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Biomedical subjects

H H Brackmann

Publications and source records attributed to H H Brackmann.

At least 109 records · Page 6Linked to original sources
PubMed1991

Prenatal diagnosis of haemophilia B by the use of polymerase chain reaction and direct sequencing.

A second prenatal diagnosis of severe haemophilia B was carried out in a family with no prior history of the disease. The first prenatal diagnosis was based on linkage analysis and showed the male fetus not to be affected because he had inherited the same X-chromosome as his healthy brother. Carrier status in the female at risk could not be assessed by restriction fragment length polymorphisms (RFLPs). She was found to have inherited the same marker constellation as her affected brother. However, due to the fact that a pedigree with no prior history of haemophilia B has been examined diagnosis was impossible. In addition factor IX coagulant and antigen values gave no definitive clue to a haemophilia B carriership. The problems with RFLP analysis in this pedigree were circumvented by polymerase chain reaction (PCR) based direct sequencing of the factor IX gene. A previously unknown mutation could be detected in patient haemophilia B (Kleve) and the carrier status in the female at risk could be confirmed. The second prenatal diagnosis showed that the male fetus had inherited the mutation and will therefore be afflicted with haemophilia B.

Base Sequence↗
PubMed1991

Detection and characterisation of two missense mutations at a cleavage site in the factor VIII light chain.

Haemophilia A is an X-linked bleeding disorder caused by a deficiency of factor VIII. As an essential cofactor in the intrinsic clotting cascade, factor VIII is activated and subsequently inactivated by proteolytic cleavages involving factor IIa (thrombin), factor Xa and activated protein C (APC). Investigation of the thrombin cleavage sites at amino acids 372 and 1689 of the factor VIII protein by oligonucleotide screening, DNA amplification and direct sequencing, enabled us to identify two missense mutations in 441 unrelated haemophiliacs. A C-to-T transition, which leads to the substitution of cysteine for arginine at position 1689, was found in a severely affected patient and a previously undescribed G-to-A substitution, causing replacement of arginine1689 with histidine, was found in a patient with mild disease.

Base Sequence↗
PubMed1991

Epidemiologically closely related viruses from hemophilia B patients display high homology in two hypervariable regions of the HIV-1 env gene.

The diversity of human immunodeficiency virus type 1 (HIV-1) is mainly caused by mutations that affect the gene encoding the gp120 envelope protein. Isolates differ to a large extent in the hypervariable regions of gp120. This study was undertaken to determine the degree of variation of HIV-1 env genes isolated from seven individuals with hemophilia B who became infected in association with administration of a suspected clotting factor lot. Two hypervariable regions and part of a constant region from proviral DNA of the peripheral blood leukocytes of these patients were amplified and the products of the polymerase chain reactions were sequenced. The sequences derived from five of the individuals displayed 100% sequence homology, 1 had two and 1 had six deviations from the consensus sequence. The alignment of the amino acid sequence so deduced revealed no comparable homology to any of these two hypervariable regions from a number of published isolates. The genetic variability of HIV-1 seems to be limited, at least in the early phase of infection, allowing the determination of close relationships between epidemiologically related strains.

Amino Acid Sequence↗
PubMed1990

Human recombinant DNA-derived antihemophilic factor (factor VIII) in the treatment of hemophilia A. recombinant Factor VIII Study Group.

BACKGROUND: Current treatment of hemophilia A, a hereditary disorder affecting approximately 1 in 10,000 males, relies on plasma-derived factor VIII concentrates. We tested the safety and efficacy of a recombinant factor VIII preparation for the treatment of this disorder. METHODS: We conducted the investigation in three stages: comparing the pharmacokinetics of plasma-derived and recombinant factor VIII, assessing the efficacy of recombinant factor VIII for home therapy, and assessing its efficacy for major surgical procedures and hemorrhage. A total of 107 subjects with hemophilia, 20 of whom had not been treated previously, enrolled in the investigation. RESULTS: The in vivo recovery and elimination half-lives of recombinant factor VIII equaled or exceeded those of plasma-derived factor VIII. Seventy-six subjects participated in a home-treatment program, using recombinant factor VIII for 69 to 807 days (median, 618); home diaries of 56 subjects treated for 5 months were analyzed. Of 540 bleeding episodes, 399 (73.9 percent) required only one treatment with recombinant factor VIII. The projected annual consumption of recombinant factor VIII was similar to that of plasma-derived factor VIII concentrate. Twenty-six subjects received recombinant factor VIII for 22 surgical procedures and 10 serious hemorrhages; hemostasis was excellent in all cases. De novo formation of inhibitors occurred in only 1 of 85 previously treated subjects. Inhibitor antibodies also developed in 6 of 21 children, 20 of whom had not previously been treated; 5 had low levels (less than or equal to 7.5 Bethesda units) despite continued treatment with recombinant factor VIII. There was no evidence of new formation of antibody to foreign proteins, and recombinant factor VIII was well tolerated. CONCLUSIONS: Recombinant factor VIII has biologic activity comparable to that of plasma factor VIII and is safe and efficacious for the treatment of hemophilia A.

