Metabolic switching of human myotubes is improved by n-3 fatty acids.

The aim of the present study was to examine whether pretreatment with different fatty acids, as well as the liver X receptor (LXR) agonist T0901317, could modify metabolic switching of human myotubes. The n-3 FA eicosapentaenoic acid (EPA) increased suppressibility, the ability of glucose to suppress FA oxidation. Substrate-regulated flexibility, the ability to increase FA oxidation when changing from a high glucose, low fatty acid condition ("fed") to a high fatty acid, low glucose ("fasted") condition, was increased by EPA and other n-3 FAs. Adaptability, the capacity to increase FA oxidation with increasing FA availability, was enhanced after pretreatment with EPA, linoleic acid (LA), and palmitic acid (PA). T0901317 counteracted the effect of EPA on suppressibility and adaptability, but it did not affect these parameters alone. EPA per se accumulated less, however, EPA, LA, oleic acid, and T0901317 treatment increased the number of lipid droplets (LD) in myotubes. LD volume and intensity, as well as mitochondrial mass, were independent of FA pretreatment. Microarray analysis showed that EPA regulated more genes than the other FAs and that specific pathways involved in carbohydrate metabolism were induced only by EPA. The present study suggests a favorable effect of n-3 FAs on skeletal muscle metabolic switching and glucose utilization.

Signs of critical illness polyneuropathy and myopathy can be seen early in the ICU course.

BACKGROUND: Critical illness polyneuropathy and myopathy (CIPNM) is recognized as a common condition that develops in the intensive care unit (ICU). It may lead to a prolonged hospital stay with subsequent increased ICU and hospital costs. Knowledge of predisposing factors is insufficient and the temporal pattern of CIPNM has not been well described earlier. This study investigated patients with critical illness in need of prolonged mechanical ventilation, describing comprehensively the time course of changes in muscle and nerve neurophysiology, histology and mitochondrial oxidative function. METHODS: Ten intensive care patients were investigated 4, 14 and 28 days after the start of mechanical ventilation. Laboratory tests, neurophysiological examination, muscle biopsies and clinical examinations were performed. Neurophysiological criteria for CIPNM were noted and measurements for mitochondrial content, mitochondrial respiratory enzymes and markers of oxidative stress were performed. RESULTS: While all patients showed pathologic changes in neurophysiologic measurements, only patients with sepsis and steroid treatment (5/5) fulfilled the CIPNM criteria. The presence of CIPNM did not affect the outcome, and the temporal pattern of CIPNM was not uniform. All CIP changes occurred early in ICU care, while myopathy changes appeared somewhat later. Citrate synthase was decreased between days 4 and 14, and mitochondrial superoxide dismutase was increased. CONCLUSION: With comprehensive examination over time, signs of CIPNM can be seen early in ICU course, and appear more likely to occur in patients with sepsis and corticosteroid treatment.

Muscle mitochondrial activity increases rapidly after an endotoxin challenge in human volunteers.

BACKGROUND: Mitochondrial derangements in muscle of patients suffering from sepsis have been established in several studies and have been related to muscle dysfunction and organ failure. It is not possible to study the early phase of sepsis in patients; therefore, we used a human endotoxaemia model to study the effect of early sepsis on muscle mitochondria. METHODS: Seven healthy male volunteers received a standardised endotoxin challenge. Muscle biopsies were obtained immediately before the challenge, and at 2 and 4 h following the endotoxin challenge. The muscle biopsies were analysed for maximal activities of citrate synthase and complexes I and IV of the respiratory chain. In addition, total and mitochondrial superoxide dismutase (SOD) activities were analysed. The concentrations of ATP, creatine phosphate and lactate were analysed to assess the cellular energy status. Total and phosphorylated AMP-activated protein kinase (AMPK-P), a key regulator in intracellular energy metabolism, was measured. RESULTS: Activities of citrate synthase and complex I were significantly increased 2 h after the endotoxin challenge. SOD activities were unaffected by the endotoxin challenge. No changes in ATP, creatine phosphate or lactate were observed. Neither total nor AMPK-P changed. CONCLUSIONS: An endotoxin challenge given to healthy volunteers rapidly increases mitochondrial enzyme activity in skeletal muscle. The results of this human model indicate that possibly early during sepsis, mitochondrial activity might be increased in contrast to what has been shown in the later phases of sepsis. It is possible that this early activation leads to exhaustion of the mitochondria and a decreased function later during sepsis.

