| 1. |
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| 2. |
- 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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| 3. |
- Clausen, Niels, et al.
(författare)
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Similar bleeding phenotype in young children with haemophilia A or B : A cohort study
- 2014
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Ingår i: Haemophilia. - : Wiley. - 1351-8216. ; 20:6, s. 747-755
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Tidskriftsartikel (refereegranskat)abstract
- The bleeding phenotype has been suggested to differ between haemophilia A and B. More knowledge on the bleeding phenotype at initiation of treatment is important to optimize patient care. The aim of this study was to investigate the severity of the bleeding phenotype and the variation in bleeding in children with severe or moderate haemophilia A and B. Consecutive, previously untreated patients with severe or moderate haemophilia A and B (factor VIII or IX activity <0.01 or 0.01-0.05 IU mL-1 respectively) born between January 1st 2000 and January 1st 2010 were included. Primary outcome was severity of bleeding tendency. Secondary outcome was variation in bleeding pattern. A total of 582 patients with severe haemophilia A and 76 with severe haemophilia B did not differ in age at first exposure to clotting factor (0.81 vs. 0.88 years, P = 0.20), age at first bleed (0.82 vs. 0.88 years, P = 0.36), and age at first joint bleed (1.18 vs. 1.20 years, P = 0.59). Patients with moderate haemophilia were older compared to patients with severe haemophilia. In patients with moderate haemophilia there were no clear differences between haemophilia A and B. Severity and variation in bleeding phenotype are similar during the early stage of treatment in patients with severe and moderate haemophilia A and B respectively. The findings imply that children with haemophilia B should be observed and treated as vigilantly as those with haemophilia A.
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| 4. |
- Halldén, Christer, 1957-, et al.
(författare)
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Investigation of disease-associated factors in haemophilia A patients without detectable mutations
- 2012
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Ingår i: Haemophilia. - : Blackwell. - 1351-8216 .- 1365-2516. ; 18:3, s. e132-e137
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Tidskriftsartikel (refereegranskat)abstract
- To investigate disease causing mechanism in haemophilia A patients without detectable mutation. Screening for F8 mutations in 307 haemophilia A patients using: re-sequencing and inversion PCR, reverse transcription (RT-PCR) of mRNA, MLPA analysis, haplotyping using SNP and microsatellite markers. No F8 mutations were detected in 9 of the 307 patients (2.9%) using re-sequencing and inversion PCR. MLPA analysis detected duplication in exon 6 in one patient and RT-PCR showed no products for different regions of mRNA in four other patients, indicating failed transcription. No obvious associations were observed between the phenotypes of the nine patients, their F8 haplotypes and the putative mutations detected. The mutation-positive patients carrying the same haplotypes as the mutation-negative patients show a multitude of different mutations, emphasizing the lack of associations at the haplotype level. VWF mutation screening and factor V measurements ruled out type 2N VWD and combined factor V and VIII deficiency respectively. To further investigate a possible role for FVIII interacting factors the haplotypes/diplotypes of F2, F9, F10 and VWF were compared. The nine patients had no specific haplotype/diplotype combination in common that can explain disease. Duplications and faulty transcription contribute to the mutational spectrum of haemophilia A patients where conventional mutation screening fail to identify mutations.
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| 5. |
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| 6. |
- Astermark, J., et al.
(författare)
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Symposium in memory of Professor Inga Marie Nilsson
- 2001
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Ingår i: Haemophilia. - : Wiley. - 1351-8216. ; 7:4, s. 401-410
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Konferensbidrag (refereegranskat)abstract
- Professor Inga Marie Nilsson (1923-99) was a pioneer in the field of bleeding and thrombo-embolic disorders and made several major scientific contributions during her career. To honour her memory, colleagues from all over the world were invited to cover several aspects of haemostasis by giving state-of-the-art lectures at an international symposium in Malmö on September 22-23, 2000, chaired by Professors Lou Aledort and Erik Berntorp. Colleagues of Professor Nilsson in Malmö gave a short introduction to each topic. A short review of the meeting will be presented.
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| 7. |
- Hoots, W. K., et al.