Adult↗
PubMed1990

Heterosexual transmission of HIV in hemophiliacs.

Of 686 hemophiliacs who are being treated at our institution, 402 (59%) are HIV-sero-positive. One hundred seventy-eight heterosexual partners of HIV-infected hemophiliacs have been serologically examined; 19 (11%) are HIV-positive. So far none of the seropositive partners suffers from ARC or AIDS. The rate of heterosexual transmission of HIV is statistically significantly correlated with the CD4+ count of the HIV-infected index patient. No such correlation was found with the index patient's clinical stage or the isolation of HIV from the index patient's blood. Of 39 seronegative female partners who were investigated clinically and immunologically, 17 showed pathologically increased numbers of CD8+ counts. In one case, HIV was transmitted from a female patient with von Willebrand's disease to her husband. As compared to other groups at risk for AIDS, the rate of heterosexual HIV transmission is comparatively low in hemophiliacs. The exact reason for this difference is not yet known. The relevance of the immunopathological findings in seronegative sexual partners of hemophiliacs also remains to be determined.

Adult↗
PubMed1990

Graded cytopathogenicity of the human immunodeficiency virus (HIV) in the course of HIV infection.

To determine whether the biological variability of HIV-1 has any clinical significance, the highly variable cytopathogenicity of 153 HIV-1 strains, isolated from 119 hemophiliacs, was related to the number of CD4+ lymphocytes present in the patient's blood at the time of virus isolation. It was shown that the cytopathogenicity of the HIV-1 isolates was inversely correlated with the number of CD4+ lymphocytes. The highest CD4+ cell number were observed in 34 latently infected patients characterized by HIV seropositivity, failure of virus isolation, and detection of viral DNA by the polymerase chain reaction. Cytopathogenicity of the HIV-1 isolates was a reliable prognostic marker and correlated well with other less-sensitive prognostic parameters, including the detection of infectious virus and p24 antigen in the plasma, and the decline of p24 antibody in the serum. The results suggest that the viral isolates - if not subjected to extensive passage - represent in vivo variants selected from a heterogeneous viral population according to the particular immunological conditions of the host.

Base Sequence↗
PubMed1990

HIV-1 infection in a cohort of haemophilic patients.

The course of HIV infection in 53 haemophilic patients aged 5-20 years was evaluated by clinical examination and laboratory tests. During the evaluation time (median 30 months) two patients died of AIDS and 32 patients (60%) deteriorated when assessed by the Brodt-Helm classification. Nineteen patients (37%) had decreased absolute helper cell counts (less than 500 CD4 positive cells/microliters), and 45 patients (87%) had reduced helper cell to lymphocyte ratios (less than 0.35). HIV-1 was isolated from peripheral lymphocytes in 29 of 46 patients. As the disease progressed the number of positive viral cultures increased. Considerable progression of the HIV infection was seen in haemophilic children and adolescents during the median evaluation period of 30 months. The transition from symptomless HIV infection to immunodeficiency was easily recognised. A lowered ratio of helper cells to lymphocytes seems to be a useful marker of the beginning of the deterioration of the immune system.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Absence of anti-human immunodeficiency virus types 1 and 2 seroconversion after the treatment of hemophilia A or von Willebrand's disease with pasteurized factor VIII concentrate.

Patients with hemophilia A or von Willebrand's disease who are treated with concentrated preparations of human factor VIII made from unscreened pooled plasma are at substantial risk of contracting human immunodeficiency virus (HIV) infection. The purpose of this study was to investigate whether by treating such patients with a pasteurized factor VIII concentrate that had been heated in aqueous solution at 60 degrees C for 10 hours, HIV infection could be avoided. Eleven hemophilia centers in the Federal Republic of Germany and two in Austria identified 155 eligible patients who had been treated exclusively with pasteurized factor VIII concentrate and had not received any other blood products. Between February 1979 and December 1986 they received a total of 15,916,260 IU of pasteurized factor VIII. The United States was the source of 80 percent of the plasma from which the concentrate was made. By September 1988, these 155 patients had been screened for antibody to HIV type 1 (anti-HIV-1) with a total of 657 tests; all were negative. Sixty-seven patients were also tested once for antibody to HIV type 2 (anti-HIV-2); all these tests were negative as well. It appears that pasteurization effectively inactivates HIV, even in plasma that is likely to be highly contaminated with the virus.

Austria↗
PubMed1989

Natural history of HIV-infection in hemophiliacs: clinical, immunological, and virological findings.

