Fibrinogen depletion after plasma-dilution: impairment of proteolytic resistance and reversal via clotting factor concentrates.

In trauma patients, resuscitation treatment of intravascular volume may cause haemodilution including blood cell- and plasma-dilution. After plasma-dilution, fibrinogen is the first factor that decreases to critically low concentrations. Fibrin formed in lowered levels is susceptible to fibrinolysis, a natural forerunner for bleeding. To assess whether a fibrinogen concentrate or a factor XIII (FXIII) concentrate can reverse the impairment of fibrin properties after plasma dilution, different laboratory methods were used to determine thrombin generation and fibrin quantity/quality in a normal plasma sample diluted in vitro. Coagulation and clot lysis by plasmin were triggered with tissue factor and rt-PA, respectively.We found that while the endogenous thrombin potential (ETP) was unaffected after plasma-dilution due to postponement of thrombin decay, levels of fibrinogen and hence fibrin were decreased in dilution degree-dependency. The imbalance between influence of the dilution on thrombin activity and fibrin formation brought unexpected outcomes of fibrin properties: the formed clots favoured the degradation by plasminbut the fibrin networks remained tighter/less permeable. This proteolytic tendency was partly overturned by the fibrinogen concentrate added (total fibrinogen ≥ 2 g/l), and much more affected if used in combination with tranexamic acid (a fibrinolysis inhibitor) at small doses. No reversal effect resulted from the FXIII concentrate added. We conclude that plasma-dilution did reduce the proteolytic resistance of formed clots. The fibrinogen concentrate, better together with small doses of tranexamic acid, may reverse the impairment of fibrin property.The FXIII concentrate is not effective in this regard in our in vitro model using platelet-poor plasma.

Description of nine nutrient loss models: capabilities and suitability based on their characteristics.

In EUROHARP, an EC Framework V project, which started in 2002 with 21 partners in 17 countries across Europe, a detailed intercomparison of contemporary catchment-scale modelling approaches was undertaken to characterise the relative importance of point and diffuse pollution of nutrients in surface freshwater systems. The study focused on the scientific evaluation of different modelling approaches, which were validated on three core catchments (the Ouse, UK; the Vansjo-Hobøl, Norway; and the Enza, Italy), and the application of each tool to three additional, randomly chosen catchments across Europe. The tools involved differ profoundly in their complexity, level of process representation and data requirements. The tools include simple loading models, statistical, conceptual and empirical model approaches, and physics-based (mechanistic) models. The results of a scientific intercomparison of the characteristics of these different model approaches are described. This includes an analysis of potential strengths and weaknesses of the nutrient models.

Evaluation of the difference of eight model applications to assess diffuse annual nutrient losses from agricultural land.

The capability of eight nutrient models to predict annual nutrient losses (nitrogen and phosphorus) at catchment scale have been studied in the EUROHARP project. The methodologies involved in these models differ profoundly in their complexity, level of process representation and data requirements. This evaluation is focused on model performance in three core catchments: the Vansjø-Hobøl (Norway), the Ouse (Yorkshire, UK) and the Enza (Italy). These three different model applications have been evaluated by comparing calculated annual nutrient loads (total N or nitrate and total P), based on observed flow and total nitrogen or nitrate and total phosphorus concentrations, and the annual nutrient loads that were simulated by the eight nutrient models. Four statistics have been applied for this purpose: the root mean squared error (RMSE), the mean absolute error (MAE), the mean error (ME), and Nash-Sutcliffe's model efficiency (NS). The results show that all model approaches can predict the calculated annual discharges. Depending on the observed statistics (RMSE, MAE, ME and NS) the scores of the model application differed, therefore no overall 'best model' could be identified. Although the water and nutrient loads from (sub)catchments can be predicted, the modelled pathways of nutrients within agricultural land and the nutrient losses to surface waters from agricultural land vary among the catchments and among those model approaches which are able to make this distinction.

Evaluation of diffuse pollution model applications in EUROHARP catchments with limited data.

The application of diffuse pollution models included in EUROHARP encompassed varying levels of parameterisation and approaches to the preparation of input data depending on the model and modelling team involved. Modellers consistently faced important decisions in relation to data interpretation, especially in those catchments with unfamiliar physical or climatic characteristics, where catchment conditions were beyond the range for which a particular model was originally developed, or where only limited input data were available. In addition to a broad discussion of data issues, this paper compares the performance of the four sub-annual output models tested in EUROHARP (EveNFlow, NL-CAT, SWAT and TRK) in three test catchments without the modelling teams having sight of measured flow and nitrate concentration data. Model performance in this "blind test" indicate that the range of predictions generated by any individual models pre and post calibration exceed the differences between the estimates yielded by all four models. Comparison of Analysis of Variance (ANOVA) statistics for simulated and observed flow, concentration and loads underscores the benefits of calibration for these intermediate and complex model formulations. Interpretation of input data (e.g. rainfall interpolation method and pedotransfer functions selected) appeared equally (or more) important than process representation. In the absence of calibration data, modeller unfamiliarity with a particular catchment and its environmental processes sometimes resulted in questionable assumptions and input errors which highlight the problems facing modellers charged with implementing policies under the Water Framework Directive (2000/60/EC) in poorly monitored catchments. Catchment data owners and modellers must therefore work more closely given that the output from diffuse pollution models is clearly modeller-limited as well as model-limited.