Human T cells stimulate fibroblast-mediated degradation of extracellular matrix in vitro.

Several chronic diseases are characterized by inflammation, T cell recruitment and tissue remodelling. We hypothesized that activated T cells may stimulate remodelling of extracellular matrix (ECM) in vitro. Total T cells (CD3+) as well as CD4+ and CD8+ subsets were isolated from peripheral blood and stimulated, after which conditioned media (CM) were obtained. CM was added to human lung fibroblasts in three-dimensional collagen gels and the area of gels was measured daily. Hydroxyproline was determined as a measure of collagen degradation in the gels. Matrix metalloproteinase (MMP) activity in the culture media was analysed by gelatine zymography. Cytokine secretion of stimulated CD4+ and CD8+ T cells was analysed. CD3+ CM augmented collagen gel contraction in a time- and dose-dependent manner (P < 0.0001). CD4+ T cell CM was more potent than CD8+ T cell CM (P < 0.001). CD3+ CM and CD4+ T cell CM, but not CD8+ T cell CM, stimulated fibroblast-mediated collagen degradation and MMP-9 activity. A broad-spectrum MMP-inhibitor added to the culture system inhibited both gel contraction and MMP activity. Activated CD4+ T cells secreted significantly more tumour necrosis factor (TNF) and interleukin (IL)-6 compared to CD8+ T cells. CD3+ CM from patients with chronic obstructive pulmonary disease stimulated fibroblast-mediated collagen gel contraction to the same magnitude as CD3+ CM from healthy controls. In conclusion, activated CD4+ T cells can stimulate fibroblast-mediated degradation of ECM in vitro. This could be a mechanism by which activated T cells stimulate degradation of lung tissue leading to pulmonary emphysema.

Red blood cells increase secretion of matrix metalloproteinases from human lung fibroblasts in vitro.

Tissue remodeling is an important process in many inflammatory and fibrotic lung disorders. RBC may in these conditions interact with extracellular matrix (ECM). Fibroblasts can produce and secrete matrix components, matrix-degrading enzymes (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). Imbalance in matrix synthesis/degradation may result in rearrangement of tissue architecture and lead to diseases such as emphysema or fibrosis. Neutrophil elastase (NE), a protease released by neutrophils, is known to activate MMP. We hypothesized that RBC can stimulate secretion of MMPs from human lung fibroblasts and that NE can augment this effect. Human fetal lung fibroblasts were cultured in floating collagen gels with or without RBC. After 4 days, the culture medium was analyzed with gelatin zymography, Western blot, and ELISA for MMP-1, -2, -3 and TIMP-1, -2. RBC augmented NE-induced fibroblast-mediated collagen gel contraction compared with NE alone (18.4+/-1.6%, 23.7+/-1.4% of initial gel area, respectively). A pan-MMP inhibitor (GM-6001) completely abolished the stimulating effect of NE. Gelatin zymography showed that RBC stimulated MMP-2 activity and that NE enhanced conversion to the active form. Addition of GM-6001 completely inhibited MMP-2 activity in controls, whereas it only partially altered RBC-induced MMP activity. Western blot confirmed the presence of MMP-1 and MMP-3 in fibroblasts stimulated with RBC, and ELISA confirmed increased concentrations of pro-MMP-1. We conclude that stimulation of MMP secretion by fibroblasts may explain the ability of RBC to augment fibroblast-mediated collagen gel contraction. This might be a potential mechanism by which hemorrhage in inflammatory conditions leads to ECM remodeling.

Effect of prolonged mechanical ventilation on diaphragm muscle mitochondria in piglets.

