1. |
- Antonarakis, S. E., et al.
(författare)
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Factor VIII gene inversions in severe hemophilia A : Results of an international consortium study
- 1995
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 86:6, s. 2206-2212
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Tidskriftsartikel (refereegranskat)abstract
- Twenty-two molecular diagnostic laboratories from 14 countries participated in a consortium study to estimate the impact of Factor VIII gene inversions in severe hemophilia A. A total of 2,093 patients with severe hemophilia A were studied; of those, 740 (35%) had a type 1 (distal) factor VIII inversion, and 140 (7%) showed a type 2 (proximal) inversion. In 25 cases, the molecular analysis showed additional abnormal or polymorphic patterns. Ninety-eight percent of 532 mothers of patients with inversions were carriers of the abnormal factor VIII gene; when only mothers of nonfamilial cases were studied, 9 de novo inversions in maternal germ cells ware observed among 225 cases (≃ 1 de novo maternal origin of the inversion in 25 mothers of sporadic cases). When the maternal grandparental origin was examined, the inversions occurred de novo in male germ cells in 69 cases and female germ cells in 1 case. The presence of factor VIII inversions is not a major predisposing factor for the development of factor VIII inhibitors; however, slightly more patients with severe hemophilia A and factor VIII inversions develop inhibitors (130 of 642 [20%]) than patients with severe hemophilia A without inversions (131 of 821 [16%]).
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2. |
- Budde, U, et al.
(författare)
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Detailed von Willebrand factor multimer analysis in patients with von Willebrand disease in the European study, molecular and clinical markers for the diagnosis and management of type 1 von Willebrand disease (MCMDM-1VWD)
- 2008
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Ingår i: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 6:5, s. 762-771
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Tidskriftsartikel (refereegranskat)abstract
- Background: Type 1 von Willebrand disease (VWD) is a congenital bleeding disorder characterized by a partial quantitative deficiency of plasma von Willebrand factor (VWF) in the absence of structural and/or functional VWF defects. Accurate assessment of the quantity and quality of plasma VWF is difficult but is a prerequisite for correct classification. Objective: To evaluate the proportion of misclassification of patients historically diagnosed with type 1 VWD using detailed analysis of the VWF multimer structure. Patients and methods: Previously diagnosed type 1 VWD families and healthy controls were recruited by 12 expert centers in nine European countries. Phenotypic characterization comprised plasma VWF parameters and multimer analysis using low- and intermediate-resolution gels combined with an optimized visualization system. VWF genotyping was performed in all index cases (ICs). Results: Abnormal multimers were present in 57 out of 150 ICs; however, only 29 out of these 57 (51%) had VWF ristocetin cofactor to antigen ratio below 0.7. In most cases multimer abnormalities were subtle, and only two cases had a significant loss of the largest multimers. Conclusions: Of the cases previously diagnosed as type 1 VWD, 38% showed abnormal multimers. Depending on the classification criteria used, 22 out of these 57 cases (15% of the total cohort) may be reclassified as type 2, emphasizing the requirement for multimer analysis compared with a mere ratio of VWF functional parameters and VWF:Ag. This is further supported by the finding that even slightly aberrant multimers are highly predictive for the presence of VWF mutations.
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3. |
- Castaman, G., et al.