Ensemble modelling of nutrient loads and nutrient load partitioning in 17 European catchments.

An ensemble of nutrient models was applied in 17 European catchments to analyse the variation that appears after simulation of net nutrient loads and partitioning of nutrient loads at catchment scale. Eight models for N and five models for P were applied in three core catchments covering European-wide gradients in climate, topography, soil types and land use (Vansjø-Hobøl (Norway), Ouse (Yorkshire, UK) and Enza (Italy)). Moreover, each of the models was applied in 3-14 other EUROHARP catchments in order to inter-compare the outcome of the nutrient load partitioning at a wider European scale. The results of the nutrient load partitioning show a variation in the computed average annual nitrogen and phosphorus loss from agricultural land within the 17 catchments between 19.1-34.6 kg N ha(-1) and 0.12-1.67 kg P ha(-1). All the applied nutrient models show that the catchment specific variation (range and standard deviation) in the model results is lowest when simulating the net nutrient load and becomes increasingly higher for simulation of the gross nutrient loss from agricultural land and highest for the simulations of the gross nutrient loss from other diffuse sources in the core catchments. The average coefficient of variation for the model simulations of gross P loss from agricultural land is nearly twice as high (67%) as for the model simulations of gross N loss from agricultural land (40%). The variation involved in model simulations of net nutrient load and gross nutrient losses in European catchments was due to regional factors and the presence or absence of large lakes within the catchment.

Nitrogen and phosphorus retention in surface waters: an inter-comparison of predictions by catchment models of different complexity.

Nitrogen and phosphorus retention estimates in streams and standing water bodies were compared for four European catchments by a series of catchment-scale modelling tools of different complexity, ranging from a simple, equilibrium input-output type to dynamic, physical-based models: source apportionment, MONERIS, EveNFlow, TRK, SWAT, and NL-CAT. The four catchments represent diverse climate, hydrology, and nutrient loads from diffuse and point sources in Norway, the UK, Italy, and the Czech Republic. The models' retention values varied largely, with tendencies towards higher scatters for phosphorus than for nitrogen, and for catchments with lakes (Vansjø-Hobøl, Zelivka) compared to mostly or entirely lakeless catchments (Ouse or Enza, respectively). A comparison of retention values with the size of nutrient sources showed that the modelled nutrient export from diffuse sources was directly proportional to retention estimates, hence implying that the uncertainty in quantification of diffuse catchment sources of nutrients was also related to the uncertainty in nutrient retention determination. This study demonstrates that realistic modelling of nutrient export from large catchments is very difficult without a certain level of measured data. In particular, even complex process oriented models require information on the retention capabilities of water bodies within the receiving surface water system and on the nutrient export from micro-catchments representing the major types of diffuse sources to surface waters.

The rate of candidaemia in preterm infants born at a gestational age of 23-28 weeks is inversely correlated to gestational age.

AIM: To assess the rate of candidaemia and the associated case fatality rate in relation to gestational age, and the variation in the rate of candidaemia over time in the neonatal period. METHODS: Retrospective review of medical records of infants with a positive blood culture for fungi while in the neonatal unit, Uppsala University Children's Hospital or at autopsy following death in the unit from 1994 to 2001 (n = 30). RESULTS: The number of cases per year was found to vary between zero and eight. The annual rate of infection did not change significantly during the study period. The preterm infants with candidaemia (n = 29) were born at a gestational age ranging from 23-28 wk. The rate of candidaemia in this group was inversely related to gestational age and varied from 2 to 24%. Five infants (17%) died from Candida infection. Of these five, four were born at a gestational age of 23 wk. CONCLUSION: candidaemia in newborns occurs predominately in infants born at a gestational age < or =28 wk, where the rate of infection is inversely correlated to gestational age in infants born at a gestational age of 23-28 wk. The highest case fatality rate is observed in infants born at a gestational age of 23 wk.

Negative spiral CT in acute pulmonary embolism.

