedicated MR- and CEUS-methods deliver (patho-)physiologic information about capillarization and fiber characteristics of skeletal muscles in vivo and hence establish a useful diagnostic tool for muscular diseases
    Type of Publication: Journal article published
    PubMed ID: 17894621
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  • 5
    Keywords: CANCER ; SURVIVAL ; tumor ; Germany ; DEATH ; DISEASE ; MORTALITY ; NEW-YORK ; PROTEIN ; SURGERY ; TIME ; PATIENT ; IMPACT ; prognosis ; NO ; PERFORMANCE ; PROGRESSION ; DIFFERENCE ; COUNTRIES ; RATES ; DATABASE ; RESECTION ; adenocarcinoma ; PREVALENCE ; pancreatic cancer ; MULTICENTER ; pancreas ; PANCREATIC-CANCER ; WEIGHT ; LEVEL ; methods ; GASTROINTESTINAL CANCER ; USA ; CURATIVE RESECTION ; ANOREXIA ; cachexia ; ENERGY-EXPENDITURE ; HEMOGLOBIN ; DEATHS ; HEAD RESECTION ; nutritional status ; UBIQUITIN-DEPENDENT PROTEOLYSIS
    Abstract: Introduction Pancreatic cancer is the fourth leading cause of cancer-related death in Western countries with a poor prognosis (5-year survival rates, 25% in patients after tumor resection with adjuvant treatment; overall, the 5-year survival rate is about 4%; Jemal et al., CA Cancer J Clin, 55:10-30, 2005). Many patients develop a cachectic status during the progression of the disease, and this syndrome accounts for up to 80% of deaths in patients with advanced pancreatic cancer. Remarkably, there are only a few data available on the impact of cachexia in patients with pancreatic cancer scheduled for tumor resection. Material and Methods Therefore, in this study, 227 consecutive patients with ductal adenocarcinoma of the pancreas were documented over an 18-month period regarding the prevalence of cachexia and its influence on perioperative morbidity and mortality with a special interest to postoperative weight gain and survival in a prospectively designed database and followed up. Results In 40.5% of the patients, cachexia was already present at the time of operation. The cachectic patients did present in a worse nutritional status, represented by lower protein, albumins, and hemoglobin levels. Despite no significant differences in tumor size, lymph node status, and CA19-9 levels, the resection rate in patients with cachexia was reduced (77.8% vs. 48.9%) due to a higher rate of metastatic disease in patients with cachexia. The morbidity and in-hospital mortality revealed no significant difference. However, patients with and without cachexia lost weight after operation, and the weight gain started not until 6 months after operation. The survival in patients with cachexia was significantly reduced in patients undergoing tumor resection as well as in palliative treated patients. Conclusion Cachexia has a significant impact on survival and performance status in palliative patients as well as in patients operated for pancreatic cancer. But tumor-related cachexia is not necessarily dependent on tumor size or load and that metastatic dedifferentiation of the tumor might be a critical step in the development of tumor-associated cachexia
    Type of Publication: Journal article published
    PubMed ID: 18347879
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  • 6
    Keywords: CANCER ; BREAST ; breast cancer ; BREAST-CANCER ; exercise ; sports ; Cognition ; Resistance training
    Type of Publication: Journal article published
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  • 7
    Keywords: EXPRESSION ; prognosis ; SKELETAL-MUSCLE ; ATROPHY ; MONONUCLEAR-CELLS ; INFLAMMATORY CYTOKINES ; SYSTEMIC INFLAMMATION
    Abstract: ABSTRACT: BACKGROUND: Cancer cachexia is a progressive wasting syndrome and the most prevalent characteristic of cancer in patients with advanced pancreatic adenocarcinoma. We hypothesize that genes expressed in wasted skeletal muscle of pancreatic cancer patients may determine the initiation and severity of cachexia syndrome. EXPERIMENTAL DESIGN: We studied gene expression in skeletal muscle biopsies from pancreatic cancer patients with and without cachexia utilizing Real-Imaging cDNA-AFLP-based transcript profiling for genome-wide expression analysis. RESULTS: Our approach yielded 183 cachexia-associated genes. Ontology analysis revealed characteristic changes for a number of genes involved in muscle contraction, actin cytoskeleton rearrangement, protein degradation, tissue hypoxia, immediate early response and acute-phase response. CONCLUSIONS: We demonstrate that Real-Imaging cDNA-AFLP analysis is a robust method for high-throughput gene expression studies of cancer cachexia syndrome in patients with pancreatic cancer. According to quantitative RT-PCR validation, the expression levels of genes encoding the acute-phase proteins alpha-antitrypsin and fibrinogen alpha and the immediate early response genes Egr-1 and IER-5 were significantly elevated in the skeletal muscle of wasted patients. By immunohistochemical and Western immunoblotting analysis it was shown, that Egr-1 expression is significantly increased in patients with cachexia and cancer. This provides new evidence that chronic activation of systemic inflammatory response might be a common and unifying factor of muscle cachexia.