(författare)
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Secondary prophylaxis with recombinant activated factor VII improves health-related quality of life of haemophilia patients with inhibitors
- 2008
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Ingår i: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 14:3, s. 466-466
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Tidskriftsartikel (refereegranskat)abstract
- Haemophilia patients with inhibitors characteristically have impaired joint function and reduced health-related quality of life (HRQoL). This analysis examined whether secondary prophylaxis with recombinant activated factor VII (rFVIIa) improves HRQoL vs. conventional on-demand therapy in patients with haemophilia with inhibitors and frequent bleeds. After a 3-month preprophylaxis period, 22 patients received daily rFVIIa prophylaxis (90 or 270 mu g kg(-1)) for 3 months, followed by 3 months' postprophylaxis. Days of hospitalization, absence from school/work and mobility aids requirements were recorded. HRQoL was assessed by EuroQoL (EQ-5D) questionnaire, visual analogue scale (VAS), derived Time to Trade-Off (TTO) scores and Quality Adjusted Life Years (QALYs). rFVIIa prophylaxis significantly (P < 0.0001) reduced bleeding frequency vs. prior on-demand therapy. Hospitalization (5.9% vs. 13.5%; P = 0.0026) and absenteeism from school/work (16.7% vs. 38.7%; P = 0.0127) decreased during prophylaxis; these effects tended to be maintained during postprophylaxis. HRQoL (evaluated by EQ-5D) tended to improve during and after rFVIIa prophylaxis. Notably, pain decreased and mobility increased in 40.9% and 27.3% of patients, respectively, at the end of the postprophylaxis period vs. preprophylaxis. Median VAS score increased from 66 to 73 (P = 0.048), and TTO scores suggested better HRQoL (0.62 vs. 0.76; P = 0.054) during postprophylaxis than preprophylaxis. Small to moderate changes in effect sizes were reported for VAS and TTO scores. Median QALYs were 0.68 (VAS) and 0.73 (TTO). Reductions in bleeding frequency with secondary rFVIIa prophylaxis were associated with improved HRQoL vs. on-demand therapy.
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| 8. |
- Sijmons, R.H., et al.
(författare)
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Piebaldism in a mentally retarded girl with rare deletion of the long arm of chromosome 4
- 1993
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Ingår i: Pediatric Dermatology. - : Wiley. - 0736-8046 .- 1525-1470. ; 10:3, s. 235-239
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Tidskriftsartikel (refereegranskat)abstract
- A 4-year-old mentally retarded girl had congenital depigmentations of ventrolateral parts of the chest, abdomen, and legs. She also showed dysmorphic features of the head, thorax, and extremities, a pigmented ring in both irises, and a hernia of the left obliquus muscle. Cytogenetic investigations revealed deletion of chromosome 4 for the long arm segment q12-q21. The typical depigmentations, reported in four other patients with a similar chromosomal deletion, correspond with those in the autosomal dominant piebald trait. Mutations in the Kit protooncogene (mapped to the chromosome (4q11-4q12 region) have been found in patients affected with this dominant disorder. Piebaldism in children with developmental delay and dysmorphic features should alert the physician to the possibility of a deletion of the long arm of chromosome 4.
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| 9. |
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| 10. |
- Billström, R, et al.
(författare)
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Anemier
- 2012
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Ingår i: Läkemedelsboken. - : Apoteksförlaget. ; , s. 239-251
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 11. |
- Björkenstam, C., et al.
(författare)
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School grades, parental education and suicide : a national register-based cohort study
- 2010
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Ingår i: Journal of Epidemiology and Community Health. - : BMJ. - 0143-005X .- 1470-2738.
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Tidskriftsartikel (refereegranskat)abstract
- Background To investigate whether school performance is a risk factor for suicide death later in life and, if so, to what extent this is explained by intergenerational effects of parental education. Methods This population-based cohort study comprises national birth cohorts between 1972 and 1981 in Sweden. We followed 898 342 students, graduating between 1988 and 1997 from the 9 years of compulsory school, equivalent to junior high school, until 31 December 2006, generating 11 148 758 person-years and 1490 suicides. Final school grades, in six categories, and risk of suicide were analysed with Poisson regression. Results The incidence rate ratio (RR) for suicide death for students with the lowest grades was 4.57 (95% CI 2.82 to 7.40) for men and 2.67 (1.42 to 5.01) for women compared to those with highest grades after adjustment for a number of sociodemographic and parental morbidity variables, such as year of graduation, parental education, lone parenthood, household receiving social welfare or disability pension, place of schooling, adoption, maternal age and parent's mental illness. Students with grades in the middle categories had RRs in between. These relationships were not modified by parental education. Conclusions The strong association between low school grades and suicide in youth and young adulthood emphasises the importance of both primary and secondary prevention in schools.