At our institution 686 hemophiliacs are being treated. Of them 402 (59%) are anti-HIV-seropositive. The general use of heat-treated clotting factor products was begun in July 1983, and from May 1984 all patients exclusively used heat-treated clotting factors. Thus, one can assume that infection occurred no later than early 1984 in our patients. Since December 1985 HIV-positive hemophiliacs have regularly been clinically and immunologically examined. Most of the 306 patients who could be investigated were clinically symptom-free at the time of their first visit. However, 45 patients have developed AIDS from 1982 through August 1988. The mean survival time of hemophiliacs with AIDS is less than 6 months. In 36% of those 274 patients who have been followed for a mean period of 14 months the clinical stage of the disease worsened by at least one stage according to the classification system proposed by the Centers for Disease Control. We did not find a correlation between clotting-factor consumption during the years 1984-1986 and the actual clinical stage of the patients. Virus isolation from peripheral blood lymphocytes (PBIs) answered the question whether anti-HIV seropositive hemophiliacs are not only immunized but really infected in many more cases than those revealed by detection of p24 antigen or decline of p24 antibody. Positive viral culture correlated strongly with a drop in CD4+ lymphocytes under the level of 400/microliters. However, HIV could not be cultured regularly in advanced cases, suggesting that virus replication in PBLs is not necessarily the cause of depletion of T-helper cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1989

Molecular defects in hemophilia A: identification and characterization of mutations in the factor VIII gene and family analysis.

Hemophilia A is an X-linked bleeding disorder caused by a deficiency or abnormality of factor VIII, affecting approximately 1 male in 10,000. A subgroup of the patients develops inhibitors against factor VIII during substitution therapy. Because a considerable percentage of all cases is thought to result from de novo mutations, it is likely that many different molecular lesions lead to hemophilia A. In order to understand the molecular basis of this disorder, we examined 160 patients with different clinical features using factor VIII gene probes. We could identify six different deletions and seven nonsense mutations within the factor VIII gene. Family analysis revealed that five of these mutations occurred de novo within two generations; two of them arose in the maternal grandfather and three in the mother. In one of these mothers we could identify a mitotic origin. Mapping of the deletions showed no deletion-prone region within the gene. Furthermore, we could not find any correlation between the particular gene defects and "inhibitor" phenotypes.

Base Sequence↗
PubMed1989

Identification of a single nucleotide C-to-T transition and five different deletions in patients with severe hemophilia B.

DNA of 70 unrelated hemophilia B patients, including three inhibitor patients, was analyzed by using various restriction enzymes and was hybridized with both a factor IX cDNA and 3'- and 5'-flanking probes. When the gene was mapped this way, six patients all afflicted with severe hemophilia B were shown to have a deviating hybridization pattern. One inhibitor patient showed a partial deletion of about 9 kb that removes exons a-c. A partial deletion of at least 11 kb that removed exon a and that had a maximum size of 35 kb in the 5'-flanking region could be identified in a patient of unknown status. In another three noninhibitor patients a complete deletion of the factor IX gene and two partial deletions could be observed. The partial deletions are of approximately 8 kb and approximately 1.5 kb, removing exons d and e and exon g, respectively. As detected by oligonucleotide probing, a C-to-T transition at amino acid 338 gave rise to an altered TaqI restriction pattern that could be observed in a sixth patient. The other 64 hemophilia B patients, including two inhibitor patients, showed a hybridization pattern indistinguishable from a normal one.

Chromosome Deletion↗
PubMed1988

Haemophilia A: carrier detection by DNA analysis.

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.

Alleles↗
PubMed1988

EEG discharges in WR 1-5 HIV-seropositive hemophiliacs.

Human immunodeficiency virus (HIV)-seropositive patients show involvement of the central and/or peripheral nervous system. We present here the results of electroencephalographic (EEG) findings in stage WR 1-5 HIV-seropositive hemophiliacs from a total of 184 who attended our clinic prior to October 1987.

Brain↗
PubMed1987

Absence of hepatitis after treatment with a pasteurized factor VIII concentrate in patients with hemophilia and no previous transfusions.

Post-transfusion hepatitis is frequent among patients with hemophilia who are treated with concentrated factor VIII prepared from pooled plasma, especially if it is obtained from paid donors. In 26 patients with hemophilia A or von Willebrand's disease who had not been treated with blood or any blood product and hence were highly susceptible to the development of post-transfusion hepatitis, we infused 32 batches of a factor VIII concentrate that had been produced from large pools of human plasma (collected from paid plasmapheresis donors) and then heated in solution at 60 degrees C for 10 hours before final lyophilization. Patients were examined clinically and serologically over a period of 12 months after the first infusion of the pasteurized concentrate. Neither hepatitis nor serologic signs of other viral infections were observed. The hemostatic effectiveness of the concentrate appeared to be satisfactory relative to untreated concentrates.

Adolescent↗