BACKGROUND: Respiratory muscle weakness is a common problem in the intensive care unit and could be involved in difficulties in weaning from the ventilator after prolonged mechanical ventilation. Animal models have shown that mechanical ventilation itself impairs diaphragm muscle function. In this study we investigated whether diaphragm contractile impairment caused by mechanical ventilation and immobilization in piglets is associated with a derangement in diaphragm mitochondria. METHODS: Seven piglets received controlled mechanical ventilation during 5 days. A control group of eight piglets were anaesthetized and surgically manipulated in the same way, but were mechanically ventilated for 4-6 h. After mechanical ventilation, diaphragm muscle biopsies were taken for measurements of mitochondria content, mitochondrial respiratory enzymes and markers of oxidative stress. RESULTS: Diaphragm mitochondrial content, as assessed by citrate synthase activities and volume density, was not different between the control and ventilated piglets. Activity of complex IV of the mitochondrial respiratory chain decreased by 21% (P=0.02) when expressed per muscle weight and by 11% (P=0.03) when expressed per citrate synthase activity. There were no changes in the markers of oxidative stress between the two groups. CONCLUSION: Five days of mechanical ventilation and immobilization decreased the activity of complex IV of the mitochondrial respiratory chain in the diaphragm muscle of the piglets.

In vivo neuroprotective adaptation of the glutamate/glutamine cycle to neuronal death.

Synaptic increase of glutamate level, when not coupled to a heightened energy production, renders neurons susceptible to death. Astrocyte uptake and recycling of synaptic glutamate as glutamine is a major metabolic pathway dependent on energy metabolism, which inter-relationships are not fully understood and remain controversial. We examine how the glutamate-glutamine cycle and glucose metabolism are modified in two in vivo models of severe and mild brain injury. Graded reductions of glutaminase, the glutamate synthetic enzyme, were evidenced combined with increases in glutamine synthetase, the inactivating glutamate enzyme. Increased lactate dhydrogenase (LDH) activity was only present after a more severe injury. These results indicate an in vivo adaptation of the glutamate-glutamine cycle in order to increase the net glutamine output, reduce glutamate excitotoxicity, and avoid neuronal death. We conclude that the graded modification of the glutamate-glutamine correlation and neuronal lactate availability may be key factors in the apoptotic and necrotic neuronal demise, whose control may prove highly useful to potentiate neuronal survival.

Red blood cells inhibit proliferation and stimulate apoptosis in human lung fibroblasts in vitro.

Cell proliferation and apoptosis are both important mechanisms for the regulation of tissue homeostasis. For instance, proliferation is crucial in wound repair, whereas apoptosis is important for removal of damaged cells and resolution of inflammation. Imbalance between cell proliferation and apoptosis can therefore lead to pathological conditions and disease. In inflammatory and fibrotic lung disorders, red blood cells (RBCs) can interact with fibroblasts and connective tissue. In the present study, we therefore hypothesized that the presence of RBCs can affect fibroblast proliferation and apoptosis. Human foetal lung fibroblasts (HFL-1) were cultured in the presence or absence of purified whole RBCs and RBC-conditioned media. RBC significantly decreased fibroblast proliferation as determined both by DNA content analysis (Hoechst 33258 staining, P < 0.01; WST-1, P < 0.001) and BrdU incorporation. After treatment with staurosporine (STS) for 48 h, apoptosis was determined by TUNEL and propidium iodide staining followed by flow cytometry analysis. RBCs augmented STS-induced apoptosis (median: 46.4%; range 12.0-90.4) compared to control cells (median 26.2%; range 7.1-45.5). Thus, our data indicate that the presence of RBCs affects both fibroblast proliferation and susceptibility to undergo apoptosis. Our findings therefore suggest a role for RBCs in regulating fibroblast homeostasis after tissue injury.

Red blood cells stimulate human lung fibroblasts to secrete interleukin-8.

Following lung injury, red blood cells (RBC) may interact with extracellular matrix (ECM). Fibroblasts, the resident cell in the ECM, have the capacity to produce and secrete a variety of mediators including interleukin-8 (IL-8). In the present study we hypothesized that RBC, or soluble factors released from them, may stimulate IL-8 production by fibroblasts. Fibroblasts were cultured in a three-dimensional collagen gel culture system in the presence or absence of RBC or conditioned medium from RBC (RBC-CM). IL-8 release from fibroblasts was significantly increased when cultured with RBC or RBC-CM and both tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) further stimulated this IL-8 secretion. The enhanced production of IL-8 within fibroblasts was accompanied by increased IL-8 mRNA expression. To evaluate whether RBC-fibroblast interaction may lead to recruitment of neutrophils, a functional migration assay was performed. RBC and RBC-CM, in the presence of IL-1beta and TNF-alpha, increased the transmigration of neutrophils. Our results indicate that RBC, when interacting with ECM, may participate in the recruitment of inflammatory cells by stimulating fibroblasts to secrete IL-8. This might be an important mechanism regulating tissue repair after injury.