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| 12. |
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| 13. |
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| 14. |
- Fagerlind, Helen, 1975, et al.
(författare)
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Development of an In-depth European Accident Causation Database and the Driving Reliability and Error Analysis Method, DREAM 3.0
- 2008
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Ingår i: 3rd International Conference ESAR (Expert Symposium on Accident Research). - Hannover, Tyskland.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- The SafetyNet project was formulated in part to address the need for safety oriented European road accident data. One of the main tasks included within the project was the development of a methodology for better understanding of accident causation together with the development of an associated database involving data obtained from on-scene or “nearly on-scene” accident investigations. Information from these investigations was complemented by data from follow-up interviews with crash participants to determine critical events and contributory factors to the accident occurrence. A method for classification of accident contributing factors, known as DREAM 3.0, was developed and tested in conjunction with the SafetyNet activities. Collection of data and case analysis for some 1 000 individual crashes have recently been completed and inserted into the database and therefore aggregation analyses of the data are now being undertaken. This paper describes the methodology development, an overview of the database and the initial aggregation analyses.
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| 15. |
- Graham, J B, et al.
(författare)
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Carrier detection in hemophilia A : a cooperative international study. I. The carrier phenotype
- 1986
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Ingår i: Blood. - 0006-4971. ; 67:6, s. 9-1554
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Tidskriftsartikel (refereegranskat)abstract
- Eight laboratories in six countries cooperated to clarify several issues concerning the phenotypes of heterozygous carriers of hemophilia "A." Plasma levels of factor VIII (F.VIII:C, formerly VIII:C) and von Willebrand factor (VWF:Ag, formerly VIIIR:Ag) of carriers and normal women were determined by various "in-house" methods; a single lyophilized plasma standard was used for all assays. Analysis of the collated data from 336 carriers (296 obligatory carriers and 40 sporadic carriers) and 137 normal women showed that there was no difference in the F.VIII:C levels of "paternal" carriers (women who had obtained the abnormal gene from their fathers) and "maternal" carriers. Neither was there a difference in the VWF:Ag levels of normal women and either type of carrier. Age was found to have a significant effect on both F.VIII:C and VWF:Ag, values being higher at very young and very old ages, the minima occurring in the 25- to 30-year range. ABO blood type had a striking effect. Women of types A, B, and AB (designated non-O in the study), both normals and carriers, had significantly higher levels of both factors than did women of type O. Analysis by laboratories showed that differences in mean levels of both factors between laboratories were highly significant. It was concluded that age, ABO blood type, and laboratory variation should be taken into account in carrier detection.
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| 16. |
- Green, P. M., et al.
(författare)
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Haemophilia B mutations in a complete Swedish population sample : a test of new strategy for the genetic counselling of diseases with high mutational heterogeneity
- 1991
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 78:3, s. 390-397
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Tidskriftsartikel (refereegranskat)abstract
- Carrier and prenatal diagnosis based on the identification of the gene defect (direct diagnosis) increases the proportion of haemophilia B families that can be offered precise genetic counselling from the 50-60% attainable by DNA markers, to 100%, and they also provide information on the molecular biology of the disease. We propose that in order to maximize the practical and scientific benefits of direct diagnosis the gene defect of complete (possibly national) populations of patients should be characterized and the information stored in appropriate confidential databases. We demonstrate the feasibility of such a strategy by characterizing the mutations of all the patients registered with the Malmo haemophilia centre. These patients (44♂ and 1♀) are from 45 unrelated families and 24 (53%) have negative family history. The 25 patients with similar reduction of factor IX:C and factor IX:Ag (24♂ + 1♀) have: two gross deletions, three frameshifts, four translation stops, six mutations expected to affect pre-mRNA splicing and 10 amino acid substitutions. The six patients with greater reduction of factor IX:C than factor IX:Ag and the seven with reduced IX:C and normal IX:Ag have only amino acid substitutions. Patients with inhibitors have: one complete deletion, one frameshift and three translation stops. One patient has both a translation stop and a functionally neutral amino acid substitution (His257→Tyr). Characterization of the factor IX mutation was successful in every case, usually entailed 4 person-days work, and has led to the identification of 12 amino acid residues essential for the factor IX structure and function.