(författare)
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Validation of a rapid test (VWF-LIA) for the quantitative determination of von Willebrand factor antigen in type 1 von Willebrand disease diagnosis within the European multicenter study MCMDM-1VWD
- 2010
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Ingår i: Thrombosis Research. - : Elsevier BV. - 1879-2472 .- 0049-3848. ; 126:3, s. 227-231
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Tidskriftsartikel (refereegranskat)abstract
- Background: Accurate measurement of von Willebrand factor (VWF) is a critical requirement for the diagnosis of von Willebrand disease (VWD). Aim of the study: To evaluate the diagnostic efficiency of a rapid quantitative test for the measurement of VWF antigen (VWF:Ag) in type 1 VWD. Patients and methods: VWF: Ag was measured with an ELISA in a robotic instrument, as a reference method, and with a fully automated latex-immunoassay (LIA) on an ACL 9000 analyser in 1,716 subjects enrolled within the Molecular and Clinical Markers for Diagnosis and Management of Type 1 von Willebrand Disease (MCMDM-1VWD) Study. Among these subjects, 1,049 were healthy controls, 281 healthy family members and 386 affected members from 127 European families with type 1 VWD. Results: The assay linearity range was 10-125 IU/dL for LIA (R-2 = 0.99) and 5-133 IU/dL for ELISA (R-2 = 0.99). The inter-assay CV for low VWF levels (similar to 30 IU/dL) was 2% for the LIA test and 8.7 % for ELISA. The sensitivity for detection of type 1 VWD affected members was 86% and the specificity 91% for LIA, 87% and 90% for ELISA. A receiver-operator (ROC) analysis disclosed only a marginal difference between the two tests, LIA having a slightly greater area under the curve (0.94 vs. 0.93, p = 0.03). Conclusion: VWF: Ag LIA compared well to standard ELISA in this large population of patients and controls, showing better CV. However the lower detection limit for the VWF: Ag LIA compared to the VWF: Ag ELISA means that the LIA assay is less good at discriminating between type 3 VWD and moderate type 1 VWD. (C) 2010 Elsevier Ltd. All rights reserved.
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4. |
- Eikenboom, J, et al.
(författare)
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Linkage analysis in families diagnosed with type 1 von Willebrand disease in the European study, molecular and clinical markers for the diagnosis and management of type 1 VWD
- 2006
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Ingår i: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 4:4, s. 774-782
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Tidskriftsartikel (refereegranskat)abstract
- Background: von Willebrand disease (VWD) type 1 is a congenital bleeding disorder caused by genetic defects in the von Willebrand factor (VWF) gene and characterized by a reduction of structurally normal VWF. The diagnosis of type 1 VWD is difficult because of clinical and laboratory variability. Furthermore, inconsistency of linkage between type 1 VWD and the VWF locus has been reported. Objectives: To estimate the proportion of type 1 VWD that is linked to the VWF gene. Patients and methods: Type 1 VWD families and healthy control individuals were recruited. An extensive questionnaire on bleeding symptoms was completed and phenotypic tests were performed. Linkage between VWF gene haplotypes and the diagnosis of type 1 VWD, the plasma levels of VWF and the severity of bleeding symptoms was analyzed. Results: Segregation analysis in 143 families diagnosed with type 1 VWD fitted a model of autosomal dominant inheritance. Linkage analysis under heterogeneity resulted in a summed lod score of 23.2 with an estimated proportion of linkage of 0.70. After exclusion of families with abnormal multimer patterns the linkage proportion was 0.46. LOD scores and linkage proportions were higher in families with more severe phenotypes and with phenotypes suggestive of qualitative VWF defects. About 40% of the total variation of VWF antigen could be attributed to the VWF gene. Conclusions: We conclude that the diagnosis of type 1 VWD is linked to the VWF gene in about 70% of families, however after exclusion of qualitative defects this is about 50%.
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5. |
- Sadler, J. E., et al.
(författare)
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Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor
- 2006
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Ingår i: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 4:10, s. 2103-2114
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Forskningsöversikt (refereegranskat)abstract
- von Willebrand disease (VWD) is a bleeding disorder caused by inherited defects in the concentration, structure, or function of von Willebrand factor (VWF). VWD is classified into three primary categories. Type 1 includes partial quantitative deficiency, type 2 includes qualitative defects, and type 3 includes virtually complete deficiency of VWF. VWD type 2 is divided into four secondary categories. Type 2A includes variants with decreased platelet adhesion caused by selective deficiency of high-molecular-weight VWF multimers. Type 2B includes variants with increased affinity for platelet glycoprotein Ib. Type 2M includes variants with markedly defective platelet adhesion despite a relatively normal size distribution of VWF multimers. Type 2N includes variants with markedly decreased affinity for factor VIII. These six categories of VWD correlate with important clinical features and therapeutic requirements. Some VWF gene mutations, alone or in combination, have complex effects and give rise to mixed VWD phenotypes. Certain VWD types, especially type 1 and type 2A, encompass several pathophysiologic mechanisms that sometimes can be distinguished by appropriate laboratory studies. The clinical significance of this heterogeneity is under investigation, which may support further subdivision of VWD type 1 or type 2A in the future.