Red blood cells stimulate fibroblast-mediated contraction of three dimensional collagen gels in co-culture.

OBJECTIVE AND DESIGN: Following injury, red blood cells (RBC) may interact with extracellular matrix (ECM). In the present study we hypothesised that RBC, and soluble factors from RBC, might mediate remodelling of ECM by affecting fibroblast-mediated contraction of three dimensional collagen gels. MATERIALS AND METHODS: Human lung fibroblasts (HFL-1), were cultured together with isolated RBC, conditioned medium from RBC (RBC-CM) and hemolysed RBC in type I collagen gels. Gel contraction was determined by an image analyser. RESULTS: Both RBC, RBC-CM and hemolysed RBC stimulated gel contraction by fibroblasts (P < 0.001), compared to fibroblasts alone. The RBC-CM stimulated (P < 0.01) gel contraction in a time and concentration dependent manner. A similar effect was observed when supernatant from hemolysed RBC was tested. The production of fibronectin was increased (P < 0.01) in the co-culture system, compared to fibroblasts cultured alone. CONCLUSIONS: The present study shows that RBC can interact with mesenchymal cells in vitro. The ability of RBC to modulate fibroblast-mediated contraction in vitro, might therefore be an important mechanism regulating repair processes after injury.

Work environment and neck and shoulder pain: the influence of exposure time. Results from a population based case-control study.

OBJECTIVES: To study associations between long term and short term exposure to different work environmental conditions and the incidence of neck or shoulder pain. The results were obtained as part of the MUSIC-Norrtälje study, which is a population based case-control study conducted in Sweden in 1993-7. METHODS: The cases were people from the study base who sought medical care or treatment for neck or shoulder pain. Information on physical and psychosocial conditions in the work environment, currently and 5 years ago, and lifestyle factors, was obtained by self administered questionnaires from 310 cases and 1277 randomly selected referents. RESULTS: Associations between both physical and psychosocial exposures in the work environment and seeking care for neck or shoulder pain were found. The risk patterns differed for the sexes, and risk ratios exceeding 1.5 were more often found among women than among men. Generally, subjects who had experienced a recent increase of exposure were more likely (relative risk (RR) 2.1-3.7) to seek care than those who had been exposed long term (RR 1.5-1.8). Among women, an increased amount of visual display terminal (VDT) work, work above shoulder level, and reduced opportunities to acquire new knowledge, and among men, an increased amount of seated work were associated with neck or shoulder pain. This might indicate short induction periods for neck or shoulder pain for these exposures. However, for repetitive work with the hands and hindrance at work among women, and possibly also local vibrations among men, the induction periods seem to be longer. Interactive effects between factors, both at work and in the family, were found, but only among women. CONCLUSIONS: Associations between some exposures in the work environment and seeking care for neck or shoulder pain were found. The high RRs for short term exposure might indicate that for many factors the induction period for neck or shoulder pain is short.

Risk factors for neck and shoulder disorders: a nested case-control study covering a 24-year period.

BACKGROUND: In 1969 a population-based study was conducted in the Stockholm region. From the 2,579 randomly selected participants (18-65 years of age in 1969), the youngest subset were asked to participate in a reexamination in 1993. Information regarding working conditions, conditions outside work, and neck and shoulder disorders was collected retrospectively for the period 1970-1993. METHODS: Of 783 eligible subjects (42-59 years of age in 1993), 484 responded. Cases of neck/shoulder disorders were defined by past sick leave or medical attention or recent symptoms, depending on available information. For each case (n = 271) two controls were randomly selected, matched by age and gender. Variables regarding both physical and psychosocial conditions were included in the matched analyses. RESULTS: Among women mainly psychosocial factors and among men mainly physical factors were associated with neck/shoulder disorders. The only gender common risk indicator found was repetitive hand work (OR approximately 1.5). Interactive effects were also observed. CONCLUSIONS: The impact on neck/shoulder disorders from separate factors was moderate but combinations of physical and psychosocial factors, as well as of work-related and non-work-related factors, produced relative risks above 2.

Physical and psychosocial factors related to low back pain during a 24-year period. A nested case-control analysis.

