Kooperativer Bibliotheksverbund

In: High Altitude Medicine & Biology, Mary Ann Liebert Inc, Vol. 19, No. 1 ( 2018-03), p. 4-6

Materialart: Online-Ressource

ISSN: 1557-8682

URL: Article

DOI: 10.1089/ham.2017.0164

Sprache: Englisch

Verlag: Mary Ann Liebert Inc

Publikationsdatum: 2018

ZDB Id: 2023581-1

SSG: 31

In: Medicine & Science in Sports & Exercise, Ovid Technologies (Wolters Kluwer Health), Vol. 38, No. 6 ( 2006-06), p. 1082-1087

Materialart: Online-Ressource

ISSN: 0195-9131

URL: Article

DOI: 10.1249/01.mss.0000222836.66391.35

Sprache: Englisch

Verlag: Ovid Technologies (Wolters Kluwer Health)

Publikationsdatum: 2006

ZDB Id: 2031167-9

SSG: 31

In: Journal of Applied Physiology, American Physiological Society, Vol. 81, No. 5 ( 1996-11-01), p. 1917-1923

Kurzfassung: Kleger, Gian-Reto, Peter Bärtsch, Peter Vock, Bernhard Heilig, L. Jackson Roberts II, and Peter E. Ballmer. Evidence against an increase in capillary permeability in subjects exposed to high altitude. J. Appl. Physiol.81(5): 1917–1923, 1996.—A potential pathogenetic cofactor for the development of acute mountain sickness and high-altitude pulmonary edema is an increase in capillary permeability, which could occur as a result of an inflammatory reaction and/or free radical-mediated injury to the lung. We measured the systemic albumin escape by intravenously injecting 5 μCi of 125 I-labeled albumin and the plasma concentrations of cytokines, F 2 -isoprostanes (products of lipid peroxidation), and acute-phase proteins in 24 subjects exposed to 4,559 m. Ten subjects developed acute mountain sickness, and four subjects developed high-altitude pulmonary edema. The transcapillary escape rate of albumin was 6.9 ± 2.0%/h (SD) at low (550 m) and 6.3 ± 1.9%/h at high (4,559 m) altitude ( P= 0.23; n = 24). The subjects with high-altitude pulmonary edema had a modest but insignificant increase in the transcapillary escape rate of albumin (4.6 ± 1.9%/h at low vs. 5.7 ± 1.9%/h at high altitude; P = 0.42; n = 4). Plasma concentrations of fibrinogen, α 1 -acid glycoprotein, C-reactive protein, and interleukin-6 were unchanged in the early phases and significantly increased by the end of the observation period in the subjects with high-altitude pulmonary edema, whereas tumor necrosis factor-α and F 2 -isoprostanes did not change at all. This suggests that the inflammatory reaction was rather a consequence than a causative factor of high-altitude pulmonary edema. In summary, these data argue against a dominant role for increased systemic capillary permeability in the development of acute mountain sickness and high-altitude pulmonary edema.

Materialart: Online-Ressource

ISSN: 8750-7587 , 1522-1601

URL: Article

DOI: 10.1152/jappl.1996.81.5.1917

Sprache: Englisch

Verlag: American Physiological Society

Publikationsdatum: 1996

ZDB Id: 1404365-8

SSG: 12

SSG: 31

In: Journal of Applied Physiology, American Physiological Society, Vol. 90, No. 2 ( 2001-02-01), p. 528-537

Kurzfassung: The acute effects of active and passive ascent to high altitude on plasma volume (PV) and rates of synthesis of albumin and fibrinogen have been examined. Measurements were made in two groups of healthy volunteers, initially at low altitude (550 m) and again on the day after ascent to high altitude (4,559 m). One group ascended by helicopter (air group, n = 8), whereas the other group climbed (foot group, n = 9), so that the separate contribution of physical exertion to the response could be delineated. PV was measured by dilution of 125 I-labeled albumin, whereas synthesis rates of albumin and fibrinogen were determined from the incorporation of isotope into protein after injection of [ ring- 2 H 5 ]phenylalanine. In the air group, there was no change in PV at high altitude, whereas, in the foot group, there was a 10% increase in PV ( P 〈 0.01). Albumin synthesis (mg · kg −1 · day −1 ) increased by 13% in the air group ( P = 0.058) and by 32% in the foot group ( P 〈 0.001). Fibrinogen synthesis (mg · kg −1 · day −1 ) increased by 40% in the air group ( P = 0.068) and by 100% in the foot group ( P 〈 0.001). Hypoxia and alkalosis at high altitude did not differ between the groups. Plasma interleukin-6 was increased modestly in both groups but C-reactive protein was not changed in either group. It is concluded that increases in PV and plasma protein synthesis at high altitude result mainly from the physical exercise associated with climbing. However, a small stimulation of albumin and fibrinogen synthesis may be attributable to hypobaric hypoxia alone.