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6. |
- Tosetto, A, et al.
(författare)
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A quantitative analysis of bleeding symptoms in type 1 von Willebrand disease: results from a multicenter European study (MCMDM-1 VWD)
- 2006
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Ingår i: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 4:4, s. 766-773
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Tidskriftsartikel (refereegranskat)abstract
- Background: A quantitative description of bleeding symptoms in type 1 von Willebrand disease (VWD) has never been reported. Objectives: The aim was to quantitatively evaluate the severity of bleeding symptoms in type 1 VWD and its correlation with clinical and laboratory features. Patients and methods: Bleeding symptoms were retrospectively recorded in a European cohort of VWD type 1 families, and for each subject a quantitative bleeding score (BS) was obtained together with phenotypic tests. Results: A total of 712 subjects belonging to 144 families and 195 controls were available for analysis. The BS was higher in index cases than in affected family members (BS 9 vs. 5, P < 0.0001) and in unaffected family members than in controls (BS 0 vs. -1, P < 0.0001). There was no effect of ABO blood group. BS showed a strong significant inverse relation with either von Willebrand ristocetin cofactor (VWF:RCo), von Willebrand antigen (VWF:Ag) or factor VIII procoagulant activity (FVIII:C) measured at time of enrollment, even after adjustment for age, sex and blood group (P < 0.001 for all the four upper quintiles of BS vs. the first quintile, for either VWF:RCo, VWF:Ag or FVIII:C). Higher BS was related with increasing likelihood of VWD, and a mucocutaneous BS (computed from spontaneous, mucocutaneous symptoms) was strongly associated with bleeding after surgery or tooth extraction. Conclusions: Quantitative analysis of bleeding symptoms is potentially useful for a more accurate diagnosis of type 1 VWD and to develop guidelines for its optimal treatment.
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7. |
- Tosetto, A., et al.
(författare)
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Impact of plasma von Willebrand factor levels in the diagnosis of type 1 von Willebrand disease: results from a multicenter European study (MCMDM-1VWD)
- 2007
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Ingår i: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 5:4, s. 715-721
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Tidskriftsartikel (refereegranskat)abstract
- Background: Presence of bleeding symptoms, inheritance and reduced von Willebrand factor (VWF) contribute to the diagnosis of type 1 von Willebrand disease (VWD). However, quantitative analysis of the importance of VWF antigen (VWF:Ag) and ristocetin cofactor activity (VWF:RCo) levels in the diagnosis is lacking. Objectives: To evaluate the relative contribution of VWF measurement to the diagnosis of VWD. Patients and methods: From the MCMDM-1VWD study cohort, 204 subjects (considered as affected by VWD based on the enrolling Center diagnoses and the presence of linkage with the VWF locus) were compared with 1155 normal individuals. Sensitivity, specificity and diagnostic positive likelihood ratios (LR) of VWF:Ag and VWF:RCo were computed. Results: ABO blood group was the variable most influencing VWF levels, but adjustment of the lower reference limit for the ABO group did not improve sensitivity and specificity of VWF:Ag or VWF:RCo. The lower reference limit (2.5th percentile) was 47 IU dL(-1) for both VWF:Ag and VWF:RCo and showed similar diagnostic performance [receiver-operator curve area: 0.962 and 0.961 for VWF:Ag and VWF:RCo, respectively; P = 0.81]. The probability of VWD was markedly increased only for values below 40 IU dL(-1) (positive LR: 95.1 for VWF:Ag), whereas intermediate values (40 to 60 IU dL(-1)) of VWF only marginally indicated the probability of VWD. Conclusions: Although the conventional 2.5 lower percentile has good sensitivity and specificity, only VWF:Ag or VWF:RCo values below 40 IU dL(-1) appear to significantly indicate the likelihood of type 1 VWD. The LR profile of VWF level could be used in a diagnostic algorithm.
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8. |
- Iversen, AKN, et al.
