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Sample records for hemophilia clinic directors

  1. Hemophilia and von Willebrand's disease: 1. Diagnosis, comprehensive care and assessment. Association of Hemophilia Clinic Directors of Canada.

    Science.gov (United States)

    1995-07-01

    be enrolled in a home self-infusion program. Patients with hemophilia and von Willebrand's disease should wear or carry Medic Alert identification. They should be vaccinated against hepatitis B and attend for routine follow-up examinations. Laboratory testing should be carried out as required, and dental and surgical care should be undertaken in consultation with a hematologist. These recommendations were reviewed and approved by the Association of Hemophilia Clinic Directors of Canada (AHCDC) and the Medical and Scientific Advisory Committee of the Canadian Hemophilia Society. No similar consensus statements or practice guidelines are available for comparison. These recommendations were developed at the request of the Canadian Blood Agency, which funds the provision of all coagulation-factor concentrates for people with congenital bleeding disorders, and were developed and endorsed by the AHCDC and the Medical and Scientific Advisory Committee of the Canadian Hemophilia Society.

  2. Hemophilia

    Science.gov (United States)

    Hemophilia is a rare disorder in which the blood does not clot normally. It is usually inherited. Hemophilia usually occurs in males. If you have hemophilia, you have little or no clotting factor. Clotting ...

  3. Clinical, instrumental, serological and histological findings suggest that hemophilia B may be less severe than hemophilia A.

    Science.gov (United States)

    Melchiorre, Daniela; Linari, Silvia; Manetti, Mirko; Romano, Eloisa; Sofi, Francesco; Matucci-Cerinic, Marco; Carulli, Christian; Innocenti, Massimo; Ibba-Manneschi, Lidia; Castaman, Giancarlo

    2016-02-01

    Recent evidence suggests that patients with severe hemophilia B may have a less severe disease compared to severe hemophilia A. To investigate clinical, radiological, laboratory and histological differences in the arthropathy of severe hemophilia A and hemophilia B, 70 patients with hemophilia A and 35 with hemophilia B with at least one joint bleeding were consecutively enrolled. Joint bleedings (50), regimen of treatment (prophylaxis/on demand), World Federation of Hemophilia, Pettersson and ultrasound scores, serum soluble RANK ligand and osteoprotegerin were assessed in all patients. RANK, RANK ligand and osteoprotegerin expression was evaluated in synovial tissue from 18 hemophilia A and 4 hemophilia B patients. The percentage of patients with either 10-50 or more than 50 hemarthrosis was greater in hemophilia A than in hemophilia B (Phemophilia B (PHemophilia (36.6 vs. 20.2; Phemophilia A patients. Serum osteoprotegerin and soluble RANK ligand were decreased in hemophilia A versus hemophilia B (Phemophilia A patients. In conclusion, the reduced number of hemarthrosis, the lower World Federation of Hemophilia and ultrasound scores, and higher osteoprotegerin expression in serum and synovial tissue in hemophilia B suggest that hemophilia B is a less severe disease than hemophilia A. Osteoprotegerin reduction seems to play a pivotal role in the progression of arthropathy in hemophilia A. Copyright© Ferrata Storti Foundation.

  4. Molecular genetics of hemophilia A: Clinical perspectives

    African Journals Online (AJOL)

    Azza A.G. Tantawy

    Evaluation of an individual with a suspected bleeding disorder includes: platelet count .... information for genetic counseling of at-risk family members. It is indicated for ... Patients with blood group O and a low von Willebrand antigen level have a ..... [4] Husain N. Carrier analysis for hemophilia A: ideal versus acceptable.

  5. Molecular genetics of hemophilia A: Clinical perspectives | Tantawy ...

    African Journals Online (AJOL)

    Since the publication of the sequence of the factor VIII (F8) gene in 1984, a large number of mutations that cause hemophilia A have been identified and a significant progress has been made in translating this knowledge for clinical diagnostic and therapeutic purposes. Molecular genetic testing is used to determine the ...

  6. Child-rearing practices toward children with hemophilia: The relative importance of clinical characteristics and parental emotional reactions

    NARCIS (Netherlands)

    Banis, Hendrika; Suurmeijer, Th.P.B.M.; van Peer, D.R.

    This study addresses the relative importance of clinical characteristics of the child and parental emotional reactions, to child-rearing practices towards children who suffer from hemophilia. The variables were assessed in a Dutch sample of 108 zero-to-twelve-year-old boys with hemophilia and their

  7. Hemophilia Diagnosis

    Science.gov (United States)

    ... and the severity. Families With a History of Hemophilia Any family history of bleeding, such as following ... for hemophilia . Families With No Previous History of Hemophilia About one-third of babies who are diagnosed ...

  8. Hemophilia - resources

    Science.gov (United States)

    Resources - hemophilia ... The following organizations provide further information on hemophilia : Centers for Disease Control and Prevention -- www.cdc.gov/ncbddd/hemophilia/index.html National Heart, Lung, and Blood Institute -- www.nhlbi.nih.gov/ ...

  9. A randomized clinical trial of prophylaxis in children with hemophilia A (the ESPRIT Study).

    Science.gov (United States)

    Gringeri, A; Lundin, B; von Mackensen, S; Mantovani, L; Mannucci, P M

    2011-04-01

    Prevention of arthropathy is a major goal of hemophilia treatment. While studies in adults have demonstrated an impact of prophylaxis on the incidence of joint bleeds and patients' well-being in terms of improved quality of life (QoL), it is unclear whether or not prophylaxis influences the outcome and perception of well- of children with hemophilia. This randomized controlled study compared the efficacy of prophylaxis with episodic therapy in preventing hemarthroses and image-proven joint damage in children with severe hemophilia A (factor VIII <1%) over a 10-year time period. Forty-five children with severe hemophilia A, aged 1-7 years (median 4), with negative clinical-radiologic joint score at entry and at least one bleed during the previous 6 months, were consecutively randomized to prophylaxis with recombinant factor VIII (25 IU kg(-1) 3 × week) or episodic therapy with ≥25 IU kg(-1) every 12-24 h until complete clinical bleeding resolution. Safety, feasibility, direct costs and QoL were also evaluated. Twenty-one children were assigned to prophylaxis, 19 to episodic treatment. Children on prophylaxis had fewer hemarthroses than children on episodic therapy: 0.20 vs. 0.52 events per patient per month (P < 0.02). Plain-film radiology showed signs of arthropathy in six patients on prophylaxis (29%) vs. 14 on episodic treatment (74%) (P < 0.05). Prophylaxis was more effective when started early (≤36 months), with patients having fewer joint bleeds (0.12 joint bleeds per patient per month) and no radiologic signs of arthropathy. This randomized trial confirms the efficacy of prophylaxis in preventing bleeds and arthropathy in children with hemophilia, particularly when it is initiated early in life. © 2011 International Society on Thrombosis and Haemostasis.

  10. Hemophilia Facts

    Science.gov (United States)

    ... public health webinars on blood disorders Basics About Hemophilia Language: English (US) Español (Spanish) Recommend on Facebook ... the 5" Key prevention messages from the National Hemophilia Foundation’s National Prevention Program Tips for Healthy Living ...

  11. Animal Models of Hemophilia

    Science.gov (United States)

    Sabatino, Denise E.; Nichols, Timothy C.; Merricks, Elizabeth; Bellinger, Dwight A.; Herzog, Roland W.; Monahan, Paul E.

    2013-01-01

    The X-linked bleeding disorder hemophilia is caused by mutations in coagulation factor VIII (hemophilia A) or factor IX (hemophilia B). Unless prophylactic treatment is provided, patients with severe disease (less than 1% clotting activity) typically experience frequent spontaneous bleeds. Current treatment is largely based on intravenous infusion of recombinant or plasma-derived coagulation factor concentrate. More effective factor products are being developed. Moreover, gene therapies for sustained correction of hemophilia are showing much promise in pre-clinical studies and in clinical trials. These advances in molecular medicine heavily depend on availability of well-characterized small and large animal models of hemophilia, primarily hemophilia mice and dogs. Experiments in these animals represent important early and intermediate steps of translational research aimed at development of better and safer treatments for hemophilia, such a protein and gene therapies or immune tolerance protocols. While murine models are excellent for studies of large groups of animals using genetically defined strains, canine models are important for testing scale-up and for longer-term follow-up as well as for studies that require larger blood volumes. PMID:22137432

  12. Duodenal Tumor Presenting as Acquired Hemophilia in an 88-Year-Old Woman: A Clinical Case and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Nigel P. Murray

    2012-01-01

    Full Text Available Acquired hemophilia is a rare disease, presenting with severe hemorrhage, we present a case caused by a duodenal tumor, the clinical management, ethical implications, treatment recommendations, and a review of the literature.

  13. Hemophilia (For Parents)

    Science.gov (United States)

    ... Staying Safe Videos for Educators Search English Español Hemophilia KidsHealth / For Parents / Hemophilia What's in this article? ... everyday mishaps are cause for concern. What Is Hemophilia? Hemophilia is a disease that prevents blood from ...

  14. Hemophilia (For Teens)

    Science.gov (United States)

    ... Staying Safe Videos for Educators Search English Español Hemophilia KidsHealth / For Teens / Hemophilia What's in this article? ... bruises can be a big deal. What Is Hemophilia? Hemophilia is a disease that prevents blood from ...

  15. Clinical characteristics and outcomes of acquired hemophilia A: experience at a single center in Japan.

    Science.gov (United States)

    Ogawa, Yoshiyuki; Yanagisawa, Kunio; Uchiumi, Hideki; Ishizaki, Takuma; Mitsui, Takeki; Gouda, Fumito; Ieko, Masahiro; Ichinose, Akitada; Nojima, Yoshihisa; Handa, Hiroshi

    2017-07-01

    Acquired hemophilia A (AHA), which is caused by autoantibodies against coagulation factor VIII (FVIII) is a rare, life-threatening bleeding disorder, the incidence of which appears to be increasing in Japan as the population ages. However, the clinical characteristics, treatment, and outcomes of AHA remain difficult to establish due to the rarity of this disease. We retrospectively analyzed data from 25 patients (median age 73 years; range 24-92 years; male n = 15) diagnosed with AHA between 1999 and 2015 at Gunma University Hospital. We identified autoimmune diseases and malignancy as underlying conditions in four and three patients, respectively. Factor VIII activity was significantly decreased in all patients (median 2.0%; range <1.0-8.0) by FVIII inhibitor (median 47.0 BU/mL; range 2.0-1010). Among 71 bleeding events, subcutaneous or intramuscular hemorrhage was the most prevalent. Seventeen patients required bypassing agents. Twenty-two (91.7%) of 24 patients treated with immunosuppressive agents achieved complete response (CR) during a median of 57.5 days (range 19-714 days). Although three patients (12%) relapsed and seven (28%) died of infection, none of the deaths were related to bleeding. Although most of our patients achieved CR after immunosuppressive therapy, the rate of infection-related mortality was unsatisfactorily high.