Materialart: Online-Ressource

ISSN: 8750-7587 , 1522-1601

URL: Article

DOI: 10.1152/jappl.2001.90.2.528

Sprache: Englisch

Verlag: American Physiological Society

Publikationsdatum: 2001

ZDB Id: 1404365-8

SSG: 12

SSG: 31

In: High Altitude Medicine & Biology, Mary Ann Liebert Inc, Vol. 2, No. 3 ( 2001-09), p. 389-403

Materialart: Online-Ressource

ISSN: 1527-0297 , 1557-8682

URL: Article

DOI: 10.1089/15270290152608561

Sprache: Englisch

Verlag: Mary Ann Liebert Inc

Publikationsdatum: 2001

ZDB Id: 2023581-1

SSG: 12

SSG: 31

In: Nature, Springer Science and Business Media LLC, Vol. 428, No. 6982 ( 2004-04-01), p. 493-521

Materialart: Online-Ressource

ISSN: 0028-0836 , 1476-4687

URL: Article

DOI: 10.1038/nature02426

Sprache: Englisch

Verlag: Springer Science and Business Media LLC

Publikationsdatum: 2004

ZDB Id: 120714-3

ZDB Id: 1413423-8

SSG: 11

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 253-253

Kurzfassung: Introduction Salvage high dose chemotherapy (HDCT) followed by autologous stem cell transplantation (ASCT) is used in fit patients with relapsed multiple myeloma (RMM) in clinical practice. However, the role of this approach in the era of continuous novel agent based treatment has not been defined in randomized trials. The ReLApsE trial compared lenalidomide/dexamethasone (Rd) re-induction, salvage HDCT/ASCT and lenalidomide (R) maintenance with standard continuous Rd in a randomized controlled multicenter trial. Methods Between 2010 and 2016, 282 patients were randomized of whom 277 constituted the intention-to-treat (ITT) population (arm B/A n=139/138). Arm B received 3 cycles of Rd (lenalidomide 25 mg, day 1-21; dexamethasone 40 mg, day 1, 8, 15, 22; 4 week cycles) re-induction, HDCT (melphalan 200 mg/m2), ASCT and R maintenance (10 mg daily) until progression (PD). Arm A was treated with Rd until PD. In both arms stem cells were harvested after the 3rd Rd cycle if no back-up transplant was available. Key inclusion criteria were 1-3 prior therapy lines, age ≤ 75 years, time to PD ≥ 12 months in case of front-line HDCT/ASCT and WHO PS ≤ 2. The primary endpoint was progression free survival (PFS). Secondary endpoints included overall survival (OS), response rates and toxicity. ISRCTN16345835, Eudra CT-No: 2009-013856-61. Results Arm B and A were balanced regarding age (median 61.3 vs. 62.2 years), ISS (I/II/III in 62.6/24.4/13% vs. 59.7/31/9.3%) and WHO PS (0/1/2 in 69.1/30.9/0% vs. 76.1/23.2/0.7%). Almost all patients had only 1 prior therapy line (arm B: 94.2% vs. arm A: 93.5%) and had received front-line HDCT/ASCT (92.8% vs. 94.2%). More patients in arm B had high risk cytogenetic aberrations (HR-CA; 42.9% vs. 31.6%) based on a higher frequency of t(4;14) (20.2% vs. 10.1%). The overall response rate (≥ partial response; ORR) for arm B and A was 77.9% and 74.6% (p=0.57) with 49.3% and 47.1% (p=0.81) achieving ≥ very good partial response as best response. Within a median follow up of 36.3 months, 183 PFS events and 76 deaths occurred. Median PFS in the ITT population was 20.7 months in arm B and 18.8 months in arm A without a statistically significant difference (HR 0.87; 95% CI 0.65-1.16; p=0.34). Median OS was not reached (NR) in arm B vs. 62.7 months in arm A (HR 0.81; 95% CI 0.52-1.28; p=0.37). In arm B, 41 patients (29.5%) did not receive the planned HDCT/ASCT. Thus, exploratory landmark (LM) analyses from HDCT and the contemporaneous Rd cycle 5 in arm A were performed (median interval from randomization to HDCT/Rd cycle 5: 117/122 days; n=103[B]/114[A] ). They showed a trend towards superior PFS (23.3 vs. 20.1 months; HR 0.74; p=0.09) and significantly superior OS (NR vs. 57 months; HR 0.56; p=0.046) in arm B vs. A. Multivariate analyses revealed significant associations of treatment in arm B with superior LM PFS (HR 0.6; p=0.01) and LM OS (HR 0.39; p=0.006). Other factors in the LM multivariate models showing significant associations with survival were HR-CA (PFS, OS), number of prior therapy lines (PFS), and age (PFS). The ORR in arm B after HDCT/ASCT was significantly higher than in arm A after Rd cycle 5 (82.3% vs. 69.6%; p=0.04). Grade ≥3 adverse events were reported in 83% (arm B) and 74.5% (arm A; p=0.11). Grade ≥3 leukopenia/neutropenia was reported in 61.5 vs. 24.8% (p 〈 0.001), grade ≥3 thrombopenia in 45.2 vs. 11% (p 〈 0.001) and grade ≥3 