(författare)
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Limited protective effect of the CCR5 Delta 32/CCR5 Delta 32 genotype on human immunodeficiency virus infection incidence in a cohort of patients with hemophilia and selection for genotypic X4 virus
- 2003
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Ingår i: Journal of Infectious Diseases. - 1537-6613. ; 187:2, s. 215-225
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Tidskriftsartikel (refereegranskat)abstract
- The relationship among CCR5 genotype, cytomegalovirus infection, and disease progression and death was studied among 159 human immunodeficiency virus (HIV)-infected patients with hemophilia. One patient (0.6%) had the CCR5Delta32/CCR5Delta32 genotype (which occurs in similar to2% of the Scandinavian population) and a rapid disease course. His HIV V3 region contained genotypic features attributable to X4 virus and resembled functionally verified X4 virus and virus from patients treated with a CD4 cell-stimulating drug, tucaresol. Age-related differences in disease progression rate and survival time were seen for CCR5/CCR5 patients. Surprisingly, no protective effect of the CCR5/CCR5Delta32 genotype on disease progression or survival was seen for children but was evident for adults. Age group-related immunologic differences might explain this variation, and transmission route and/or viral phenotype variation within donor virus may be related to the limited protection of the CCR5Delta32/ CCR5Delta32 genotype. Sequence comparisons indicate that X4 virus can be selected in vivo due to either absence of CCR5 receptors or relative increase of CXCR4 receptors.
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11. |
- Kaspersen, M. D., et al.
(författare)
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No increased sperm DNA fragmentation index in semen containing human papillomavirus or herpesvirus
- 2013
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Ingår i: Andrology. - : Wiley. - 2047-2927 .- 2047-2919. ; 1:3, s. 361-364
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Tidskriftsartikel (refereegranskat)abstract
- It remains unknown whether human papillomaviruses (HPVs) or human herpesviruses (HHVs) in semen affect sperm DNA integrity. We investigated whether the presence of these viruses in semen was associated with an elevated sperm DNA fragmentation index. Semen from 76 sperm donors was examined by a PCR-based hybridization array that identifies all HHVs and 35 of the most common HPVs. Sperm DNA integrity was determined by the sperm chromatin structure assay. HPVs or HHVs, or both, were found in 57% of semen samples; however, sperm DNA fragmentation index was not increased in semen containing these viruses.
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12. |
- Verstraeten, A., et al.
(författare)
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Effects of tree pollen on throughfall element fluxes in European forests
- 2023
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Ingår i: Biogeochemistry. - Göteborg : Springer. - 0168-2563 .- 1573-515X. ; 165:3, s. 311-325
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Tidskriftsartikel (refereegranskat)abstract
- The effects of tree pollen on precipitation chemistry are not fully understood and this can lead to misinterpretations of element deposition in European forests. We investigated the relationship between forest throughfall (TF) element fluxes and the Seasonal Pollen Integral (SPIn) using linear mixed-effects modelling (LME). TF was measured in 1990-2018 during the main pollen season (MPS, arbitrary two months) in 61 managed, mostly pure, even-aged Fagus, Quercus, Pinus, and Picea stands which are part of the ICP Forests Level II network. The SPIn for the dominant tree genus was observed at 56 aerobiological monitoring stations in nearby cities. The net contribution of pollen was estimated as the TF flux in the MPS minus the fluxes in the preceding and succeeding months. In stands of Fagus and Picea, two genera that do not form large amounts of flowers every year, TF fluxes of potassium (K+), ammonium-nitrogen (NH4+-N), dissolved organic carbon (DOC), and dissolved organic nitrogen (DON) showed a positive relationship with SPIn. However- for Fagus- a negative relationship was found between TF nitrate-nitrogen (NO3--N) fluxes and SPIn. For Quercus and Pinus, two genera producing many flowers each year, SPIn displayed limited variability and no clear association with TF element fluxes. Overall, pollen contributed on average 4.1-10.6% of the annual TF fluxes of K+ > DOC > DON > NH4+--N with the highest contribution in Quercus > Fagus > Pinus > Picea stands. Tree pollen appears to affect TF inorganic nitrogen fluxes both qualitatively and quantitatively, acting as a source of NH4+--N and a sink of NO3--N. Pollen appears to play a more complex role in nutrient cycling than previously thought.
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14. |
- Astermark, Jan, et al.
(författare)
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Malignant disease in the haemophilic population: moving towards a management consensus?