  16. How to Deal with Hemophilia

    Science.gov (United States)

    ... Educators Search English Español How to Deal With Hemophilia KidsHealth / For Kids / How to Deal With Hemophilia ... mild case of hemophilia. Why Do Kids Get Hemophilia? Hemophilia almost always affects boys. Why? Because the ...

  17. Both Hemophilia Health Care Providers and Hemophilia A Carriers Report that Carriers have Excessive Bleeding

    Science.gov (United States)

    Paroskie, Allison; Oso, Olatunde; DeBaun, Michael R.; Sidonio, Robert F

    2014-01-01

    Introduction Hemophilia A, the result of reduced factor VIII (FVIII) activity, is an X-linked recessive bleeding disorder. Previous reports of Hemophilia A carriers suggest an increased bleeding tendency. Our objective was to determine the attitudes and understanding of the Hemophilia A carrier bleeding phenotype, and opinions regarding timing of carrier testing from the perspective of both medical providers and affected patients. Data from this survey was used as preliminary data for an ongoing prospective study. Material and Methods An electronic survey was distributed to physicians and nurses employed at Hemophilia Treatment Centers (HTC), and Hemophilia A carriers who were members of Hemophilia Federation of America. Questions focused on the clinical understanding of bleeding symptoms and management of Hemophilia A carriers, and the timing and intensity of carrier testing. Results Our survey indicates that 51% (36/51) of providers compared to 78% (36/46) of carriers believe that Hemophilia A carriers with normal FVIII activity have an increased bleeding tendency (pHemophilia A carriers report a high frequency of bleeding symptoms. Regarding carrier testing, 72% (50/69) of medical providers recommend testing after 14 years of age, conversely 65% (29/45) of Hemophilia A carriers prefer testing to be done prior to this age (pHemophilia A carriers self-report a higher frequency of bleeding than previously acknowledged, and have a preference for earlier testing to confirm carrier status. PMID:24309601

  18. Hemophilia A

    Science.gov (United States)

    ... PA: Elsevier; 2016:chap 476. Srivastava A, Brewer AK, Mauser-Bunschoten EP, et al. Treatment Guidelines Working Group on Behalf of The World Federation Of Hemophilia. Haemophilia. 2013;19:e1-47. PMID: 22776238 www.ncbi.nlm.nih.gov/pubmed/ ...

  19. Research leadership: should clinical directors be distinguished researchers?

    Science.gov (United States)

    Allison, Stephen; Goodall, Amanda H; Bastiampillai, Tarun

    2016-06-01

    Clinical directors established research-led healthcare by combining research, teaching and clinical excellence within the teaching hospitals. This research culture created high clinical standards, which benefited patients, the workforce and healthcare organisations. The current paper explores this research leadership role for clinical directors. It reviews studies arising from the theory of expert leadership, which focuses on the relationship between a leader's core knowledge and organisational performance. More specifically, we examine the expert leader's research track record, the associations with their organisation's performance, and the influence of research activity on clinical excellence. Distinguished researchers still lead the most prestigious teaching hospitals and the most trusted departments of psychiatry in the United States where the clinical directorate structure originated. It is also known that good scholars can improve research output when appointed to leadership positions. This suggests that the clinical director's research track record should be a consideration at a time when research is being embedded in Australia's local health networks. A clinical director's leadership may influence the research performance of their department and contribute to the quality of mental healthcare. © The Royal Australian and New Zealand College of Psychiatrists 2015.

  20. Safety, efficacy and pharmacokinetics of rVIII-SingleChain in children with severe hemophilia A: results of a multicenter clinical trial.

    Science.gov (United States)

    Stasyshyn, O; Djambas Khayat, C; Iosava, G; Ong, J; Abdul Karim, F; Fischer, K; Veldman, A; Blackman, N; St Ledger, K; Pabinger, I

    2017-04-01

    Essentials rVIII-SingleChain is a novel recombinant factor VIII with covalently bonded heavy and light chains. Efficacy, safety and pharmacokinetics were studied in pediatric patients with severe hemophilia A. Across all prophylaxis regimens, the median annualized spontaneous bleeding rate was 0.00. rVIII-SingleChain showed excellent hemostatic efficacy and a favorable safety profile. Background rVIII-SingleChain is a novel B-domain truncated recombinant factor VIII (rFVIII) comprised of covalently bonded FVIII heavy and light chains, demonstrating a high binding affinity to von Willebrand factor. Objectives This phase III study investigated the safety, efficacy and pharmacokinetics of rVIII-SingleChain in previously treated pediatric patients hemophilia A. Patients/Methods Patients could be assigned to prophylaxis or on-demand therapy by the investigator. For patients assigned to prophylaxis, the treatment regimen and dose were based on the bleeding phenotype. For patients receiving on-demand therapy, dosing was guided by World Federation of Hemophilia recommendations. The primary endpoint was treatment success, defined as a rating of 'excellent' or 'good' on the investigator's clinical assessment of hemostatic efficacy for all treated bleeding events. Results The study enrolled 84 patients (0 to 50 EDs. In the 347 bleeds treated and evaluated by the investigator, hemostatic efficacy was rated as excellent or good in 96.3%. The median annualized spontaneous bleeding rate was 0.00 (Q1, Q3: 0.00, 2.20), and the median annualized bleeding rate was 3.69 (Q1, Q3: 0.00, 7.20) across all prophylaxis regimens. No participant developed an inhibitor. Conclusions rVIII-SingleChain is a novel rFVIII molecule showing excellent hemostatic efficacy and a favorable safety profile in a clinical study in children hemophilia A. © 2017 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and

  1. The Effectiveness of a New Hemostatic Agent (Ankaferd Blood Stopper for the Control of Bleeding following Tooth Extraction in Hemophilia: A Controlled Clinical Trial

    Directory of Open Access Journals (Sweden)

    Hakkı Oğuz Kazancıoğlu

    2013-03-01

    Full Text Available Objective: To assess the hemostatic efficacy of a new local hemostatic agent, Ankaferd Blood Stopper (ABS, for the control of bleeding following tooth extraction in hemophiliacs. Materials and Methods: Simple tooth extractions were performed in 27 hemophilia A patients. In the treatment group (n=17 local hemostasis was achieved via application of ABS to the extraction sockets, whereas in the control group (n=10 local hemostasis was achieved via direct packing with gauze. Results: In all, 57 (21 primary and 36 permanent teeth extractions were performed in 27 hemophilia A patients. There were no significant differences in age or factor VIII level distribution between the 2 groups (p>0.05. The most significant clinical difference between the groups was associated with the use of ABS; those in the treatment group had significantly shorter duration of bleeding (p=0.002. Conclusion: This is the first study to evaluate the efficacy of ABS for the control of bleeding following tooth extraction in hemophiliacs. ABS can be considered an alternative local hemostatic agent for reducing clotting factor concentrates in hemophilia patients.

  2. Animal Models of Hemophilia and Related Bleeding Disorders

    Science.gov (United States)

    Lozier, Jay N.; Nichols, Timothy C.

    2013-01-01

    Animal models of hemophilia and related diseases are important for development of novel treatments and to understand the pathophysiology of bleeding disorders in humans. Testing in animals with the equivalent human disorder provides informed estimates of doses and measures of efficacy, which aids in design of human trials. Many models of hemophilia A, hemophilia B, and von Willebrand disease have been developed from animals with spontaneous mutations (hemophilia A dogs, rats, sheep; hemophilia B dogs; and von Willebrand disease pigs and dogs), or by targeted gene disruption in mice to create hemophilia A, B, or VWD models. Animal models have been used to generate new insights into the pathophysiology of each bleeding disorder and also to perform pre-clinical assessments of standard protein replacement therapies as well as novel gene transfer technology. Both the differences between species and differences in underlying causative mutations must be considered in choosing the best animal for a specific scientific study PMID:23956467

  3. Hemophilia Data and Statistics

    Science.gov (United States)

    ... View public health webinars on blood disorders Data & Statistics Language: English (US) Español (Spanish) Recommend on Facebook ... genetic testing is done to diagnose hemophilia before birth. For the one-third ... rates and hospitalization rates for bleeding complications from hemophilia ...

  4. Gene therapy for hemophilia

    Science.gov (United States)

    Rogers, Geoffrey L.; Herzog, Roland W.

    2015-01-01

    Hemophilia is an X-linked inherited bleeding disorder consisting of two classifications, hemophilia A and hemophilia B, depending on the underlying mutation. Although the disease is currently treatable with intravenous delivery of replacement recombinant clotting factor, this approach represents a significant cost both monetarily and in terms of quality of life. Gene therapy is an attractive alternative approach to the treatment of hemophilia that would ideally provide life-long correction of clotting activity with a single injection. In this review, we will discuss the multitude of approaches that have been explored for the treatment of both hemophilia A and B, including both in vivo and ex vivo approaches with viral and nonviral delivery vectors. PMID:25553466

  5. Demographic and clinical data in acquired hemophilia A: results from the European Acquired Haemophilia Registry (EACH2).

    Science.gov (United States)

    Knoebl, P; Marco, P; Baudo, F; Collins, P; Huth-Kühne, A; Nemes, L; Pellegrini, F; Tengborn, L; Lévesque, H

    2012-04-01

    Acquired hemophilia A (AHA) is a rare autoimmune disease caused by autoantibodies against coagulation factor VIII and characterized by spontaneous hemorrhage in patients with no previous family or personal history of bleeding. Although data on several AHA cohorts have been collected, limited information is available on the optimal management of AHA. The European Acquired Hemophilia Registry (EACH2) was established to generate a prospective, large-scale, pan-European database on demographics, diagnosis, underlying disorders, bleeding characteristics, treatment and outcome of AHA patients. Five hundred and one (266 male, 235 female) patients from 117 centers and 13 European countries were included in the registry between 2003 and 2008. In 467 cases, hemostasis investigations and AHA diagnosis were triggered by a bleeding event. At diagnosis, patients were a median of 73.9 years. AHA was idiopathic in 51.9%; malignancy or autoimmune diseases were associated with 11.8% and 11.6% of cases. Fifty-seven per cent of the non-pregnancy-related cases were male. Four hundred and seventy-four bleeding episodes were reported at presentation, and hemostatic therapy initiated in 70.5% of patients. Delayed diagnosis significantly impacted treatment initiation in 33.5%. Four hundred and seventy-seven patients underwent immunosuppression, and 72.6% achieved complete remission. Representing the largest collection of consecutive AHA cases to date, EACH2 facilitates the analysis of a variety of open questions in AHA. © 2012 International Society on Thrombosis and Haemostasis.