mucositis in 10.4% vs. 2.1% (p=0.005). No significant difference in grade ≥3 infections/infestations (33.3 vs. 27.6%; p=0.3) was observed. Eleven patients died on protocol treatment (B: 4 vs. A: 7). No deaths occurred in the HDCT/ASCT phase. Conclusions This is the first RCT comparing salvage HDCT/ASCT with continuous novel agent based treatment. No significant PFS or OS difference was observed in the overall trial population. However, HR-CA were more frequent in the HDCT/ASCT arm and ~30% of patients did not receive the planned HDCT/ASCT. Landmark analyses from the time of HDCT indicate superior PFS and OS in patients actually undergoing salvage HDCT/ASCT. Salvage HDCT/ASCT was safe with an expected increase in hematological as wells as gastrointestinal toxicity but without treatment-related mortality in patients up to the age of 75 years in this multicenter trial. However, the number of patients not undergoing salvage HDCT/ASCT and the approval of more active Rd-based triplet regimens after the initiation of this trial prevents definite conclusions on the role of salvage HDCT/ASCT. Disclosures Goldschmidt: Amgen: Consultancy, Research Funding; Novartis: Honoraria, Research Funding; ArtTempi: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; Mundipharma: Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Adaptive Biotechnology: Consultancy; Chugai: Honoraria, Research Funding. Baertsch:Takeda: Consultancy; Novartis: Consultancy, Research Funding. Raab:Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Hillengass:Novartis: Honoraria, Other: Advisory Board; Sanofi: Research Funding; Takeda: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; amgen: Consultancy, Honoraria, Other: Advisory Board; BMS: Honoraria, Other: Advisory Board; Celgene: Consultancy, Honoraria, Other: Advisory Board, Research Funding. Graeven:AbbVie: Honoraria; Roche: Membership on an entity's Board of Directors or advisory committees. Fenk:Takeda: Honoraria; Bristol-Meyers Squibb: Honoraria, Other: travel grant; Celgene: Honoraria, Other: Travel grant, Research Funding; Janssen: Honoraria; Amgen: Honoraria. Haenel:Novartis: Honoraria; Roche: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Scheid:Novartis: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Janssen: Honoraria; Celgene: Honoraria; BMS: Honoraria; Amgen: Honoraria. Salwender:Celgene: Honoraria, Other: travel suppport, Research Funding; Janssen: Honoraria, Other: travel support, Research Funding; Novartis: Honoraria, Other: travel suppport, Research Funding; Takeda: Honoraria; Amgen: Honoraria, Other: travel suppport, Research Funding; Bristol-Myers Squibb: Honoraria, Other: travel suppport, Research Funding. Weisel:Amgen, Celgene, Janssen, and Sanofi: Research Funding; Amgen, BMS, Celgene, Janssen, and Takeda: Honoraria; Amgen, BMS, Celgene, Janssen, Juno, Sanofi, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Materialart: Online-Ressource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-111203

Sprache: Englisch

Verlag: American Society of Hematology

Publikationsdatum: 2018

ZDB Id: 1468538-3

ZDB Id: 80069-7

In: Journal of Cerebral Blood Flow & Metabolism, SAGE Publications, Vol. 28, No. 9 ( 2008-09), p. 1635-1642

Kurzfassung: Vasogenic edema in the corpus callosum is a characteristic finding in high-altitude cerebral edema (HACE). Furthermore, microhemorrhages have been found at autopsies in brains of HACE victims. The objective of this study was to determine if microhemorrhages also occur in nonlethal HACE. Consequently, magnetic resonance imaging (MRI) was performed in patients who had suffered from HACE and in patients who had suffered from severe acute mountain sickness (AMS) by applying imaging techniques highly susceptible to blood or blood remnants. Two experienced neuroradiologists independently evaluated the exams blinded to clinical data. The MRI was performed 2 to 31 months after the event. The MRI of the HACE patients revealed multiple hemosiderin depositions in the brain—predominantly found in the corpus callosum—indicative of microhemorrhages. These changes were not present in the three AMS patients. In summary, hemosiderin deposits detectable by MRI predominantly in the corpus callosum indicate that microhemorrhages occur in nonlethal HACE, which may serve as a novel diagnostic MRI sign for HACE even many months after the event.