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| 17. |
- Green, P M, et al.
(författare)
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The incidence and distribution of CpG----TpG transitions in the coagulation factor IX gene. A fresh look at CpG mutational hotspots
- 1990
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Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 18:11, s. 31-3227
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Tidskriftsartikel (refereegranskat)abstract
- The mutations of 76 haemophilia B patients representing the whole population registered with the Malmö haemophilia centre (42) and referrals from the UK, were characterised. RFLP haplotype analysis of the defective genes indicated that 51 single base pair substitutions were definitely of independent origin and 27 of these were CpG----TpG or CpA transitions. This represents a 38-fold excess over other single-base changes. Most of such transitions (82%) occur at 9 CpG sites occupying critical positions (transitions at 3 sites substitute essential arginines, while at 6 sites transition to TpG creates stop codons). Sixteen of the 18 possible transitions at these 9 sites cause clear haemophilia B and should be fully ascertained in our haemophilia B population. This allowed the direct estimate of the rate of CpG transitions. This is 1.05 x 10(-7) substitutions per base per gamete per generation. The marked excess of CpG transitions in haemophilia B appears partly due to the high proportion of CpG sites at critical positions (at least 9 out of 20). We propose that this follows from the fact that male hemizygosity makes X-linked genes particularly susceptible to selective forces that tend to fix CpG sites arising at critical positions.
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| 18. |
- Green, P P, et al.
(författare)
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Carrier detection in hemophilia A : a cooperative international study. II. The efficacy of a universal discriminant
- 1986
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Ingår i: Blood. - 0006-4971. ; 67:6, s. 7-1560
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Tidskriftsartikel (refereegranskat)abstract
- Factor VIII (F.VIII) and von Willebrand factor (VWF):Ag data collected by eight laboratories on a total of 336 obligatory carriers of hemophilia A and 137 normal women were used to answer several questions concerning the construction of linear discriminants for carrier detection. It was found: that a "universal" linear discriminant can be constructed which is suitable for use in all laboratories and is nearly as effective as laboratory-specific discriminants; that inclusion of age and ABO blood type data improved the efficacy of these discriminants; that substitution of alternative assays for F.VIII and VWF:Ag did not generally improve the efficacy of the discriminants over that obtained using the bioassay for F.VIII:C and Laurell's immunoassay for VWF:Ag; that linear discriminants were far more effective than discriminants based on the F.VIII:C/VWF:Ag ratio. A step-wise procedure is given which any laboratory may follow in using the universal discriminant for carrier detection.
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| 19. |
- Lee, C A, et al.
(författare)
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Prophylactic treatment in Sweden - Overtreatment or optimal model?
- 1998
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Ingår i: Haemophilia. - : Wiley. - 1351-8216. ; 4:4, s. 409-412
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Tidskriftsartikel (refereegranskat)abstract
- At the haemophilia centre in Malmo, Sweden, regular prophylactic treatment is begun at 1-1 1/4 years of age, before the onset of joint bleeds. The dose and dose interval are optimised by means of pharmacokinetic studies to determine the individual patient's FVIII or IX metabolism, the goal of maintaining a level > 1% of normal being taken as a guideline which experience has shown to yield satisfactory control of bleeding diathesis. An optimal model for prophylactic treatment needs to be applicable to haemophiliacs and acceptable to health authorities in a majority of the countries in the world. To fulfill these criteria, the Swedish model, which has been shown to yield most satisfactory outcome, can hopefully be further refined in the future. Were continuous infusion, using a recombinate concentrate with a prolonged half-life, technically feasible and socially acceptable to the child, we would probably have attained the optimal model of prophylactic treatment.
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| 20. |
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| 21. |
- Ljung, R. C R
(författare)
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Gene mutations and inhibitor formation in patients with hemophilia B
- 1995
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Ingår i: Acta Haematologica. - : S. Karger AG. - 0001-5792 .- 1421-9662. ; 94:SUPPL. 1, s. 49-52
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Tidskriftsartikel (refereegranskat)abstract
- The nature of the mutation in the factor IX gene is an important factor in determining whether a patient with hemophilia B will develop an inhibitor. In a series of 62 Swedish families with hemophilia B, including 30 with the severe form, approximately one third of the families exhibiting deletions or nonsense mutations contained one member who developed an inhibitor. The risk for inhibitor development in family members carrying missense mutations was virtually zero.