PURPOSE: To retrospectively evaluate the clinical outcome of non-anticoagulated patients with clinically suspected acute pulmonary embolism (PE) and no symptoms or signs of deep venous thrombosis (DVT) following a negative contrast medium-enhanced spiral CT of the pulmonary arteries (s-CTPA). MATERIAL AND METHODS: During a 24-month period, 739 of 751 patients underwent s-CTPA with acceptable diagnostic quality for clinically suspected acute PE. All patients who had a CT study not positive for PE were followed up with a questionnaire, a telephone interview and review of all medical reports, including autopsies and death certificates for any episodes of venous thromboembolism (VTE) during a 3-month period. RESULTS: PE was diagnosed in 158 patients. Of the remaining 581 patients with a negative s-CTPA, 45 patients were lost to follow-up. 88 patients were excluded because of anticoagulation treatment (cardiac disorder n=32, chronic VTE or acute symptomatic DVT n=31, PE diagnosed at pulmonary angiography n=1, thrombus prophylaxis during diagnostic work-up or other reasons than VTE n=24) and 7 patients undergoing lower extremity venous studies because of symptoms of DVT (all negative). Thus, 441 patients with a negative s-CTPA and no DVT symptoms, venous studies or anticoagulant treatment constituted the follow-up cohort. Four of these patients had proven VTE (all PE) during the 3-month follow-up period. Two of the PE episodes contributed to the patient's death. CONCLUSION: Patients with clinically suspected acute PE, no symptoms or signs of DVT and a negative single slice s-CTPA using 3-5 mm collimation, may safely be left without anticoagulation treatment unless they are critically ill, have a limited cardiopulmonary reserve and/or if a high clinical suspicion remains.

Antenatal terbutaline administration decreases the lung hyaluronan concentration in preterm rabbit pups.

OBJECTIVE: To determine whether antenatal exposure to terbutaline alters the lung hyaluronan concentration or lung water content at birth in preterm rabbit pups. STUDY DESIGN: Rabbit dams (n = 18) with timed pregnancies were injected with 30 microg terbutaline or saline (controls) one day before delivery at 27-29 days of gestation. Pups were killed immediately after delivery. Lung water content and hyaluronan concentrations were determined. RESULTS: Pups exposed antenatally to terbutaline had lower mean lung hyaluronan concentrations than control pups. Lung hyaluronan/dry lung weight was significantly lower in pups delivered at 28 (p = 0.034) or 29 days (p < 0.001), while lung hyaluronan/wet lung weight was significantly lower at all three gestational ages. CONCLUSION: Antenatal exposure to terbutaline lowers the lung hyaluronan concentration at birth in preterm (27-29 days) rabbit pups without altering the lung water content.

Antenatal betamethasone administration decreases the lung hyaluronan concentration in preterm rabbit pups.

Maternal treatment with corticosteroids before preterm delivery is effective in reducing the incidence of respiratory distress syndrome and neonatal mortality. We hypothesized that corticosteroids might lower the lung hyaluronan concentration. Twenty-five rabbit dams (term = 31 d) with timed pregnancies were injected s.c. with 0.75 mg of betamethasone or saline (controls) 1 d before delivery. In addition, two dams delivered at 25 d of gestation were injected with 0.75 mg of betamethasone on two consecutive days before delivery. A total of 238 live pups were delivered by preterm cesarean section at 25, 27, 28, or 29 d of gestation and killed immediately. Their lung hyaluronan concentrations were measured with a radiometric assay, and wet/dry lung weight ratios were determined. Lungs of rabbit pups exposed antenatally to betamethasone and delivered at 25 or 27 d of gestation, but not at 28 or 29 d, displayed significantly (p = 0.001 and p = 0.008, respectively) lower hyaluronan concentrations than control pups, accompanied by less intense subepithelial staining for hyaluronan in alveolar walls. There was no significant difference in wet/dry lung weight ratio between pups exposed to one dose of betamethasone and controls. Antenatal corticosteroid exposure lowers the lung hyaluronan concentration in preterm rabbit pups delivered at 25 or 27 d of gestation, but not in those delivered at 28 or 29 d.

Caesarean section in previously untreated acute promyelocytic leukaemia. Report of two patients.

Acute promyelocytic leukaemia (APL) is characterised by a life-threatening hemorrhagic diathesis which is attributed to a DIC-like coagulopathy. This report describes the problems of childbirth in two patients with untreated APL. It is concluded that caesarean section can be performed without major complications. A prerequisite is an active treatment of the coagulopathy and a close collaboration between the obstetrician and the haematologist.

Pulmonary embolism: a follow-up study of the relation between the degree of right ventricle overload and the extent of perfusion defects.