Materialart: Online-Ressource

ISSN: 0271-678X , 1559-7016

URL: Article

DOI: 10.1038/jcbfm.2008.55

Sprache: Englisch

Verlag: SAGE Publications

Publikationsdatum: 2008

ZDB Id: 2039456-1

In: Journal of Applied Physiology, American Physiological Society, Vol. 92, No. 1 ( 2002-01-01), p. 211-218

Kurzfassung: In healthy individuals, prolonged intensive physical exercise leads to an activation of blood coagulation that results in the formation of thrombin and fibrin. This study investigated whether oxidative stress during intensive physical exercise induces tissue factor (TF) via activation of the redox-responsive transcription factor nuclear factor-κB (NF-κB). Twelve young men performed a standardized 1-h maximal run on a treadmill that gave rise to significant increases of markers of thrombin and fibrin formation. The ratio of intracellular reduced to oxidized glutathione as measured by HPLC decreased from 23.3 ± 10.7 to 14.2 ± 6.5 ( P 〈 0.05), indicating the generation of free radicals during exercise. Electrophoretic mobility shift assays from nuclear extracts of peripheral blood mononuclear cells revealed that exercise testing increased NF-κB (p50/p65) binding activity to a NF-κB consensus sequence by 105 ± 68% ( P 〈 0.01) but did not affect NF-κB (p65/c-Rel) binding to a nonconsensus-κB-like site present in the TF promoter. Consistently, there was no exercise-induced increase in TF expression as demonstrated by TF-specific immunofluorescence staining and ELISA. Thus selective activation of NF-κB (p50/p65) during intensive physical exercise does not result in the expression of TF, suggesting that the TF-dependent pathway in peripheral blood mononuclear cells does not account for exercise-induced formation of thrombin and fibrin.

Materialart: Online-Ressource

ISSN: 8750-7587 , 1522-1601

URL: Article

DOI: 10.1152/jappl.2002.92.1.211

Sprache: Englisch

Verlag: American Physiological Society

Publikationsdatum: 2002

ZDB Id: 1404365-8

SSG: 12

SSG: 31

In: Journal of Applied Physiology, American Physiological Society, Vol. 96, No. 4 ( 2004-04), p. 1459-1463

Kurzfassung: Free radical-mediated changes in vascular permeability and subsequent inflammatory response may be a contributory pathogenetic cofactor responsible for the development of neurological sequelae associated with acute mountain sickness (AMS). To investigate this, 49 subjects were examined at sea level and serially after rapid ascent to 4,559 m. Although the venous concentration of total creatine phosphokinase activity was measured in all subjects, a complementary examination of lipid peroxidation (F 2 -isoprostanes), inflammatory (TNF-α, IL-1β, IL-2, IL-6, IL-8, C-reactive protein), and cerebrovascular tissue damage (neuron-specific enolase) biomarkers was confined to a subcohort of 24 subjects. A selective increase ( P 〈 0.05) in total creatine phosphokinase was observed in subjects diagnosed with AMS at high altitude ( n = 25) compared with apparently healthy controls ( n = 24). However, despite a marked increase in IL-6 and C-reactive protein attributable primarily to subjects developing high-altitude pulmonary edema, subcohort analyses demonstrated no selective differences in F 2 -isoprostanes, neuron-specific enolase, or remaining proinflammatory cytokines due to AMS ( n = 14). The present findings are the first to demonstrate that free radical-mediated neuronal damage of sufficient degree to be detected in the peripheral circulation does not occur and is, therefore, unlikely to be an important, initiating event that is critical for the development of AMS. The pathophysiological significance of increased sarcolemmal membrane permeability and inflammatory response, either as a cause or epiphenomenon of AMS and/or high-altitude pulmonary edema, remains to be elucidated.

Materialart: Online-Ressource

ISSN: 8750-7587 , 1522-1601

URL: Article

DOI: 10.1152/japplphysiol.00704.2003

Sprache: Englisch

Verlag: American Physiological Society

Publikationsdatum: 2004

ZDB Id: 1404365-8

SSG: 12

SSG: 31