- 2012
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Ingår i: Haemophilia. - : Wiley. - 1351-8216. ; 18:5, s. 664-671
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Tidskriftsartikel (refereegranskat)abstract
- The Malignancy in Haemophilia Workshop Group convened a consensus working group of haematologists and oncologists to review topics related to malignancy in haemophilia. The treatment of malignant disease in this population is increasingly relevant as both outcome and lifespan continue to improve. Although adequate guidance exists for control of spontaneous bleeding episodes and of haemostasis in general surgery, information for management of haemostasis in patients with various malignancies is sparse. To date, no clinical guidelines exist for management of complex bleeding problems, diagnosis, therapy and follow-up of malignancies in haemophilia. Furthermore, it remains unclear whether or not morbidity and mortality outcomes associated with malignancies are affected by haemophilia or by its treatment. Through presentation of five malignancies - prostate cancer, colorectal cancer, acute leukaemia, bladder cancer and hepatocellular carcinoma - important issues are highlighted, such as risk from bleeding as a symptom of malignancy; risks from invasive screenings and how these should be handled in haemophilic individuals; the implications of chemotherapy and treatment schedules, bone marrow suppression, radiotherapy, or surgery; and the likelihood of an interaction between treatment for haemophilia and malignancy outcomes. Ultimately, the aim is to establish consensus guidelines to direct and harmonize future treatment policy for malignant disease in the haemophilic population.
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20. |
- Colvin, B. T., et al.
(författare)
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European principles of haemophilia care
- 2008
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Ingår i: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 14:2, s. 361-374
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Tidskriftsartikel (refereegranskat)abstract
- As the management of haemophilia is complex, it is essential that those with the disorder should have ready access to a range of services provided by a multidisciplinary team of specialists. This document sets out the principles of comprehensive haemophilia care in Europe. Within each country there should be a national organization which oversees the provision of specialist Comprehensive Care Centres that provide the entire spectrum of clinical and laboratory services. Depending upon the size and geographical distribution of the population, a network of smaller haemophilia centres may also be necessary. There should be arrangements for the supply of safe clotting factor concentrates which can also be used in home treatment and prophylaxis programmes. A national register of patients is recommended along with collection of treatment statistics. As comprehensive haemophilia care is multidisciplinary by nature, the need for education and research programmes for all staff members is emphasized: Members of the Interdisciplinary Working Group not represented in the list of authors are mentioned in Section 4 of this document.
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22. |
- Etzold, Sophia, et al.
(författare)
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Nitrogen deposition is the most important environmental driver of growth of pure, even-aged and managed European forests
- 2020
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Ingår i: Forest Ecology and Management. - : Elsevier BV. - 0378-1127 .- 1872-7042. ; 458
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Tidskriftsartikel (refereegranskat)abstract
- Changing environmental conditions may substantially interact with site quality and forest stand characteristics, and impact forest growth and carbon sequestration. Understanding the impact of the various drivers of forest growth is therefore critical to predict how forest ecosystems can respond to climate change. We conducted a continental-scale analysis of recent (1995–2010) forest volume increment data (ΔVol, m3 ha−1 yr−1), obtained from ca. 100,000 coniferous and broadleaved trees in 442 even-aged, single-species stands across 23 European countries. We used multivariate statistical approaches, such as mixed effects models and structural equation modelling to investigate how European forest growth respond to changes in 11 predictors, including stand characteristics, climate conditions, air and site quality, as well as their interactions. We found that, despite the large environmental gradients encompassed by the forests examined, stand density and age were key drivers of forest growth. We further detected a positive, in some cases non-linear effect of N deposition, most pronounced for beech forests, with a tipping point at ca. 30 kg N ha−1 yr−1. With the exception of a consistent temperature signal on Norway spruce, climate-related predictors and ground-level ozone showed much less generalized relationships with ΔVol. Our results show that, together with the driving forces exerted by stand density and age, N deposition is at least as important as climate to modulate forest growth at continental scale in Europe, with a potential negative effect at sites with high N deposition.
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24. |
- Mariani, G, et al.
(författare)
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Thrombosis in inherited factor VII deficiency
- 2003
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Ingår i: Journal of thrombosis and haemostasis : JTH. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 1:10, s. 2153-2158
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Tidskriftsartikel (refereegranskat)
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