  6. Understanding Hemophilia. Implications for the Physical Educator.

    Science.gov (United States)

    Coelho, Jeffrey D.

    1998-01-01

    Describes hemophilia and ways to provide appropriate physical education experiences to children with hemophilia. The article focuses on what hemophilia is, how to treat hemophilia, benefits of physical activity, how to teach children with hemophilia, choosing and modifying sports and activities, and safety and emergency situations. (SM)

  7. Experience of Preimplantation Genetic Diagnosis for Hemophilia at the University Hospital Virgen Del Rocío in Spain: Technical and Clinical Overview

    Directory of Open Access Journals (Sweden)

    Raquel M. Fernández

    2015-01-01

    Full Text Available Hemophilia A and B are the most common hereditary hemorrhagic disorders, with an X-linked mode of inheritance. Reproductive options for the families affected with hemophilia, aiming at the prevention of the birth of children with severe coagulation disorders, include preimplantation genetic diagnosis (PGD. Here we present the results of our PGD Program applied to hemophilia, at the Department of Genetics, Reproduction and Fetal Medicine of the University Hospital Virgen del Rocío in Seville. A total of 34 couples have been included in our program since 2005 (30 for hemophilia A and 4 for hemophilia B. Overall, 60 cycles were performed, providing a total of 508 embryos. The overall percentage of transfers per cycle was 81.7% and the live birth rate per cycle ranged from 10.3 to 24.1% depending on the methodological approach applied. Although PGD for hemophilia can be focused on gender selection of female embryos, our results demonstrate that methodological approaches that allow the diagnosis of the hemophilia status of every embryo have notorious advantages. Our PGD Program resulted in the birth of 12 healthy babies for 10 out of the 34 couples (29.4%, constituting a relevant achievement for the Spanish Public Health System within the field of haematological disorders.

  8. Experience of Preimplantation Genetic Diagnosis for Hemophilia at the University Hospital Virgen Del Rocío in Spain: Technical and Clinical Overview

    Science.gov (United States)

    Fernández, Raquel M.; Peciña, Ana; Sánchez, Beatriz; Lozano-Arana, Maria Dolores; García-Lozano, Juan Carlos; Pérez-Garrido, Rosario; Núñez, Ramiro; Antiñolo, Guillermo

    2015-01-01

    Hemophilia A and B are the most common hereditary hemorrhagic disorders, with an X-linked mode of inheritance. Reproductive options for the families affected with hemophilia, aiming at the prevention of the birth of children with severe coagulation disorders, include preimplantation genetic diagnosis (PGD). Here we present the results of our PGD Program applied to hemophilia, at the Department of Genetics, Reproduction and Fetal Medicine of the University Hospital Virgen del Rocío in Seville. A total of 34 couples have been included in our program since 2005 (30 for hemophilia A and 4 for hemophilia B). Overall, 60 cycles were performed, providing a total of 508 embryos. The overall percentage of transfers per cycle was 81.7% and the live birth rate per cycle ranged from 10.3 to 24.1% depending on the methodological approach applied. Although PGD for hemophilia can be focused on gender selection of female embryos, our results demonstrate that methodological approaches that allow the diagnosis of the hemophilia status of every embryo have notorious advantages. Our PGD Program resulted in the birth of 12 healthy babies for 10 out of the 34 couples (29.4%), constituting a relevant achievement for the Spanish Public Health System within the field of haematological disorders. PMID:26258137

  9. Porcine model of hemophilia A.

    Directory of Open Access Journals (Sweden)

    Yuji Kashiwakura

    Full Text Available Hemophilia A is a common X chromosome-linked genetic bleeding disorder caused by abnormalities in the coagulation factor VIII gene (F8. Hemophilia A patients suffer from a bleeding diathesis, such as life-threatening bleeding in the brain and harmful bleeding in joints and muscles. Because it could potentially be cured by gene therapy, subhuman animal models have been sought. Current mouse hemophilia A models generated by gene targeting of the F8 have difficulties to extrapolate human disease due to differences in the coagulation and immune systems between mice and humans. Here, we generated a porcine model of hemophilia A by nuclear transfer cloning from F8-targeted fibroblasts. The hemophilia A pigs showed a severe bleeding tendency upon birth, similar to human severe hemophiliacs, but in contrast to hemophilia A mice which rarely bleed under standard breed conditions. Infusion of human factor VIII was effective in stopping bleeding and reducing the bleeding frequency of a hemophilia A piglet but was blocked by the inhibitor against human factor VIII. These data suggest that the hemophilia A pig is a severe hemophilia A animal model for studying not only hemophilia A gene therapy but also the next generation recombinant coagulation factors, such as recombinant factor VIII variants with a slower clearance rate.

  10. Radiological findings of hemophilia

    International Nuclear Information System (INIS)

    Choi, Chul Uk; Choi, Kwung Uk; Kim, Yong Chul; Shin, Kyoung Ja; Lee, Sang Chun

    1987-01-01

    A hemophilia is a well known hereditary disorder of blood coagulation which bleeds mostly in the large joints and frequently in central nervous system, abdominal organs and soft tissues. Recently using combined computed tomography and ultrasonography, more accurate location and extent of the lesion can be detected. Authors views proven 36 cases of hemophilia with analysis of their simple X-ray, computed tomography and ultrasonography. The results were as follows: 1. All 36 patients were male, and age distribution was 2-16 year. 2. Most patients showed type A (97.2%) and type B (2.8%) in 36 cases. 3. A hemophilia arthropathy (30 cases) was developed mostly hemophilia in the knee joint (67%), and rest of involvement in the elbow, ankle and hip joint. 4. On computed tomography of CNS lesion (14/36 cases); ICH in 6 cases (43%), EDH in 2 cases (14%), combined type in 3 cases (21%) and SAH in 3 cases (21%). 5. Ultrasonography, retroperitoneal hematoma were detected in 4 cases, including ileopsoas hematoma (2 cases)

  11. Radiological findings of hemophilia

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Chul Uk; Choi, Kwung Uk; Kim, Yong Chul; Shin, Kyoung Ja; Lee, Sang Chun [Seoul Red Cross Hospital, Seoul (Korea, Republic of)

    1987-08-15

    A hemophilia is a well known hereditary disorder of blood coagulation which bleeds mostly in the large joints and frequently in central nervous system, abdominal organs and soft tissues. Recently using combined computed tomography and ultrasonography, more accurate location and extent of the lesion can be detected. Authors views proven 36 cases of hemophilia with analysis of their simple X-ray, computed tomography and ultrasonography. The results were as follows: 1. All 36 patients were male, and age distribution was 2-16 year. 2. Most patients showed type A (97.2%) and type B (2.8%) in 36 cases. 3. A hemophilia arthropathy (30 cases) was developed mostly hemophilia in the knee joint (67%), and rest of involvement in the elbow, ankle and hip joint. 4. On computed tomography of CNS lesion (14/36 cases); ICH in 6 cases (43%), EDH in 2 cases (14%), combined type in 3 cases (21%) and SAH in 3 cases (21%). 5. Ultrasonography, retroperitoneal hematoma were detected in 4 cases, including ileopsoas hematoma (2 cases)

  12. Mutation spectrum of 122 hemophilia A families from Taiwanese population by LD-PCR, DHPLC, multiplex PCR and evaluating the clinical application of HRM

    Directory of Open Access Journals (Sweden)

    Chang Chieh-Ting

    2008-06-01

    Full Text Available Abstract Background Hemophilia A represents the most common and severe inherited hemorrhagic disorder. It is caused by mutations in the F8 gene, which leads to a deficiency or dysfunctional factor VIII protein, an essential cofactor in the factor X activation complex. Methods We used long-distance polymerase chain reaction and denaturing high performance liquid chromatography for mutation scanning of the F8 gene. We designed the competitive multiplex PCR to identify the carrier with exonal deletions. In order to facilitate throughput and minimize the cost of mutation scanning, we also evaluated a new mutation scanning technique, high resolution melting analysis (HRM, as an alternative screening method. Results We presented the results of detailed screening of 122 Taiwanese families with hemophilia A and reported twenty-nine novel mutations. There was one family identified with whole exons deletion, and the carriers were successfully recognized by multiplex PCR. By HRM, the different melting curve patterns were easily identified in 25 out of 28 cases (89% and 15 out of 15 (100% carriers. The sensitivity was 93 % (40/43. The overall mutation detection rate of hemophilia A was 100% in this study. Conclusion We proposed a diagnostic strategy for hemophilia A genetic diagnosis. We consider HRM as a powerful screening tool that would provide us with a more cost-effective protocol for hemophilia A mutation identification.

  13. Advances in hemophilia care: report of two symposia at the Hemophilia 2010 World Congress.

    Science.gov (United States)

    Dolan, Gerry; Cruz, Jussara Almeida; Steinhagen-Thiessen, Elisabeth; Kessler, Craig; Haaning, Jesper; Lemm, Georg; Altisent, Carmen; Guerrero, Caesar; Hermans, Cedric; Riske, Brenda; Bolton-Maggs, Paula

    2012-04-01

    The World Federation of Hemophilia (WFH) 2010 World Congress held in Buenos Aires, Argentina, in July 2010, attracted more than 4,300 participants from 106 countries. This report summarizes two symposia held during the congress. The first, titled "Emerging Co-Morbidities in the Aging Hemophilia Population: Healthcare Challenges and Treatment Opportunities," chaired by Gerry Dolan, MD, and Jussara Almeida Cruz, MD, examined the co-morbidities experienced by the aging hemophilic patient population, such as cardiovascular disease, cancer, arthritis, osteoporosis, hypertension, and obesity. In addition, Bayer's products in preclinical and clinical development were reviewed, including a novel factor VIIa variant and a long-acting factor VIII molecule, i.e., one that has undergone site-specific PEGylation (attachment of polyethylene glycol [PEG] polymer chains to another molecule). The other symposium, titled "Practical Steps to Making Better Care for Hemophilia Patients a Reality," chaired by Carmen Altisent, MD, and Cesar Guerrero, RN, reviewed the steps that hemophilia caregivers can take to improve the care of their patients. Issues such as the treatment of hemarthroses, the role of the research nurse, and the management of pediatric patients transitioning to adulthood were discussed.