    Type of Publication: Journal article published
    PubMed ID: 22721276
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  • 8
    Keywords: AGENTS ; BLOOD ; Germany ; PERFUSION ; QUANTIFICATION ; VOLUME ; BLOOD-FLOW ; FLOW ; SIGNAL ; PARAMETERS ; RECRUITMENT ; KINETICS ; BODY ; SONOGRAPHY ; OXYGEN ; POWER DOPPLER SONOGRAPHY ; VASCULARIZATION ; ULTRASOUND-INDUCED DESTRUCTION ; exercise ; RE ; WEIGHT ; HEALTHY-VOLUNTEERS ; replenishment kinetics ; TUMOR PERFUSION ; muscle perfusion ; replenishment kinetics of microbubbles ; CAPILLARIES ; microvascular density ; contrast-enhanced sonography
    Abstract: Objective. The purpose of this study was to compare skeletal muscle perfusion measured by contrast-enhanced ultrasonography (CEUS) with microvascular density in muscle biopsies. Methods. Power Doppler sonography after intravenous bolus injection of Levovist (SH U 508A; Schering AG, Berlin, Germany) was used to examine perfusion of vastus lateralis muscle in 23 healthy volunteers. Local blood volume (B), blood flow velocity (v), and blood flow (f) were calculated by analyzing replenishment kinetics. CEUS perfusion was compared with vascularization of biopsy samples from vastus lateralis muscle. Subjects were selected such that their aerobic capacity (maximal oxygen uptake [VO(2)max]) per body weight ranged between 23 and 66 mL - min(-1) - kg(-1) to render a large variability of skeletal muscle capillarization. Moreover, subjects' venous blood hematocrit (Hkt) was determined to estimate the plasmatic intravascular volume fraction (1 - Hkt = PVF) in which the microbubbles can distribute. Results. Median capillary density was 331/mm(2) (range, 207-469/mm(2)), and median capillary fiber contacts (CFC) were 3.6 (range, 2.3-6.5). CFC was correlated with VO2max (r= 0.59; P 〈.01). Among CEUS parameters, B showed the closest correlation to CFC (r = 0.53; P 〈.01). When CFC was normalized for PVF, correlation of B to CFC was r = 0.64 (P 〈.01). CEUS could depict the physiologic large variability of vastus lateralis muscle perfusion at rest (median [range]: B, 2.5 [0.1-12.3] similar to mL; v, 0.3 [0.1-3.7] mm/s; f, 0.7 [0.1-5.3] similar to mL - min(-1) - 100 g tissue(-1)). Conclusions. B is significantly related to fiber-adjacent capillarization and may represent physiologic capillary recruitment (eg, through metabolic fiber-related signals). CEUS is feasible for skeletal muscle perfusion quantification
    Type of Publication: Journal article published
    PubMed ID: 16632781
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  • 9
    Abstract: PURPOSE: To quantitatively assess local muscle micro-circulation with real-time contrast-enhanced ultrasound (CEUS) during different exercises and compare the results with performed muscle work and global blood flow. MATERIALS AND METHODS: Sixteen low mechanical index CEUS examinations of the right lower leg flexors of healthy volunteers were performed using a continuous infusion of SonoVue((R)) (4.8mL/300s). Several muscle perfusion parameters were extracted from derived CEUS signal intensity time curves during different isometric exercises (10-50% of maximum individual strength for 20-30s) and then correlated with the performed muscle work or force, and the whole lower leg blood flow which we measured simultaneously by venous occlusion plethysmography (VOP). RESULTS: The shapes of the CEUS curve during and after exercise differed individually depending on the