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| 22. |
- Ljung, R. C R, et al.
(författare)
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Origin of mutation in sporadic cases of haemophilia A
- 1999
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048. ; 106:4, s. 870-874
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to define the origin of mutation in sporadic cases of severe haemophilia A. The series was composed of 31 families with sporadic severe haemophilia A in the geographical catchment area of the Malmo haemophilia centre. The mutation was characterized in 29/31 families: inversion type 1 (n = 11), inversion type 2 (n = 3), other inversion (n= 1), small or partial deletion (n = 6), insertion (n = 2), non-sense mutation (n = 4) and mis-sense mutation (n = 2). Of 29 probands, eight carried a de novo mutation, whereas the proband's mother was found to carry the mutation in 21/29 families. Of the 21 carrier mothers, 16 had de novo mutations (i.e. the proband's maternal grandfather and grandmother were non-carriers). Owing to the lack of samples from the grandparents, origin could not be determined in the remaining five families. Polymorphisms of the FVIII gene were used to determine whether the de novo mutation of the carrier mother was of paternal or maternal origin. In 15/16 cases the mutation was of paternal origin and in 1/16 cases of maternal origin. In the series as a whole, mutation frequency was 6-fold higher in males than in females, but no differences in the ratio of sex-specific mutations rates was found among different types of mutation.
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| 23. |
- Ljung, R.C.R.
(författare)
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Prenatal diagnosis of haemophilia
- 1999
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Ingår i: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 5:2, s. 84-87
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Forskningsöversikt (refereegranskat)abstract
- Genotype assessment based on direct identification of the pathogenic mutation in a chorionic villi sample obtained in the 11-12th gestational week is the most reliable method for prenatal diagnosis and should be used if available. Genetic linkage studies of polymorphisms should be the second choice in the assessment of carriers and in prenatal diagnosis. Carriers of haemophilia should be offered adequate psychosocial support before, during and after the prenatal diagnostic procedures.
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| 24. |
- Ljung, R. C.R.
(författare)
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Prenatal diagnosis of haemophilia
- 1996
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Ingår i: Bailliere's Clinical Haematology. - 0950-3536. ; 9:2, s. 243-257
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Tidskriftsartikel (refereegranskat)abstract
- Prenatal diagnosis of haemophilia A or B is possible by means of chorionic villus biopsy in the first trimester which traces the mutation or informative genetic markers. If possible, direct gene analysis of the mutation is preferred, The natural starting point in haemophilia A is to ascertain whether the disease is due to inversion in the X-chromosome, which is the case in almost half of the severe cases, In haemophilia B, most families carry a unique mutation which needs to be characterized, In the immediate future, much of the prenatal diagnosis will be based on indirect genetic markers, repeats or polymorphisms, of the F.VIII and IX genes, Today chorionic villus sampling is the most widely used method but amniotic fluid, fetal blood and pre-implantation genetic diagnostics can also be used in selected cases, Prenatal diagnosis must be preceded by adequate genetic counselling and risk assessment of the potential carrier and subsequent support during the diagnostic process.
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| 25. |
- Ljung, R. C R
(författare)
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Prophylactic infusion regimens in the management of hemophilia
- 1999
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Ingår i: Thrombosis and Haemostasis. - 0340-6245. ; 82:2, s. 525-530
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Tidskriftsartikel (refereegranskat)abstract
- To summarize, prophylactic treatment of hemophilia begun at an early age has been gaining acceptance as the optimal therapeutic option in an increasing number of hemophilia centers in the developed world in recent years. In all too many parts of the world, however, this option must be viewed as a long-range goal in hemophilia care, since national economic resources are insufficient for regular prophylactic treatment to be feasible at the moment. The future development of prophylaxis seems to be focused on three different areas. First, research has focused on improving the cost-effectiveness of the current model by testing daily, frequent injections using novel devices for venous access or continuous infusion with portable or implantable mini-pumps and administration of bioengineered concentrates with a prolonged half-life at a reduced price. Secondly, a breakthrough in gene therapy, which will enable us to introduce a gene producing an amount of clotting factor sufficient to provide a continuous prophylactic concentration in the blood. Finally, the most mind-challenging option makes most of the discussion in this chapter obsolete and focuses on the development of an oral compound, peptide, or peptidomimetic agent with the capacity to activate the coagulation cascade in a controllable way.
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