  14. Platelets and hemophilia: A review of the literature.

    Science.gov (United States)

    Riedl, Julia; Ay, Cihan; Pabinger, Ingrid

    2017-07-01

    Hemophilia A and B are inherited bleeding disorders due to deficiencies of the clotting factors VIII and IX, respectively. The severity of the disease correlates with remaining factor levels, although individual differences in bleeding tendency are seen despite similar factor levels. While thrombin generation is severely impaired in persons with hemophilia, primary hemostasis, i.e. platelet function, has been generally considered to be normal. However, some studies reported prolonged bleeding times in hemophilia, suggesting that also primary hemostasis is affected. In several other studies different aspects of platelet function in hemophilia have been investigated in more detail and various alterations were discovered, such as increased platelet P-selectin expression, a lower number of procoagulant, so-called 'coated' platelets, lower aggregation upon co-incubation with tissue factor, or reduced platelet contractile forces during clot formation in comparison to healthy individuals. An influence of platelet function on clinical phenotype was suggested, which might contribute in part to variations in bleeding tendency in hemophilic patients with similar factor levels. However, the available evidence is currently limited and no clear correlations between platelet function parameters and clinical phenotypes have been demonstrated. The impact of alterations of platelet function in hemophilia remains to be better defined. Another interesting role of platelets in hemophilia has been reported recently by establishing a novel gene-therapeutic strategy using platelets as a delivery system for FVIII, showing promising results in animal models. This review gives an overview on the currently published literature on platelet function and the potential roles of platelets in hemophilia. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. [Study of gene mutation in 62 hemophilia A children].

    Science.gov (United States)

    Hu, Q; Liu, A G; Zhang, L Q; Zhang, A; Wang, Y Q; Wang, S M; Lu, Y J; Wang, X

    2017-11-02

    Objective: To analyze the mutation type of FⅧ gene in children with hemophilia A and to explore the relationship among hemophilia gene mutation spectrum, gene mutation and clinical phenotype. Method: Sixty-two children with hemophilia A from Department of Pediatric Hematology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology between January 2015 and March 2017 were enrolled. All patients were male, aged from 4 months to 7 years and F Ⅷ activity ranged 0.2%-11.0%. Fifty cases had severe, 10 cases had moderate and 2 cases had mild hemophilia A. DNA was isolated from peripheral blood in hemophilia A children and the target gene fragment was amplified by PCR, in combination with the second generation sequencing, 22 and 1 introns were detected. Negative cases were detected by the second generation sequencing and results were compared with those of the international FⅧ gene mutation database. Result: There were 20 cases (32%) of intron 22 inversion, 2 cases (3%) of intron 1 inversion, 18 cases (29%) of missense mutation, 5 cases (8%) of nonsense mutation, 7 cases (11%) of deletion mutation, 1 case(2%)of splice site mutation, 2 cases (3%) of large fragment deletion and 1 case of insertion mutation (2%). No mutation was detected in 2 cases (3%), and 4 cases (7%) failed to amplify. The correlation between phenotype and genotype showed that the most common gene mutation in severe hemophilia A was intron 22 inversion (20 cases), accounting for 40% of severe patients, followed by 11 cases of missense mutation (22%). The most common mutation in moderate hemophilia A was missense mutation (6 cases), accounting for 60% of moderate patients. Conclusion: The most frequent mutation type in hemophilia A was intron 22 inversion, followed by missense mutation, again for missing mutation. The relationship between phenotype and genotype: the most frequent gene mutation in severe hemophilia A is intron 22 inversion, followed by missense

  16. Efficacy and safety of rVIII-SingleChain: results of a phase 1/3 multicenter clinical trial in severe hemophilia A

    Science.gov (United States)

    Mahlangu, Johnny; Kuliczkowski, Kazimierz; Karim, Faraizah Abdul; Stasyshyn, Oleksandra; Kosinova, Marina V.; Lepatan, Lynda Mae; Skotnicki, Aleksander; Boggio, Lisa N.; Klamroth, Robert; Oldenburg, Johannes; Hellmann, Andrzej; Santagostino, Elena; Baker, Ross I.; Fischer, Kathelijn; Gill, Joan C.; P’Ng, Stephanie; Chowdary, Pratima; Escobar, Miguel A.; Khayat, Claudia Djambas; Rusen, Luminita; Bensen-Kennedy, Debra; Blackman, Nicole; Limsakun, Tharin; Veldman, Alex; St. Ledger, Katie

    2016-01-01

    Recombinant VIII (rVIII)-SingleChain is a novel B-domain–truncated recombinant factor VIII (rFVIII), comprised of covalently bonded factor VIII (FVIII) heavy and light chains. It was designed to have a higher binding affinity for von Willebrand factor (VWF). This phase 1/3 study investigated the efficacy and safety of rVIII-SingleChain in the treatment of bleeding episodes, routine prophylaxis, and surgical prophylaxis. Participants were ≥12 years of age, with severe hemophilia A (endogenous FVIII <1%). The participants were allocated by the investigator to receive rVIII-SingleChain in either an on-demand or prophylaxis regimen. Of the 175 patients meeting study eligibility criteria, 173 were treated with rVIII-SingleChain, prophylactically (N = 146) or on-demand (N = 27). The total cumulative exposure was 14 306 exposure days (EDs), with 120 participants reaching ≥50 EDs and 52 participants having ≥100 EDs. Hemostatic efficacy was rated by the investigator as excellent or good in 93.8% of the 835 bleeds treated and assessed. Across all prophylaxis regimens, the median annualized spontaneous bleeding rate was 0.00 (Q1, Q3: 0.0, 2.4) and the median overall annualized bleeding rate (ABR) was 1.14 (Q1, Q3: 0.0, 4.2). Surgical hemostasis was rated as excellent/good in 100% of major surgeries by the investigator. No participant developed FVIII inhibitors. In conclusion, rVIII-SingleChain is a novel rFVIII molecule showing excellent hemostatic efficacy in surgery and in the control of bleeding events, low ABR in patients on prophylaxis, and a favorable safety profile in this large clinical study. This trial was registered at www.clinicaltrials.gov as #NCT01486927. PMID:27330001

  17. Emicizumab Prophylaxis in Hemophilia A with Inhibitors.

    Science.gov (United States)

    Oldenburg, Johannes; Mahlangu, Johnny N; Kim, Benjamin; Schmitt, Christophe; Callaghan, Michael U; Young, Guy; Santagostino, Elena; Kruse-Jarres, Rebecca; Negrier, Claude; Kessler, Craig; Valente, Nancy; Asikanius, Elina; Levy, Gallia G; Windyga, Jerzy; Shima, Midori

    2017-08-31

    Emicizumab (ACE910) bridges activated factor IX and factor X to restore the function of activated factor VIII, which is deficient in persons with hemophilia A. This phase 3, multicenter trial assessed once-weekly subcutaneous emicizumab prophylaxis in persons with hemophilia A with factor VIII inhibitors. We enrolled participants who were 12 years of age or older. Those who had previously received episodic treatment with bypassing agents were randomly assigned in a 2:1 ratio to emicizumab prophylaxis (group A) or no prophylaxis (group B). The primary end point was the difference in bleeding rates between group A and group B. Participants who had previously received prophylactic treatment with bypassing agents received emicizumab prophylaxis in group C. A total of 109 male participants with hemophilia A with inhibitors were enrolled. The annualized bleeding rate was 2.9 events (95% confidence interval [CI], 1.7 to 5.0) among participants who were randomly assigned to emicizumab prophylaxis (group A, 35 participants) versus 23.3 events (95% CI, 12.3 to 43.9) among those assigned to no prophylaxis (group B, 18 participants), representing a significant difference of 87% in favor of emicizumab prophylaxis (Phemophilia A with inhibitors. (Funded by F. Hoffmann-La Roche and Chugai Pharmaceutical; HAVEN 1 ClinicalTrials.gov number, NCT02622321 .).

  18. Clinical skills assessment of procedural and advanced communication skills: performance expectations of residency program directors

    Science.gov (United States)

    Langenau, Erik E.; Zhang, Xiuyuan; Roberts, William L.; DeChamplain, Andre F.; Boulet, John R.

    2012-01-01

    Background High stakes medical licensing programs are planning to augment and adapt current examinations to be relevant for a two-decision point model for licensure: entry into supervised practice and entry into unsupervised practice. Therefore, identifying which skills should be assessed at each decision point is critical for informing examination development, and gathering input from residency program directors is important. Methods Using data from previously developed surveys and expert panels, a web-delivered survey was distributed to 3,443 residency program directors. For each of the 28 procedural and 18 advanced communication skills, program directors were asked which clinical skills should be assessed, by whom, when, and how. Descriptive statistics were collected, and Intraclass Correlations (ICC) were conducted to determine consistency across different specialties. Results Among 347 respondents, program directors reported that all advanced communication and some procedural tasks are important to assess. The following procedures were considered ‘important’ or ‘extremely important’ to assess: sterile technique (93.8%), advanced cardiovascular life support (ACLS) (91.1%), basic life support (BLS) (90.0%), interpretation of electrocardiogram (89.4%) and blood gas (88.7%). Program directors reported that most clinical skills should be assessed at the end of the first year of residency (or later) and not before graduation from medical school. A minority were considered important to assess prior to the start of residency training: demonstration of respectfulness (64%), sterile technique (67.2%), BLS (68.9%), ACLS (65.9%) and phlebotomy (63.5%). Discussion Results from this study support that assessing procedural skills such as cardiac resuscitation, sterile technique, and phlebotomy would be amenable to assessment at the end of medical school, but most procedural and advanced communications skills would be amenable to assessment at the end of the first

  19. Hemophilia Treatments Have Come a Long Way

    Science.gov (United States)

    ... Products For Consumers Home For Consumers Consumer Updates Hemophilia Treatments Have Come a Long Way Share Tweet ... tissues and even be life-threatening. Treatments for Hemophilia "We have seen shifting toward the prevention of ...

  20. Previously undiagnosed hemophilia patient with intracerebral hemorrhage

    Directory of Open Access Journals (Sweden)

    Eray Atalay

    2015-09-01

    Full Text Available Intracranial bleeding in hemophilia patients is a rare but a mortal complication. Diagnosis of hemophilia in adulthood is an uncommon occurrence. In this case report an adult patient with intracranial hemorrhage is presented.

  1. Unraveling the genetics of inhibitors in hemophilia

    NARCIS (Netherlands)

    Gouw, Samantha C.; Fijnvandraat, Karin

    2013-01-01

    In this issue of Blood, Astermark et al have identified novel genetic markers of inhibitory antibody formation in hemophilia patients that may ultimately lead to prediction and even prevention of this severe complication of hemophilia treatment.(1)

  2. Myositis ossificans in hemophilia

    Energy Technology Data Exchange (ETDEWEB)

    Vas, W.; Cockshott, W.P.; Martin, R.F.; Pai, M.K.; Walker, I.

