The importance of genetic factors for the development of arthropathy: a longitudinal study of children and adolescents with haemophilia A.

Haemophilia A is a congenital bleeding disorder characterised by recurrent haemorrhages into the major joints. Haemophilic arthropathy is a well-established outcome of recurrent joint bleeding; however, it is clear that multiple factors determine the extent and severity of its occurrence. We sought to identify genetic factors related to abnormalities in range of motion (ROM) in the knees, ankles and elbows in a cohort of children and adolescents with haemophilia A not treated primarily with regular prophylaxis.

Evaluation of Viremia Frequencies of a Novel Human Pegivirus by Using Bioinformatic Screening and PCR.

Next-generation sequencing has critical applications in virus discovery, diagnostics, and environmental surveillance. We used metagenomic sequence libraries for retrospective screening of plasma samples for the recently discovered human hepegivirus 1 (HHpgV-1). From a cohort of 150 hepatitis C virus (HCV)-positive case-patients, we identified 2 persons with HHpgV-1 viremia and a high frequency of human pegivirus (HPgV) viremia (14%).

The polygenic nature of inhibitors in hemophilia A: results from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort.

Studies of determinants of development of inhibitory Abs to factor VIII in people with hemophilia A indicate a complex process involving multiple factors. The Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort was formed to extend our understanding of the genetic background of risk. The study group contains 833 subjects from 3 independent cohorts: brother pairs and singletons with and without a history of inhibitors, as well as 104 brother pairs discordant for inhibitor status.

Virologic and clinical features of primary infection with human parvovirus 4 in subjects with hemophilia: frequent transmission by virally inactivated clotting factor concentrates.

Background: Human parvovirus 4 (PARV4) is a newly discovered parvovirus prevalent in injecting drug users and other groups with histories of parenteral exposure including persons with hemophilia exposed to non-virally inactivated clotting factor concentrates. To investigate its potential ongoing transmission to persons with hemophilia treated with plasma-derived, virally inactivated clotting factors, we screened a large cohort of persons with hemophilia for antibody seroconversion to PARV4 over a 5-year observation period.

Study Design And Methods: Samples from 195 persons with hemophilia enrolled in the Hemophilia Growth and Development Study cohort were screened for PARV4 antibodies at the start and end of a 5-year period of treatment with exclusively virally inactivated clotting factor concentrates.

Genetic variants in nuclear-encoded mitochondrial genes influence AIDS progression.

Background: The human mitochondrial genome includes only 13 coding genes while nuclear-encoded genes account for 99% of proteins responsible for mitochondrial morphology, redox regulation, and energetics. Mitochondrial pathogenesis occurs in HIV patients and genetically, mitochondrial DNA haplogroups with presumed functional differences have been associated with differential AIDS progression.

Methodology/principal Findings: Here we explore whether single nucleotide polymorphisms (SNPs) within 904 of the estimated 1,500 genes that specify nuclear-encoded mitochondrial proteins (NEMPs) influence AIDS progression among HIV-1 infected patients.

High frequencies of exposure to the novel human parvovirus PARV4 in hemophiliacs and injection drug users, as detected by a serological assay for PARV4 antibodies.

Background: PARV4 is a human parvovirus that was first detected in and cloned from an individual with a human immunodeficiency virus (HIV) seroconversion-like illness and that subsequently persisted in the lymphoid tissue and bone marrow. In contrast to human parvovirus B19 infections, PARV4 infections are most frequently detected in injection drug users (IDUs), particularly those who are coinfected with HIV type 1 (HIV-1). To investigate the routes of transmission of PARV4 and to ascertain whether infections are acquired through plasma-derived blood products, we developed a novel anti-PARV4 enzyme-linked immunosorbent assay (ELISA) to determine its seroprevalence in subjects with parenteral exposure.

Quantitation of anti-factor VIII antibodies in human plasma.

The presence of antibodies (Abs) in hemophilia A patients can potentially influence the therapeutic qualities of factor VIII (fVIII) administration. Much work has been focused on the presence of inhibitory antibodies, whereas the quantitation of noninhibitory anti-fVIII antibodies has been largely undetermined. Our objective was to develop a sensitive and specific fluorescence-based immunoassay (FLI) for the quantitation of anti-fVIIIAbs in human plasma.

Naturally occurring dominant resistance mutations to hepatitis C virus protease and polymerase inhibitors in treatment-naïve patients.

Unlabelled: Resistance mutations to hepatitis C virus (HCV) nonstructural protein 3 (NS3) protease inhibitors in <1% of the viral quasispecies may still allow >1000-fold viral load reductions upon treatment, consistent with their reported reduced replicative fitness in vitro. Recently, however, an R155K protease mutation was reported as the dominant quasispecies in a treatment-naïve individual, raising concerns about possible full drug resistance. To investigate the prevalence of dominant resistance mutations against specifically targeted antiviral therapy for HCV (STAT-C) in the population, we analyzed HCV genome sequences from 507 treatment-naïve patients infected with HCV genotype 1 from the United States, Germany, and Switzerland.

From theory to practice: applying current clinical knowledge and treatment strategies to the care of hemophilia a patients with inhibitors.

Two bypassing agents are currently available to circumvent the need for factor FVIII in hemophilia A patients with inhibitors: the activated prothrombin complex FEIBA VH and recombinant activated factor VII (NovoSeven. Both products are highly effective in controlling bleeding in the presence of inhibitory alloantibodies, yet their hemostatic efficacy can be unpredictable. As the results of the FEIBA NovoSeven( Comparative (FENOC) study illustrate, patients may respond better to one bypassing agent than the other.

Platelet count is associated with plasma HIV type 1 RNA and disease progression.

Thrombocytopenia is a common finding among HIV-1-infected individuals. In addition to their function in hemostasis, platelets have been found to play a role in host immune defenses and to directly interact with HIV-1. To explore the role of platelets in HIV-1 infection, we examined the relationship between platelet number and the natural history of HIV-1 disease in the well-characterized Hemophilia Growth and Development Study cohort.

Delays in maturation among adolescents with hemophilia and a history of inhibitors.

Inhibitory antibodies to factors VIII or IX have the potential to affect a broad range of outcomes among people with hemophilia; however, their possible effect on growth and maturation has not been explored. We evaluated skeletal maturation (bone age), pubertal progression, serum testosterone levels, height velocity, and stature in the multicenter Hemophilia Growth and Development Study. A total of 333 children and adolescents (mean age, 12.

Baseline HIV type 1 coreceptor tropism predicts disease progression.

Background: Human immunodeficiency virus type 1 (HIV-1) coreceptor tropism, the ability of the virus to enter cells via CCR5 or CXCR4, is a viral characteristic mediated by the envelope gene. The impact of coreceptor tropism on the natural history of HIV-1 infection has not been fully explored.

Methods: Coreceptor tropism was measured using a recombinant virus single-cycle assay on plasma specimens obtained at baseline from 126 children and adolescents in the Hemophilia Growth and Development Study cohort who were enrolled from 1989 through 1990 and underwent follow-up through 1997.

Antibodies to heterologous proteins in hemophilia A patients receiving recombinant factor VIII (Recombinate).

As a consequence of the manufacturing process, trace quantities of Chinese hamster ovary cell protein, bovine serum albumin and murine immunoglobulin G are present in Recombinate recombinant human factor VIII (rhFVIII). The development of antibodies (Abs) to these heterologous proteins was evaluated during long-term rhFVIII therapy of hemophilia A in 68 previously treated and 73 previously untreated patients. Ab prevalence was also assessed in 157 non-hemophilic subjects.