STUDY DESIGN: A retrospective nested case-control study. OBJECTIVES: To identify occupational factors related to low back pain, and to study how interactions between psychosocial and physical factors, and between work-related and leisure-related factors affect low back pain in women and men. SUMMARY OF BACKGROUND DATA: A cohort of 484 subjects drawn from the general population was examined in 1969 and 1993, with a focus on occupational working conditions and musculoskeletal disorders. METHODS: Information about the physical and psychosocial working conditions and low back pain during the period 1970 to 1993 was collected retrospectively. Odds ratios and confidence intervals were calculated for different potential risk factors. RESULTS: During the 24-year period, 46% of the subjects became patients with low back pain. Among women, heavy physical workload, sedentary work, smoking, and the combination of whole-body vibrations and low influence over work conditions were associated with an excess risk of low back pain. Among men, excess risk for low back pain was seen in heavy physical workload, sedentary work, high perceived load outside work, and the combination of poor social relations and overtime. CONCLUSIONS: Factors at work were seen to be risk indicators for low back pain among both genders. Low influence over work conditions among women and poor social relations at work among men, in combination with other factors, seem to be of high relevance for the occurrence of low back pain.

Risk factors for neck and upper limb disorders: results from 24 years of follow up.

OBJECTIVES: To investigate associations between different potential risk factors, related and not related to work, and disorders of the neck and upper extremities occurring up to 24 years later. METHODS: The study comprised 252 women and 232 men, Swedish citizens, 42-59 years of age and in a broad range of occupations. Information about potential risk factors was available from a former study conducted in 1969. Data on disorders of the neck, shoulder, and hand-wrist disorders were obtained retrospectively for the period 1970-93. RESULTS: Risk factors were found to differ between the sexes. Among women over-time work, high mental workload, and unsatisfactory leisure time were associated with disorders in the neck-shoulder region. Interaction was found between high mental workload and unsatisfactory leisure time. Neck symptoms earlier in life were associated with recurrent disorders. Hand and wrist disorders were associated mainly with physical demands at work. Among men blue collar work and a simultaneous presence of high mental workload and additional domestic workload predicted disorders in the neck-shoulder region. CONCLUSIONS: Factors related and not related to work were associated with disorders of the neck, shoulders, and hands and wrist up to 24 years later in life. These included factors related to working hours which previously have not been noted in this context. Interactions between risk factors both related and not related to work were commonly found.

Validity and reliability of self-reported retrospectively collected data on sick leave related to musculoskeletal diseases.

OBJECTIVES: The aim was to study the reliability and validity of retrospective data, collected by self-report, on sick leave related to musculoskeletal diseases. METHODS: The study groups consisted of 66 and 306 subjects, for the reliability and validity studies, respectively. They were all part of a wider study of risk factors for musculoskeletal disorders, the REBUS study, conducted in Stockholm in 1993. Reliability was tested using a test-retest design regarding self-reported sick leave related to musculoskeletal diseases in 1970-1993. The validity study comprised the period 1990-1994. Self-reported and registered sick-leave data related to musculoskeletal diseases were collected and analyzed regarding concordance. Data about current musculoskeletal disorders and different work-related conditions were collected and analyzed regarding possible effect- and exposure-dependent misclassification. RESULTS: The test-retest reliability study showed the percentage of agreement to be between 0.88 and 0.97, and the kappa values were between 0.73 and 0.93. The validity study of the concordance between the self-reported and registered data showed high agreement and specificity, but the sensitivity was sometimes lower. All the kappa values exceeded 0.50. No effect- or exposure-dependent misclassification was found. CONCLUSIONS: The validity of retrospectively collected self-reported sick-leave data was sufficient for use as a measure of musculoskeletal morbidity in the analyses of associations with work-related conditions. Because of the relatively low sensitivity, such data will underestimate the prevalence of sick leave and should not be used for surveys of morbidity.

Psychosocial and physical risk factors associated with low back pain: a 24 year follow up among women and men in a broad range of occupations.