    1981-10-01

    A review of the radiographs of 60 hemophilia patients showed nine (15%) with ectopic new bone formation. Three of these patients had multiple sites of involvement. The high frequency discovered in this series contrasts with the paucity of descriptions to be found in the literature. This process of myositis ossificans affects the lower half of the body and probably represents dysplastic metaplasia developing at the site of an intramuscular hematoma when remote from bone, as well as ossification of hemorrhagic lesions related to the periosteum. In conventional radiographs anatomic localization of bone foci is difficult, but use of computed tomography permits precise identification of the affected muscle. There is negligible disability associated with this condition.

  3. Myositis ossificans in hemophilia

    International Nuclear Information System (INIS)

    Vas, W.; Cockshott, W.P.; Martin, R.F.; Pai, M.K.; Walker, I.

    1981-01-01

    A review of the radiographs of 60 hemophilia patients showed nine (15%) with ectopic new bone formation. Three of these patients had multiple sites of involvement. The high frequency discovered in this series contrasts with the paucity of descriptions to be found in the literature. This process of myositis ossificans affects the lower half of the body and probably represents dysplastic metaplasia developing at the site of an intramuscular hematoma when remote from bone, as well as ossification of hemorrhagic lesions related to the periosteum. In conventional radiographs anatomic localization of bone foci is difficult, but use of computed tomography permits precise identification of the affected muscle. There is negligible disability associated with this condition. (orig.)

  4. Inhibitor development and mortality in non-severe hemophilia A.

    Science.gov (United States)

    Eckhardt, C L; Loomans, J I; van Velzen, A S; Peters, M; Mauser-Bunschoten, E P; Schwaab, R; Mazzucconi, M G; Tagliaferri, A; Siegmund, B; Reitter-Pfoertner, S E; van der Bom, J G; Fijnvandraat, K

    2015-07-01

    The life expectancy of non-severe hemophilia A (HA) patients equals the life expectancy of the non-hemophilic population. However, data on the effect of inhibitor development on mortality and on hemophilia-related causes of death are scarce. The development of neutralizing factor VIII antibodies in non-severe HA patients may dramatically change their clinical outcome due to severe bleeding complications. We assessed the association between the occurrence of inhibitors and mortality in patients with non-severe HA. In this retrospective cohort study, clinical data and vital status were collected for 2709 non-severe HA patients (107 with inhibitors) who were treated between 1980 and 2011 in 34 European and Australian centers. Mortality rates for patients with and without inhibitors were compared. During 64,200 patient-years of follow-up, 148 patients died (mortality rate, 2.30 per 1000 person-years; 95% confidence interval (CI), 1.96-2.70) at a median age of 64 years (interquartile range [IQR], 49-76). In 62 patients (42%) the cause of death was hemophilia related. Sixteen inhibitor patients died at a median age of 71 years (IQR, 60-81). In ten patients the inhibitor was present at time of death; seven of them died of severe bleeding complications. The all-cause mortality rate in inhibitor patients was > 5 times increased compared with that for those without inhibitors (age-adjusted mortality rate ratio, 5.6). Inhibitor development in non-severe hemophilia is associated with increased mortality. High rates of hemophilia-related mortality in this study indicate that non-severe hemophilia is not mild at all and stress the importance of close follow-up for these patients. © 2015 International Society on Thrombosis and Haemostasis.

  5. Looking good or doing better? Patterns of decoupling in the implementation of clinical directorates.

    Science.gov (United States)

    Mascia, Daniele; Morandi, Federica; Cicchetti, Americo

    2014-01-01

    The interest toward hospital restructuring has risen significantly in recent years. In spite of its potential benefits, often organizational restructuring in health care produces unexpected consequences. Extant research suggests that institutional theory provides a powerful theoretical lens through which hospital restructuring can be described and explained. According to this perspective, the effectiveness of change is strongly related to the extent to which innovative arrangements, tools, or practices are adopted and implemented within hospitals. Whenever these new arrangements require a substantial modification of internal processes and practices, resistance to implementation emerges and organizational change is likely to become neutralized. This study analyzes how hospital organizations engage in decoupling by adopting but not implementing a new organizational model named clinical directorate. We collected primary data on the diffusion of the clinical directorate model, which was mandated by law in the Italian National Health Service to improve hospital services. We surveyed the adoption and implementation of the clinical directorate model by monitoring the presence of clinical governance tools (measures for the quality improvement of hospital services) within single directorates. In particular, we compared hospitals that adopted the model before (early adopters) or after (later adopters) the mandate was introduced. Hospitals were engaged in decoupling by adopting the new arrangement but not implementing internal practices and tools for quality improvement. The introduction of the law significantly affected the decoupling, with late-adopter hospitals being less likely to implement the adopted model. The present research shows that changes in quality improvement processes may vary in relation to policy makers' interventions aimed at boosting the adoption of new hospital arrangements. Hospital administrators need to be aware and identify the institutional changes

  6. Manual therapy in the treatment of patients with hemophilia B and inhibitor.

    Science.gov (United States)

    Cuesta-Barriuso, Rubén; Trelles-Martínez, Roberto O

    2018-01-22

    The main clinical manifestations of hemophilia are muscle and joint bleeding. Recurrent bleeding leads to a degenerative process known as hemophilic arthropathy. The development of inhibitors (antibodies against FVIII/FIX concentrates) is the main complication in the treatment of hemophilia. The objective was to assess the safety and efficacy of manual therapy treatment in a patient with hemophilia and inhibitor. A 26-year-old patient with hemophilia B and inhibitor received physiotherapy treatment based on manual therapy for 3 months, with a frequency of 2 sessions per week. The joint status was evaluated using the Hemophilia Joint Health Score; pain was assessed with the Visual Analog Scale; and the range of movement was evaluated using a universal goniometer. The patient developed no joint bleeding in the knees or ankles as a result of the physiotherapy treatment. Following treatment, improvements were noted in the range of movement of knees and ankles, the perception of pain in both knees, and ankle functionality. Until now, manual therapy using joint traction was contraindicated in patients with hemophilia and inhibitor, as it was feared to cause possible joint bleeding. This is the first case study to address the safety and efficacy of manual therapy in a patient with hemophilia and an inhibitor. The results of this study may help to establish which manual therapy treatments are indicated in patients with hemophilic arthropathy and inhibitors. Thus, a physiotherapy program based on manual therapy may be safe in patients with hemophilia and inhibitor and such therapy may improve joint condition, pain, and joint range of motion in patients with hemophilia and inhibitor. Randomized clinical trials are needed to confirm the results of this case study.

  7. Neonatal hemophilia: a rare presentation

    Directory of Open Access Journals (Sweden)

    Nuno Ferreira

    2015-12-01

    Full Text Available Hemophilia A is a X-linked hereditary condition that lead to decreased factor VIII activity, occurs mainly in males. Decreased factor VIII activity leads to increased risk of bleeding events. During neonatal period, diagnosis is made after post-partum bleeding complication or unexpected bleeding after medical procedures. Subgaleal hemorrhage during neonatal period is a rare, severe extracranial bleeding with high mortality and usually related to traumatic labor or coagulation disorders. Subgaleal hemorrhage complications result from massive bleeding. We present a neonate with unremarkable family history and uneventful pregnancy with a vaginal delivery with no instrumentation, presenting with severe subgaleal bleeding at 52 hours of life. Aggressive support measures were implemented and bleeding managed. The unexpected bleeding lead to a coagulation study and the diagnosis of severe hemophilia A. There were no known sequelae. This case shows a rare hemophilia presentation reflecting the importance of coagulation studies when faced with unexplained severe bleeding.

  8. The influence of prophylactic factor VIII in severe hemophilia A

    Science.gov (United States)

    Gissel, Matthew; Whelihan, Matthew F; Ferris, Lauren A; Mann, Kenneth G; Rivard, Georges E; Brummel-Ziedins, Kathleen E

    2013-01-01

    Introduction Hemophilia A individuals displaying a similar genetic defect have heterogeneous clinical phenotypes. Aim To evaluate the underlying effect of exogenous factor (f)VIII on tissue factor (Tf)-initiated blood coagulation in severe hemophilia utilizing both empirical and computational models. Methods We investigated twenty-five clinically severe hemophilia A patients. All individuals were on fVIII prophylaxis and had not received fVIII from 0.25 to 4 days prior to phlebotomy. Coagulation was initiated by the addition of Tf to contact-pathway inhibited whole blood ± an anti-fVIII antibody. Aliquots were quenched over 20 min and analyzed for thrombin generation and fibrin formation. Coagulation factor levels were obtained and used to computationally predict thrombin generation with fVIII set to either zero or its value at the time of the draw. Results Due to prophylactic fVIII, at the time of the blood draw, the individuals had fVIII levels that ranged from hemophilia A. The combination of each individual's coagulation factors (outside of fVIII) determine each individual's baseline thrombin potential and may affect bleeding risk. PMID:21899664

  9. Surgeon Involvement in Pre-Clinical Medical Education: Attitudes of Directors of Education

    Directory of Open Access Journals (Sweden)

    Simon Turner

    2012-04-01

    Full Text Available Background: Application rates to surgical residencies have shown a downward trend recently. Introducing students to surgeons early in medical school can increase interest in surgery as a career and enhance the instruction of important surgical topics. Directors of undergraduate medical education have unique insight and influence regarding the participation of surgeons in pre-clinical education. Methods: To understand the attitudes of these educators towards surgeons as teachers in pre-clinical programs, a survey was administered to the directors of undergraduate medical education at each of the English-language medical schools in Canada. Results: Educators estimate the participation of surgeons in all categories of pre-clinical education to be low, despite being valuable, and think that it should be increased. The most significant barrier to participation identified was a lack of surgeons’ time. Conclusions: Despite the value of surgeons participating in pre-clinical education, their rate of participation is low. Steps should be taken to facilitate the involvement of surgeons in this phase of education, which may lead to improved education for students and increased student interest in surgery residencies.

  10. THROMBIN GENERATION AND BLEEDING IN HEMOPHILIA A

    Science.gov (United States)

    Brummel-Ziedins, Kathleen E.; Whelihan, Matthew F.; Gissel, Matthew; Mann, Kenneth G.; Rivard, Georges E.