performed muscle work. The maximum blood volume MAX was observed only after exercise cessation and was significantly correlated with the performed muscle force (r=0.77, p〈0.0001). The blood volume over exercise time was inversely correlated with the spent muscle work (r=-0.60, p=0.006). CEUS and VOP measurements correlated only at rest and after the exercise. During exercise, mean CEUS local blood volume decreased (from 3.48 to 2.19 ( approximately mL)), while mean VOP global blood flow increased (mean, from 3.96 to 7.71mL/100mg/min). CONCLUSION: Real-time low-MI CEUS provides complementary information about the local muscle micro-circulation compared to established blood flow measures. CEUS may be used for a better understanding of muscle perfusion physiology and in the diagnosis of micro-circulation alterations such as in peripheral arterial occlusive disease or diabetic angiopathy
    Type of Publication: Journal article published
    PubMed ID: 19541442
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  • 10
    Keywords: PERFUSION ; QUANTIFICATION ; DISEASE ; REACTIVE HYPEREMIA ; Dynamic contrast-enhanced ultrasound ; Perfusion reserve ; Skeletal muscle perfusion ; Transient arterial occlusion ; LIMB ; LOWER-EXTREMITIES ; peripheral arterial disease
    Abstract: Objective: This feasibility study was performed to assess whether dynamic contrast-enhanced ultrasound (CEUS) and transient arterial occlusion are able to detect alterations in the microvascular perfusion and arterial perfusion reserve in patients suffering from peripheral arterial disease (PAD) in comparison with healthy volunteers. Materials and Methods: Twenty patients with PAD, Rutherford classification grade I, category III (mean age, 64 years; mean height, 173 cm; mean weight, 81.8 kg), and 20 volunteers (mean age, 50 years; mean height, 174 cm; mean weight, 77.8 kg) participated in the study. Low-mechanical index CEUS (7 MHz; MI, 0.28) was performed to the dominant lower leg after start of a continuous automatic intravenous injection of 4.8 mL suspension with microbubbles containing sulfur hexafluoride (SonoVue) within 5 minutes. Perfusion of the calf muscle was monitored by CEUS before, during, and after release of arterial occlusion at the thigh level lasting for 60 seconds. Several parameters, especially the time to maximum enhancement after release of occlusion (t(max)), the maximum enhancement after release of occlusion (max(enh)), the total vascular response after release of occlusion (AUC(post)), and the resulting slope (m 2) to maximum enhancement were calculated. Results: After release of the occlusion, a significantly delayed increase of the CEUS signal to max(enh) was observed in the patients with PAD (32 +/- 17 seconds) compared with volunteers (17 +/- 8 seconds, P = 0.0009). max(enh) was 66.5 +/- 36.6 (similar to mL) in PAD versus 135.6 +/- 75.1 (similar to mL) in volunteers (P = 0.0016). AUC(post) was 3016.5 +/- 1825.8 (similar to mL.s) in PAD versus 5906.4 +/- 3173.1 (similar to mL.s) in volunteers (P = 0.0013), and m 2 was significantly lower in PAD (3.8 +/- 5.2 vs. 14.8 +/- 9.7 [similar to mL/s], P = 0.0001). Conclusions: Microvascular perfusion deficits and reduced arterial perfusion reserve in patients with PAD are clearly detectable with dynamic CEUS after transient arterial occlusion
    Type of Publication: Journal article published
    PubMed ID: 21487300
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