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  • 1
    ISSN: 0888-7543
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Medicine
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1432-1203
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Screening of the factor VIII (FVIII) gene which spans 186 kb and codes for 26 exons, was originally hampered by its size but is now feasible because rapid DNA scanning methodologies have been developed. The present study for the first time directly compares the three most widely applied screening methods, denaturing gradient gel electrophoresis (DGGE), single-stranded conformational polymorphism (SSCP) and chemical mismatch cleavage (CMC) for their sensitivity of mutation detection in a selected group of ten haemophilia A patients. Nine of these patients are known to be cross-reacting material positive and eight exhibited a mild to moderate phenotype. Of the ten patients screened, we identified mutations in nine by all three screening methods. Of the mutations characterised, two are previously unpublished. T to C (S373P) and G to A (D525N). In one mildly affected haemophiliac, we identified a second T to C sequence change in the 5′ untranslated region at –601 bp, probably having no effect on FVIII gene expression. Modelling studies were performed on those mutations lying within the A domains of FVIII (D525N, R527W, I566T) to study the possible effect of these mutations on structure and/or function. When the three methods are performing optimally and have been standardised, our experience is that CMC and DGGE are equally efficient at sequence variation detection while SSCP is slightly less sensitive.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1432-0584
    Keywords: Key words FVIII ; B-domain ; Transient expression ; Specific activity ; Cell type specific
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract. Transient expression of full-length wild-type (wt) and a new B-domain truncated (ΔB) FVIII has been investigated in three eukaryotic cell lines (HEK-293, COS, CHO). When expressed in CHO cells, both FVIII proteins reached the same peak antigen levels, whereas in HEK-293 and COS cells those of FVIII/ΔB were up to sixfold those of FVIII/wt. Investigation of specific activity of the recombinant FVIII proteins using a chromogenic and a one-stage assay in addition to the FVIII-antigen ELISA revealed large variations: In HEK-293 cells specific activity of FVIII/ΔB measured with both assays was higher than that of FVIII/wt. In COS cells specific activity of both FVIII proteins was higher measured in the one-stage assay than in the chromogenic assay. In CHO cells both FVIII proteins had similar specific activity in each assay. In summary, expression kinetics and specific activity of conditioned medium vary depending on cell type used.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1432-0584
    Keywords: Haemophilia ; Heterozygotes ; DNA-Analysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary From 46 families of predominantly German origin, afflicted with haemophilia A, 178 females were tested for carrier status. Two polymorphic restriction endonuclease sites, the extragenic marker locus DXS 52 (St 14 probe) and the intragenic Bcl I RFLP were investigated in these families. In some cases the results were corroborated by identifying (i) deletions within the factor VIII:C gene and (ii) eliminating a restriction endonuclease site. Two new alleles of the DXS 52 marker locus were found. According to this strategy, 27 women were classified as carriers and 74 as non-carriers. Forty-six women were classified as carriers according to pedigree analysis. Twenty-five females of families with sporadic cases and 6 test persons, who had mothers who where homozygous for the marker alleles, were diagnosed by additional use of conventional carrier detection.