    2012-01-01

    Introduction Hemophilia A displays phenotypic heterogeneity with respect to clinical severity. Aim To determine if tissue factor (TF)-initiated thrombin generation profiles in whole blood in the presence of corn trypsin inhibitor (CTI) are predictive of bleeding risk in hemophilia A. Methods We studied factor(F) VIII deficient individuals (11 mild, 4 moderate and 12 severe) with a well-characterized five-year bleeding history that included hemarthrosis, soft tissue hematoma and annual FVIII concentrate usage. This clinical information was used to generate a bleeding score. The bleeding scores (range 0–32) were separated into three groups (bleeding score groupings: 0, 0 and ≤9.6, >9.6), with the higher bleeding tendency having a higher score. Whole blood collected by phlebotomy and contact pathway suppressed by 100μg/mL CTI was stimulated to react by the addition of 5pM TF. Reactions were quenched at 20min by inhibitors. Thrombin generation, determined by ELISA for thrombin – antithrombin was evaluated in terms of clot time (CT), maximum level (MaxL) and maximum rate (MaxR) and compared to the bleeding score. Results Data are shown as the mean±SD. MaxL was significantly different (phemophilia A. PMID:19563500

  11. Emerging drugs for hemophilia B.

    Science.gov (United States)

    Mannucci, Pier Mannuccio; Franchini, Massimo

    2014-09-01

    Hemophilia B is a rare congenital bleeding disorder characterized by a deficiency of coagulation factor IX (FIX). Hemophilia B patients experience mild-to-severe bleeding complications according to the degree of FIX defect. Prophylaxis, with regular infusion of FIX concentrates, is nowadays, the mainstay of hemophilia care. However, because the relatively short half-life of such products necessitates frequent infusions and thus makes patients' adherence difficult, a number of strategies have been implemented to improve the pharmacokinetics of FIX clotting factors. This review summarizes the main results of Phase I/II and III studies on new FIX molecules engineered to have a longer half-life. Several technologies are being applied to extend FIX half-life, including Fc fusion, recombinant (r) albumin fusion and the addition of PEG polymers. By prolonging the FIX half-life up to 5 times, long-acting FIX products are expected to substantially improve the management of hemophilia B patients, allowing less frequent infusions and improving patients' adherence to prophylactic regimens and individualized treatments. Some of them are at an advanced stage of development, such as the rFIX-Fc which has been launched in March 2014. Along with the ongoing Phase III trials, long-term post-marketing surveillance studies are needed to assess their safety and effectiveness and their impact on patients' quality of life.

  12. Using the Hemophilia Joint Health Score for assessment of children: Reliability of the Spanish version.

    Science.gov (United States)

    R, Cuesta-Barriuso; A, Torres-Ortuño; S, Pérez-Alenda; J, Carrasco Juan; F, Querol; J, Nieto-Munuera; Ja, López-Pina

    2018-02-27

    Numerous measuring instruments for the evaluation of hemophilic arthropathy have been developed. One of the most used systems is the Hemophilia Joint Health Score (HJHS) given its sensitivity to clinical changes appearing in the joints because of recurrent hemarthrosis. Assessing the interrater reliability, using the Spanish version of the HJHS (version 2.1) in children with hemophilia. Reliability study to assess the interrater reliability of the Spanish version of HJHS. A sample of 36 children aged 7-13 years diagnosed with hemophilia A or B was used. Two physiotherapists performed physical assessments with the Spanish version of the HJHS. Descriptive statistics (range, mean, standard deviation) and the analysis of interrater reliability were calculated. The interrater reliability was heterogeneous since the Kappa coefficient range (ĸ), although significant (p reliability of the Spanish population version of the HJHS is high. This scale should be used generically in evaluating musculoskeletal pediatric patients with hemophilia.

  13. Biodistribution of Liver-Derived Mesenchymal Stem Cells After Peripheral Injection in a Hemophilia A Patient.

    Science.gov (United States)

    Sokal, Etienne M; Lombard, Catherine Anne; Roelants, Véronique; Najimi, Mustapha; Varma, Sharat; Sargiacomo, Camillo; Ravau, Joachim; Mazza, Giuseppe; Jamar, François; Versavau, Julia; Jacobs, Vanessa; Jacquemin, Marc; Eeckhoudt, Stéphane; Lambert, Catherine; Stéphenne, Xavier; Smets, Françoise; Hermans, Cédric

    2017-08-01

    With the exception of liver transplantation, there is no cure for hemophilia, which is currently managed by preemptive replacement therapy. Liver-derived stem cells are in clinical development for inborn and acquired liver diseases and could represent a curative treatment for hemophilia A. The liver is a major factor VIII (FVIII) synthesis site, and mesenchymal stem cells have been shown to control joint bleeding in animal models of hemophilia. Adult-derived human liver stem cells (ADHLSCs) have mesenchymal characteristics and have been shown able to engraft in and repopulate both animal and human livers. Thus, the objectives were to evaluate the potency of ADHLSCs to control bleeding in a hemophilia A patient and assess the biodistribution of the cells after intravenous injection. A patient suffering from hemophilia A was injected with repeated doses of ADHLSCs via a peripheral vein (35 million In-oxine-labeled cells, followed by 125 million cells the next day, and 3 infusions of 250 million cells every 2 weeks thereafter; total infusion period, 50 days). After cell therapy, we found a temporary (15 weeks) decrease in the patient's FVIII requirements and severe bleeding complications, despite a lack of increase in circulating FVIII. The cells were safely administered to the patient via a peripheral vein. Biodistribution analysis revealed an initial temporary entrapment of the cells in the lungs, followed by homing to the liver and to a joint afflicted with hemarthrosis. These results suggest the potential use of ADHLSCs in the treatment of hemophilia A.

  14. Factoring nonviral gene therapy into a cure for hemophilia A.

    Science.gov (United States)

    Gabrovsky, Vanessa; Calos, Michele P

    2008-10-01

    Gene therapy for hemophilia A has fallen short of success despite several clinical trials conducted over the past decade. Challenges to its success include vector immunogenicity, insufficient transgene expression levels of Factor VIII, and inhibitor antibody formation. Gene therapy has been dominated by the use of viral vectors, as well as the immunogenic and oncogenic concerns that accompany these strategies. Because of the complexity of viral vectors, the development of nonviral DNA delivery methods may provide an efficient and safe alternative for the treatment of hemophilia A. New types of nonviral strategies, such as DNA integrating vectors, and the success of several nonviral animal studies, suggest that nonviral gene therapy has curative potential and justifies its clinical development.

  15. Novel approach to genetic analysis and results in 3000 hemophilia patients enrolled in the My Life, Our Future initiative

    Science.gov (United States)

    Johnsen, Jill M.; Fletcher, Shelley N.; Huston, Haley; Roberge, Sarah; Martin, Beth K.; Kircher, Martin; Josephson, Neil C.; Shendure, Jay; Ruuska, Sarah; Koerper, Marion A.; Morales, Jaime; Pierce, Glenn F.; Aschman, Diane J.

    2017-01-01

    Hemophilia A and B are rare, X-linked bleeding disorders. My Life, Our Future (MLOF) is a collaborative project established to genotype and study hemophilia. Patients were enrolled at US hemophilia treatment centers (HTCs). Genotyping was performed centrally using next-generation sequencing (NGS) with an approach that detected common F8 gene inversions simultaneously with F8 and F9 gene sequencing followed by confirmation using standard genotyping methods. Sixty-nine HTCs enrolled the first 3000 patients in under 3 years. Clinically reportable DNA variants were detected in 98.1% (2357/2401) of hemophilia A and 99.3% (595/599) of hemophilia B patients. Of the 924 unique variants found, 285 were novel. Predicted gene-disrupting variants were common in severe disease; missense variants predominated in mild–moderate disease. Novel DNA variants accounted for ∼30% of variants found and were detected continuously throughout the project, indicating that additional variation likely remains undiscovered. The NGS approach detected >1 reportable variants in 36 patients (10 females), a finding with potential clinical implications. NGS also detected incidental variants unlikely to cause disease, including 11 variants previously reported in hemophilia. Although these genes are thought to be conserved, our findings support caution in interpretation of new variants. In summary, MLOF has contributed significantly toward variant annotation in the F8 and F9 genes. In the near future, investigators will be able to access MLOF data and repository samples for research to advance our understanding of hemophilia. PMID:29296726

  16. Understanding patient preferences and willingness to pay for hemophilia therapies

    Directory of Open Access Journals (Sweden)

    Chaugule SS

    2015-11-01

    Full Text Available Shraddha S Chaugule,1 Joel W Hay,1 Guy Young2 1Department of Clinical Pharmacy, Pharmaceutical Economics and Policy, University of Southern California, 2Hemostasis and Thrombosis Center, Children’s Hospital Los Angeles, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA Background: Despite clearly improved clinical outcomes for prophylaxis compared to on-demand therapy, on average only 56% of patients diagnosed with severe hemophilia receive prophylactic factor replacement therapy in the US. Prophylaxis rates generally drop as patients transition from childhood to adulthood, partly due to patients becoming less adherent when they reach adulthood. Assessment of patient preferences is important because these are likely to translate into increased treatment satisfaction and adherence. In this study, we assessed preferences and willingness to pay (WTP for on-demand, prophylaxis, and longer acting prophylaxis therapies in a sample of US hemophilia patients.Methods: Adult US hemophilia patients and caregivers (N=79 completed a discrete-choice survey that presented a series of trade-off questions, each including a pair of hypothetical treatment profiles. Using a mixed logit model for analysis, we compared the relative importance of five treatment characteristics: 1 out-of-pocket treatment costs (paid by patients, 2 factor dose adjustment, 3 treatment side effects, 4 availability of premixed factor, and 5 treatment effectiveness and dosing frequency. Based on these attribute estimates, we calculated patients’ WTP.Results: Out-of-pocket treatment costs (P<0.001, side effects (P<0.001, and treatment effectiveness and dosing frequency (P<0.001 were found to be statistically significant in the model. Patients were willing to pay US $410 (95% confidence interval: $164–$656 out of pocket per month for thrice-weekly prophylaxis therapy compared to on-demand therapy and $360 (95% confidence interval: $145–$575 for a switch

  17. What is Hemophilia?

    Science.gov (United States)

    ... In general, some safe physical activities are swimming, biking (wearing a helmet), walking, and golf. To prevent ... their experiences with clinical research. More Information Related Health Topics Blood Tests Von Willebrand Disease Other Resources ...

  18. Clinical Reasoning Education at US Medical Schools: Results from a National Survey of Internal Medicine Clerkship Directors.