OBJECTIVES: To investigate the relation between psychosocial and physical factors at work, as well as conditions during leisure time, and low back pain (LBP) over 24 years. METHODS: The study group consisted of 252 women and 232 men. From a previous study conducted in 1969, data on psychosocial and physical conditions and LBP were available. Data on LBP for 1971-93 were obtained retrospectively in 1993. RESULTS: The prevalence of LBP in 1969 among women and men were 34% and 24%, the cumulative incidences of LBP during 1970-92 were 38% and 43%, and the prevalences in 1993 of having had LBP during the past 12 months were 44% and 39%, respectively. Monotonous work and few or unsatisfactory social contacts outside work were risk factors for LBP in 1969 among women. LBP in 1969 and dissatisfaction with leisure time were risk factors among both sexes for LBP in 1970-92. LBP in 1969 was a risk factor for LBP in 1993 among women and dissatisfaction with leisure time a risk factor among men. Interactions between few or unsatisfactory social contacts outside work, as well as dissatisfaction with leisure time, and several factors related to work were found to increase the risk of LBP among both sexes during the studied periods. CONCLUSIONS: Conditions in leisure time exert a long term influence on LBP. In this study factors related to work had a long term effect only in interaction with leisure time factors.

Laboratory work with automatic pipettes: a study on how pipetting affects the thumb.

The aim of this study was to assess the strain that is exerted on the thumb when working with automatic pipettes. The study consisted of three parts: a survey concerning stress-related symptoms in general and in the thumb in particular, a study of the working conditions in the laboratory with the help of a video-film, and a power test. In the survey the Nordic Council of Ministers' questionnaire and a newly developed questionnaire about the thumb were used. A usual and frequently carried out analysis that included several different methods of pipetting was filmed on video. The power test measured two things, the power that is necessary to press down the button of the pipette into different positions and the maximal strength when performing a movement in the same direction. It was shown that the strain on the thumb for a woman with weak muscular structures is unacceptably high. The symptoms increase with the amount of time spent with pipetting and with age. In addition, pipetting is done in a position where the thumb is not stable but nevertheless has to work to stabilize the grip around the pipette and to press down the button of the pipette. Therefore the muscles have to work both as mobilizing and stabilizing structures. It is concluded, therefore, that some form of automation ought to be taken into consideration if the amount of pipetting work tends to increase. The pipettes should be constructed with as little button resistance as possible and the handle should be designed to fit different hand sizes.

MRI in acute transverse myelopathy.

The MRI examinations of seven patients with acute transverse myelopathy (ATM) were analysed. The patients were examined 2-5 times during the course of their disease with short and long TR/TE spin-echo sequences in the sagittal projection. A previous history of autoimmune disorder and/or signs of infection at the onset of ATM were present in all cases. Cerebrospinal fluid analysis showed local synthesis of immunoglobulin in the nervous system in three cases and signs of infectious myelitis in one. During the acute phase four patients had local enlargement of the cord and all had increased signal on long TR/TE sequences. The outcome was grave in the majority of patients and there seemed to be a correlation between the degree of cord enlargement, persistence of increased signal intensity and limited recovery. Atrophy and remaining high signal intensity were noted on late MRI in patients with poor outcome. In one patient with probable anterior spinal artery occlusion, cavitation of the cord was seen.

Emergency reversal of anticoagulation after intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Although intracerebral hemorrhage is one of the most serious complications during oral anticoagulant therapy, there are no guidelines on emergency treatment with respect to reversal of anticoagulation effect in these patients. METHODS: We retrospectively compared laboratory data and clinical features in 17 cases of anticoagulant-related intracerebral hemorrhage treated with prothrombin complex concentrate (n = 10) or fresh-frozen plasma (n = 7). RESULTS: In the group of patients treated with prothrombin complex concentrate, the mean prothrombin time decreased from 2.83 to 1.22 International Normalized Ratio within 4.8 hours, compared with a decrease from 2.97 to 1.74 within 7.3 hours in those given fresh-frozen plasma (i.e., four to five times more rapidly after treatment with prothrombin complex concentrate) (p less than 0.001). Symptoms and signs of intracerebral hemorrhage, measured on an eight-graded Reaction Level Scale, progressed on average 0.2 grades in patients given prothrombin complex concentrate compared with 1.9 grades in those given fresh-frozen plasma (p less than 0.05). In patients with prothrombin values above 1.46, clinical progression within 12 hours occurred in five of six cases. CONCLUSIONS: Treatment with prothrombin complex concentrate reverses anticoagulation more rapidly than fresh-frozen plasma, which might be of importance for the prevention of further bleeding.