OBJECTIVES: To describe the course of changes in perfusion lung scintigraphy (LS) after acute pulmonary embolism (PE) and test the hypothesis that patients with persistent pulmonary hypertension (PH)/right ventricle (RV) dysfunction after acute PE can be differentiated from those without through larger perfusion defects (PDf) on LS. Design. Prospective, one-year follow-up study with repeated LS and echocardiography-Doppler investigations. SETTING: Single centre, University Hospital. SUBJECTS: Patients with clinical suspicion of acute PE with a diagnosis confirmed by LS and/or pulmonary angiography and able to undergo repeated investigations. Of the 78 patients included, a six-week follow-up was completed in 67 and a one-year follow-up in 64. MAIN OUTCOME MEASURES: Time course of PDf in relation to time course of pulmonary artery systolic pressure (PAsP) and RV function. RESULTS: Initially, PDf decreased exponentially, until the beginning of a stable phase, which was achieved within 54 days for 90% of the patients and within 148 days for all. The temporal relation for the regress of PDf and decrease in PAsP was loose. Patients with persistent PDf suffered PH/RV dysfunction more often than those without. However, the variability in the degree of haemodynamic changes for a given extent of PDf was large. CONCLUSIONS: After acute PE, LS is of use for the identification of the group of patients that may have persistent PH/RV dysfunction. However. since the identification of individual patients is uncertain, LS cannot replace echocardiography-Doppler in the identification of persistent PH/RV dysfunction after acute PE.

The risk of recurrent venous thromboembolism in carriers and non-carriers of the G1691A allele in the coagulation factor V gene and the G20210A allele in the prothrombin gene. DURAC Trial Study Group. Duration of Anticoagulation.

The results concerning the risk of recurrent venous thromboembolism (VTE) in carriers of the G1691A mutation in the coagulation factor V gene are not consistent and this risk in carriers of the G20210A polymorphism in the prothrombin gene has hitherto not been reported. We followed 534 patients for 48 months after their first episode of objectively documented VTE. The prevalence of the G1691A allele in 467 (87.5%) of the patients and in 207 controls was 25.3% and 8.2%, respectively, in heterozygote form and 2.4% and 0.5%, respectively, in homozygote form. The adjusted odds ratio (OR) for the first VTE was 4.4 (95% CI 2.6-7.8). The risk of recurrent VTE in heterozygotes was not statistically different from non-carriers (17.8% vs 17.6%), with 85% power to detect a hazard ratio of 2.35. Homozygotes had a significantly increased risk (p = 0.036) of recurrent VTE. The prevalence of the G20210A allele in 456 patients and 207 controls was 6.1% and 1.4%, respectively. The adjusted OR was 4.6 (95% CI 1.6-19.3) for the first VTE in 28 carriers of this polymorphism. The risk of recurrent VTE for these was not statistically different from non-carriers with an OR of 0.9 (95% CI 0.2-2.9).

[Centralized care is the basis of care programs for hemophilia patients]. / Centraliserad vård grundläggande i vårdprogram för blödarsjuka.

Haemophilia is a rare and potentially life-threatening disease. In Sweden, with a population of approximately 8.5 million, about 350 people suffer from the more severe forms of haemophilia or von Willebrand disease. Meticulous management is important if the patients are to be spared chronic disability and serious treatment complications. The disease is lifelong and affects psychosocial aspects of life among patients and their families. With the help of a grant from the Swedish Board of Halth and Welfare, a care programme has been designed to guarantee Swedish haemophiliacs comparable and optimal care. The programme has been drawn up by representatives of the three haemophilia centres in Sweden (at University Hospital, Malmö, Sahlgrenska University Hospital, Gothenburg, and Karolinska Hospital, Stockholm) in co-operation with the World Federation of National Haemophilia Organisations. To ensure optimal individual application of the programme, individualised management strategies and patient information leaflets have been prepared.

Pulmonary embolism: one-year follow-up with echocardiography doppler and five-year survival analysis.

BACKGROUND: The long-term prognosis for patients with pulmonary embolism (PE) is dependent on the underlying disease, degree of pulmonary hypertension (PH), and degree of right ventricular (RV) dysfunction. A precise description of the time course of pulmonary artery pressure (PAsP)/RV function is therefore of importance for the early identification of persistent PH/RV dysfunction in patients treated for acute PE. Other objectives were to identify variables associated with persistent PH/RV dysfunction and to analyze the 5-year survival rate for patients alive 1 month after inclusion. METHODS AND RESULTS: Echocardiography Doppler was performed in 78 patients with acute PE at the time of diagnosis and repeatedly during the next year. A 5-year survival analysis was made. The PAsP decreased exponentially until the beginning of a stable phase, which was 50 mm Hg at the time of diagnosis of acute PE was associated with persistent PH after 1 year. The 5-year mortality rate was associated with underlying disease. Only patients with persistent PH in the stable phase required pulmonary thromboendarterectomy within 5 years. CONCLUSIONS: An echocardiography Doppler investigation performed 6 weeks after diagnosis of acute PE can identify patients with persistent PH/RV dysfunction and may be of value in planning the follow-up and care of these patients.