    Science.gov (United States)

    Rencic, Joseph; Trowbridge, Robert L; Fagan, Mark; Szauter, Karen; Durning, Steven

    2017-11-01

    Recent reports, including the Institute of Medicine's Improving Diagnosis in Health Care, highlight the pervasiveness and underappreciated harm of diagnostic error, and recommend enhancing health care professional education in diagnostic reasoning. However, little is known about clinical reasoning curricula at US medical schools. To describe clinical reasoning curricula at US medical schools and to determine the attitudes of internal medicine clerkship directors toward teaching of clinical reasoning. Cross-sectional multicenter study. US institutional members of the Clerkship Directors in Internal Medicine (CDIM). Examined responses to a survey that was emailed in May 2015 to CDIM institutional representatives, who reported on their medical school's clinical reasoning curriculum. The response rate was 74% (91/123). Most respondents reported that a structured curriculum in clinical reasoning should be taught in all phases of medical education, including the preclinical years (64/85; 75%), clinical clerkships (76/87; 87%), and the fourth year (75/88; 85%), and that more curricular time should be devoted to the topic. Respondents indicated that most students enter the clerkship with only poor (25/85; 29%) to fair (47/85; 55%) knowledge of key clinical reasoning concepts. Most institutions (52/91; 57%) surveyed lacked sessions dedicated to these topics. Lack of curricular time (59/67, 88%) and faculty expertise in teaching these concepts (53/76, 69%) were identified as barriers. Internal medicine clerkship directors believe that clinical reasoning should be taught throughout the 4 years of medical school, with the greatest emphasis in the clinical years. However, only a minority reported having teaching sessions devoted to clinical reasoning, citing a lack of curricular time and faculty expertise as the largest barriers. Our findings suggest that additional institutional and national resources should be dedicated to developing clinical reasoning curricula to improve

  19. Progress in the contemporary management of hemophilia: The new issue of patient aging.

    Science.gov (United States)

    Mannucci, Pier Mannuccio; Iacobelli, Massimo

    2017-09-01

    The management of inherited coagulation disorders such as hemophilia A and B has witnessed dramatic progresses since the last few decades of the last century. Accordingly, persons with hemophilia (PWH) now enjoy a life expectancy at birth not different from that of males in the general population, at least in high income countries. Nowadays, a substantial proportion of PWH are aging, like their peers in the general population. This outstanding progress is accompanied by problems that are in part similar to those of any old person (multiple concomitant diseases and the resulting intake of multiple drugs other than those specific for hemophilia treatment). In addition, older PWH suffer from the consequences of the comorbidities that developed when their treatment was at the same time poorly available and unsafe. Typical hemophilia comorbidities affect the musculoskeletal system following joint and muscle bleeds, but also the liver and kidney are often impaired due to previous bloodborne infections such as viral hepatitis and HIV. Thus, the comorbidities of hemophilia superimposed on the multimorbidity and polypharmacy associated with aging create peculiar problems in the current management of these patients, that demand the coordinated holistic intervention of internists, geriatricians and clinical pharmacologists in addition to the care traditionally provided by pediatricians and hematologists. Copyright © 2017 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

  20. Treatment of hemophilia in the near future.

    Science.gov (United States)

    Peyvandi, Flora; Garagiola, Isabella

    2015-11-01

    Advancements and debacles have characterized hemophilia treatment over the past 50 years. The 1970s saw the availability of plasma-derived concentrates making prophylaxis and home therapy possible. This optimistic perception changed extremely in the early 1980s, when most people with hemophilia were infected with HIV and hepatitis viruses. Then, also in the 1980s, the rapid progress in molecular biology led to the development of recombinant therapeutic products. This important advancement was a huge technological leap fresh off from the earlier 1980s disaster. Now in the 21st century, the newer bioengineering drugs open a new hopeful phase for the management of hemophilia. The current efforts are concentrated on producing novel coagulation factors with prolonged bioavailability, increased potency, and resistance to inactivation and potentially reduced immunogenicity; this phase of evolution is improving very quickly. 2014 is the year of marketing approval by the Food and Drug Administration of the first bioengineered FVIII and FIX long-acting drugs, using Fc-fusion strategy. This represents the first significant advance in the hemophilia therapy that dramatically transforms patient management by substantially reducing the frequency of injections, improving compliance, and simplifying prophylaxis and, in turn, refining the quality of life of hemophilia patients, offering them a nearly normal life expectancy, particularly to newborns with hemophilia B. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  1. Mortality caused by intracranial bleeding in non-severe hemophilia A patients.

    Science.gov (United States)

    Loomans, J I; Eckhardt, C L; Reitter-Pfoertner, S E; Holmström, M; van Gorkom, B Laros; Leebeek, F W G; Santoro, C; Haya, S; Meijer, K; Nijziel, M R; van der Bom, J G; Fijnvandraat, K

    2017-06-01

    Essentials Data on bleeding-related causes of death in non-severe hemophilia A (HA) patients are scarce. Such data may provide new insights into areas of care that can be improved. Non-severe HA patients have an increased risk of dying from intracranial bleeding. This demonstrates the need for specialized care for non-severe HA patients. Background Non-severe hemophilia (factor VIII concentration [FVIII:C] of 2-40 IU dL -1 ) is characterized by a milder bleeding phenotype than severe hemophilia A. However, some patients with non-severe hemophilia A suffer from severe bleeding complications that may result in death. Data on bleeding-related causes of death, such as fatal intracranial bleeding, in non-severe patients are scarce. Such data may provide new insights into areas of care that can be improved. Aims To describe mortality rates, risk factors and comorbidities associated with fatal intracranial bleeding in non-severe hemophilia A patients. Methods We analyzed data from the INSIGHT study, an international cohort study of all non-severe hemophilia A patients treated with FVIII concentrates during the observation period between 1980 and 2010 in 34 participating centers across Europe and Australia. Clinical data and vital status were collected from 2709 patients. We report the standardized mortality rate for patients who suffered from fatal intracranial bleeding, using a general European male population as a control population. Results Twelve per cent of the 148 deceased patients in our cohort of 2709 patients died from intracranial bleeding. The mortality rate between 1996 and 2010 for all ages was 3.5-fold higher than that in the general population (95% confidence interval [CI] 2.0-5.8). Patients who died from intracranial bleeding mostly presented with mild hemophilia without clear comorbidities. Conclusion Non-severe hemophilia A patients have an increased risk of dying from intracranial bleeding in comparison with the general population. This demonstrates the

  2. A newborn with moderate hemophilia A with severe intracranial and extracranial hemorrhage: A case report

    Directory of Open Access Journals (Sweden)

    Şebnem Kader

    2017-09-01

    Full Text Available Intracranial hemorrhage among term newborns is a rare clinical condition with high morbidity and mortality. Although major bleeding is relatively uncommon, the incidence of intracranial hemorrhage in hemophilic children is higher during the first few days of life than at any other stage in childhood, which relates to the trauma of delive ry. Here, we reported a newborn case diagnosed with moderate hemophilia A, without the presence of a positive family history of hemophilia and presenting with intracranial and extracranial hemorrhage and we aimed to emphasize that the early diagnosis and replacement therapy carries an essential importance.

  3. The Utilization of Rehabilitation in Patients with Hemophilia A in Taiwan: A Nationwide Population-Based Study.

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    Chien-Min Chen

    Full Text Available Rehabilitation plays an important role in the physical health of patients with hemophilia. However, comprehensive information regarding the utilization of rehabilitation for such patients remains scarce.This population-based study aimed to examine the characteristics, trends, and most important factors affecting rehabilitation usage in patients with hemophilia A using a nationwide database in Taiwan.Data from 777 patients with hemophilia A who were registered in the National Health Insurance Research Database between 1998 and 2008 were analyzed using SAS 9.0.Musculoskeletal or nervous system-related surgical procedures and clotting factor VIII concentrate costs were identified as factors affecting rehabilitation usage; musculoskeletal or nervous system-related surgical procedures (odds ratio = 3.788; P < 0.001 were the most important predictor of whether a patient with hemophilia A would use rehabilitation services. Joint disorders, arthropathies, bone and cartilage disorders, intracranial hemorrhage, and brain trauma were common diagnoses during rehabilitation use. The costs of physical therapy (physiotherapy comprised the majority (71.2% of rehabilitation therapy categories. Increasingly, rehabilitation therapy was performed at physician clinics. The total rehabilitation costs were <0.1% of the total annual medical costs.Musculoskeletal or nervous system-related surgical procedures and increased use of clotting factor VIII concentrate affect the rehabilitation utilization of patients with hemophilia A the most. The findings in this study could help clinicians comprehensively understand the rehabilitation utilization of patients with hemophilia A.

  4. Effects of FVIII immunity on hepatocyte and hematopoietic stem cell–directed gene therapy of murine hemophilia A

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    Allison M Lytle

    2016-01-01

    Full Text Available Immune responses to coagulation factors VIII (FVIII and IX (FIX represent primary obstacles to hemophilia treatment. Previously, we showed that hematopoietic stem cell (HSC retroviral gene therapy induces immune nonresponsiveness to FVIII in both naive and preimmunized murine hemophilia A settings. Liver-directed adeno-associated viral (AAV-FIX vector gene transfer achieved similar results in preclinical hemophilia B models. However, as clinical immune responses to FVIII and FIX differ, we investigated the ability of liver-directed AAV-FVIII gene therapy to affect FVIII immunity in hemophilia A mice. Both FVIII naive and preimmunized mice were administered recombinant AAV8 encoding a liver-directed bioengineered FVIII expression cassette. Naive animals receiving high or mid-doses subsequently achieved near normal FVIII activity levels. However, challenge with adjuvant-free recombinant FVIII induced loss of FVIII activity and anti-FVIII antibodies in mid-dose, but not high-dose AAV or HSC lentiviral (LV vector gene therapy cohorts. Furthermore, unlike what was shown previously for FIX gene transfer, AAV-FVIII administration to hemophilia A inhibitor mice conferred no effect on anti-FVIII antibody or inhibitory titers. These data suggest that functional differences exist in the immune modulation achieved to FVIII or FIX in hemophilia mice by gene therapy approaches incorporating liver-directed AAV vectors or HSC-directed LV.

  5. Effects of FVIII immunity on hepatocyte and hematopoietic stem cell–directed gene therapy of murine hemophilia A

    Science.gov (United States)

    Lytle, Allison M; Brown, Harrison C; Paik, Na Yoon; Knight, Kristopher A; Wright, J Fraser; Spencer, H Trent; Doering, Christopher B

    2016-01-01

    Immune responses to coagulation factors VIII (FVIII) and IX (FIX) represent primary obstacles to hemophilia treatment. Previously, we showed that hematopoietic stem cell (HSC) retroviral gene therapy induces immune nonresponsiveness to FVIII in both naive and preimmunized murine hemophilia A settings. Liver-directed adeno-associated viral (AAV)-FIX vector gene transfer achieved similar results in preclinical hemophilia B models. However, as clinical immune responses to FVIII and FIX differ, we investigated the ability of liver-directed AAV-FVIII gene therapy to affect FVIII immunity in hemophilia A mice. Both FVIII naive and preimmunized mice were administered recombinant AAV8 encoding a liver-directed bioengineered FVIII expression cassette. Naive animals receiving high or mid-doses subsequently achieved near normal FVIII activity levels. However, challenge with adjuvant-free recombinant FVIII induced loss of FVIII activity and anti-FVIII antibodies in mid-dose, but not high-dose AAV or HSC lentiviral (LV) vector gene therapy cohorts. Furthermore, unlike what was shown previously for FIX gene transfer, AAV-FVIII administration to hemophilia A inhibitor mice conferred no effect on anti-FVIII antibody or inhibitory titers. These data suggest that functional differences exist in the immune modulation achieved to FVIII or FIX in hemophilia mice by gene therapy approaches incorporating liver-directed AAV vectors or HSC-directed LV. PMID:26909355

  6. The Hemophilia Games: An Experiment in Health Education Planning.

    Science.gov (United States)

    National Heart and Lung Inst. (DHEW/PHS), Bethesda, MD.