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  • 5
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Science, Ltd
    Haemophilia 8 (2002), S. 0 
    ISSN: 1365-2516
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Summary.  Alloantibodies (inhibitors) against factor VIII (FVIII) develop in 20–30% of patients with severe haemophilia A and render classical FVIII substitution therapy ineffective. Several studies have shown that genetic factors, the type of FVIII gene mutation and immune response genes (e.g. the Major Histocompatibility Complexes), influence the risk of inhibitor formation. In particular, the type of FVIII gene mutation has proven to be a decisive risk factor. Patients with severe molecular gene defects (e.g. large deletions, nonsense mutations, intron-22 inversion) and no endogenous FVIII synthesis have a 7–10 times higher inhibitor prevalence than patients with milder molecular gene defects (e.g. missense mutations, small deletions, splice site mutations). To date, at least 10 distinct classes of mutations have been shown which have differing risks of associated inhibitor formation. A challenging observation in inhibitor patients is the heterogeneity of the antibody epitopes with respect to their number and their specifity. At least five epitopes in the FVIII molecule have been identified that constitute the targets for antibodies in most inhibitor patients. These epitopes are located in the ar3 region and the A2, A3, C1, C2 domains which correspond to the functional binding sites of the ligands of the FVIII protein. At present, the determinants of the characteristics of these epitopes and the subsequent inhibitor titre are unknown. A relationship of the mutation site and the epitope localization has been shown for some individual patients with mild haemophilia A. However, in severely affected haemophilia A patients, the influence of patient genetics on inhibitor titre and epitope specifity has yet to be elucidated.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1365-2516
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Summary.  The severe clotting defects associated with the diagnosis of severe haemophilia A and B require a quality management and quality assurance system designed to avoid both bleeding sequelae (such as damaged joints) through early on-demand or prophylactic treatment in a home-care setting, and side-effects such as infectious diseases (hepatitis A–G and human immunodeficiency virus), allergic reactions, haemolysis and if possible inhibitor formation, by using highly purified, virus-inactivated or recombinant products in which the factor VIII and IX proteins are as natural as possible. As the intravenous injection of the required clotting factor is entrusted to the patients in home treatment, the haemophilia centre has to check treatment protocols and, when necessary, joint and muscle status. In addition, it is imperative to ensure the safety of the product, and checks must be carried out to make sure that batch numbers are recalled as soon as possible if side-effects are observed. These are the reasons for several Acts of Parliament in Germany requiring special treatments and regular checks (the Disabled Act, recommendations by the German Medical Council, the Transfusion Act). Thus, at the haemophilia centre in Bonn we have established a special quality management and quality assurance system taking into account the great number of patients (〉 800), the often considerable distance between the centre and the patient, and the aforementioned regulations and laws. Quality management involves dealing with daily practicalities such as 24-h availability of a physician, medical technologist and nurse, careful instruction of patient and family in home care, genetic counselling, regular laboratory tests (especially recovery time, half-life, inhibitors and gene defects, clinical chemistry and serology) and clinical investigations (especially joint and muscle status). It also includes co-operation with family doctors and different departments at our university hospital (e.g. orthopaedic, microbiology), daily conferences with staff, information for nursery schools, schools, training institutions and/or the workplace in case of emergency, and cooperation with German haemophilia foundations. For quality assurance, several self-controlling systems are in place, such as distribution of concentrate, laboratory data, treatment protocols, joint and muscle status and bleeding tendencies. All these and more are double-checked and interactive, controlling data and activities with the help of EDP. Exceptional staff motivation and patient compliance are important for this quality system.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1365-2516
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Since 1977, desmopressin acetate (DDAVP) has established its important role in the clinical management of bleeding in milder cases of von Willebrand’s disease and haemophilia A. We present in vivo DDAVP response data from a large kindred suffering from mild haemophilia A. Levels of FVIII: C in 22 affected family members ranged from 0.11 to 0.24 IU mL−1 of FVIII: C (0.18 ± 0.04, mean ± SD), increasing to 0.22–0.92 IU mL−1 after DDAVP, giving a mean response ratio of 3.5. Response rates by various routes of administration did not differ significantly, being 3.3 for subcutaneous administration (n= 17), 3.7 for intravenous administration (n= 4) and 3.2 for intranasal spray application (n= 1). No significant correlation was found between the pretreatment level and the response rate. In three individuals, the post-DDAVP level of FVIII:C was below 0.40 IU mL−1, the value we arbitrarily regard as the lower limit of a successful response for haemostatic efficacy suited for self-management purposes, demonstrating that the response rate in a given member of the family cannot be predicted from previous experiences with other haemophilic members of the same subset.
    Type of Medium: Electronic Resource
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