    The Hemophilia Health Education Planning Project was designed to (1) create a set of tools useful in hemophilia planning and education, and (2) create a planning model for other diseases with similar factors. The project used the game-simulations technique which was felt to be particularly applicable to hemophilia health problems, since as a…

  7. Hemophilia Care in the Pediatric Age

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    Marta Bertamino

    2017-05-01

    Full Text Available Hemophilia is the most common of the severe bleeding disorders and if not properly managed since early infancy can lead to chronic disease and lifelong disabilities. However, it enjoys the most efficacious and safe treatment among the most prevalent monogenic disorders. Hemophilia should be considered in the neonatal period in the case of unusual bleeding or in the case of positive family history. Later, hemophilia should be suspected mainly in males because of abnormal bruising/bleeding or unusual bleeding following invasive procedures—for example, tonsillectomy or circumcision. Prophylactic treatment that is started early with clotting-factor concentrates has been shown to prevent hemophilic arthropathy and is, therefore, the gold standard of care for hemophilia A and B in most countries with adequate resources. Central venous access catheters and arterovenous fistulas play an important role in the management of hemophilia children requiring repeated and/or urgent administration of coagulation factor concentrates. During childhood and adolescence, personalized treatment strategies that suit the patient and his lifestyle are essential to ensure optimal outcomes. Physical activity is important and can contribute to better coordination, endurance, flexibility and strength. The present article focuses also on questions frequently posed to pediatric hematologists like vaccinations, day-care/school access and dental care.

  8. Comparing thrombin generation in patients with hemophilia A and patients on vitamin K antagonists

    NARCIS (Netherlands)

    de Koning, M L Y; Fischer, K; de Laat, B; Huisman, A; Ninivaggi, M; Schutgens, R E G

    Essentials: It is unknown if hemophilia patients with atrial fibrillation need anticoagulation. Endogenous thrombin potentials (ETP) in hemophilia patients and patients on coumarins were compared. Severe hemophilia patients had comparable ETP to therapeutic international normalized ratio (INR). In

  9. AAV5-Factor VIII Gene Transfer in Severe Hemophilia A.

    Science.gov (United States)

    Rangarajan, Savita; Walsh, Liron; Lester, Will; Perry, David; Madan, Bella; Laffan, Michael; Yu, Hua; Vettermann, Christian; Pierce, Glenn F; Wong, Wing Y; Pasi, K John

    2017-12-28

    Patients with hemophilia A rely on exogenous factor VIII to prevent bleeding in joints, soft tissue, and the central nervous system. Although successful gene transfer has been reported in patients with hemophilia B, the large size of the factor VIII coding region has precluded improved outcomes with gene therapy in patients with hemophilia A. We infused a single intravenous dose of a codon-optimized adeno-associated virus serotype 5 (AAV5) vector encoding a B-domain-deleted human factor VIII (AAV5-hFVIII-SQ) in nine men with severe hemophilia A. Participants were enrolled sequentially into one of three dose cohorts (low dose [one participant], intermediate dose [one participant], and high dose [seven participants]) and were followed through 52 weeks. Factor VIII activity levels remained at 3 IU or less per deciliter in the recipients of the low or intermediate dose. In the high-dose cohort, the factor VIII activity level was more than 5 IU per deciliter between weeks 2 and 9 after gene transfer in all seven participants, and the level in six participants increased to a normal value (>50 IU per deciliter) that was maintained at 1 year after receipt of the dose. In the high-dose cohort, the median annualized bleeding rate among participants who had previously received prophylactic therapy decreased from 16 events before the study to 1 event after gene transfer, and factor VIII use for participant-reported bleeding ceased in all the participants in this cohort by week 22. The primary adverse event was an elevation in the serum alanine aminotransferase level to 1.5 times the upper limit of the normal range or less. Progression of preexisting chronic arthropathy in one participant was the only serious adverse event. No neutralizing antibodies to factor VIII were detected. The infusion of AAV5-hFVIII-SQ was associated with the sustained normalization of factor VIII activity level over a period of 1 year in six of seven participants who received a high dose, with

  10. Hemophilia A in Brazil – epidemiology and treatment developments

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    Ferreira AA

    2014-09-01

    Full Text Available Adriana Aparecida Ferreira,1 Isabel Cristina Gonçalves Leite,2 Maria Teresa Bustamante-Teixeira,2 Maximiliano Ribeiro Guerra2 1Foundation and Center for Hematology and Hemotherapy of Minas Gerais (Hemominas, 2Department of Collective Health, Federal University of Juiz de Fora, Juiz de Fora, Minas Gerais, BrazilAbstract: Hemophilia A is an inherited disorder characterized by deficiency of coagulation factor VIII, which predisposes patients to bleeding events. Treatment is based on replacement of the deficient factor, in a therapeutic or prophylactic manner. Brazil is the country with the third largest population of people with hemophilia, for which the public health system provides free comprehensive care. Maintaining an updated registry of patients, documenting the prevalence of complications, and assessing the effectiveness of resource use are indispensable elements in the design of a well-coordinated national program. According to sociodemographic, clinical, and laboratory data collected by the computerized Brazilian system on coagulopathies, in June 2013, there were 9,122 registered patients with hemophilia A in Brazil, of which 36.1% had a severe form of the disease. Clotting factor inhibitors were present in 7.5%, but 25.7% of records did not provide this type of data. Around 70% of the patients belonged to the economically active population, being between 15 and 59 years old. Infection by the human immunodeficiency virus was present in 23.4% of the patients tested and infection by hepatitis C virus antibodies in 59.3%. Infection by the hepatitis B virus and human T-lymphotropic virus was also reported. The high percentage of incomplete records regarding serological data shows the fragility of the information system to date. There was also no information available on the prevalence of permanent or disabling joint damage. Although few hemophiliacs receive adequate care in developing countries, and despite Brazil exhibiting great social

  11. Ambulatory-based education in internal medicine: current organization and implications for transformation. Results of a national survey of resident continuity clinic directors.

    Science.gov (United States)

    Nadkarni, Mohan; Reddy, Siddharta; Bates, Carol K; Fosburgh, Blair; Babbott, Stewart; Holmboe, Eric

    2011-01-01

    Many have called for ambulatory training redesign in internal medicine (IM) residencies to increase primary care career outcomes. Many believe dysfunctional, clinic environments are a key barrier to meaningful ambulatory education, but little is actually known about the educational milieu of continuity clinics nationwide. We wished to describe the infrastructure and educational milieu at resident continuity clinics and assess clinic readiness to meet new IM-RRC requirements. National survey of ACGME accredited IM training programs. Directors of academic and community-based continuity clinics. Two hundred and twenty-one out of 365 (62%) of clinic directors representing 49% of training programs responded. Wide variation amongst continuity clinics in size, structure and educational organization exist. Clinics below the 25th percentile of total clinic sessions would not meet RRC-IM requirements for total number of clinic sessions. Only two thirds of clinics provided a longitudinal mentor. Forty-three percent of directors reported their trainees felt stressed in the clinic environment and 25% of clinic directors felt overwhelmed. The survey used self reported data and was not anonymous. A slight predominance of larger clinics and university based clinics responded. Data may not reflect changes to programs made since 2008. This national survey demonstrates that the continuity clinic experience varies widely across IM programs, with many sites not yet meeting new ACGME requirements. The combination of disadvantaged and ill patients with inadequately resourced clinics, stressed residents, and clinic directors suggests that many sites need substantial reorganization and institutional commitment.New paradigms, encouraged by ACGME requirement changes such as increased separation of inpatient and outpatient duties are needed to improve the continuity clinic experience.

  12. Impact of mild to severe hemophilia on education and work by US men, women, and caregivers of children with hemophilia B: The Bridging Hemophilia B Experiences, Results and Opportunities into Solutions (B-HERO-S) study.

    Science.gov (United States)

    Cutter, Susan; Molter, Don; Dunn, Spencer; Hunter, Susan; Peltier, Skye; Haugstad, Kimberly; Frick, Neil; Holot, Natalia; Cooper, David L

    2017-04-01

    The psychosocial impact of hemophilia on work was recently investigated in the Hemophilia Experiences, Results and Opportunities (HERO) study. The findings revealed that hemophilia had an impact for adults with moderate/severe hemophilia and caregivers of children with hemophilia. HERO did not specifically evaluate impact on education in adults/children with mild/moderate hemophilia or the impact on employment of spouses/partners of caregivers of affected children. The Bridging Hemophilia B Experiences, Results and Opportunities into Solutions (B-HERO-S) study evaluated the impact of hemophilia on the lives of adult men/women with mild-severe hemophilia B and caregivers of boys/girls with hemophilia B and their spouses/partners. Many adults with hemophilia B (94%) reported that hemophilia had a negative effect on their ability to complete a formal education, often attributed to the inability to attend or concentrate in school as a result of hemophilia-related bleeding or pain. Most adults with hemophilia B (95%) and caregivers/partners (89%/84%) indicated that hemophilia had a negative impact on employment. Most adults with hemophilia were employed (81%), with construction/manufacturing (35%) as the most frequently reported industry; many worked in jobs requiring manual labor (39%). Of those unemployed, 62% never worked, and those who stopped working reported that they left the workforce due to financial issues (59%), including insurance coverage/co-pays, or hemophilia-related issues (55%). Nearly one-third of caregivers voluntarily left the workforce to care for children with hemophilia. These results suggest a need to focus more effort on career counseling for adults with hemophilia B and caregivers of affected children, especially around mild/moderate hemophilia, as this population may not be as well informed regarding potential impact in school and the workplace. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  13. The benefit of low dose prophylaxis in the treatment of hemophilia: a focus on China.

    Science.gov (United States)

    Wu, Runhui; Luke, Koon Hung

    2017-11-01

    Currently full dose prophylaxis is the standard of care in the treatment of hemophilia (World Federation of Hemophilia). However, the high costs prevent the use of standard or intermediate dose prophylaxis in China and other developing countries. Low dose prophylaxis would be a viable alternative treatment. At present global research data on the use of low dose prophylaxis is limited. Areas covered: Since 2007, China has been developing low dose prophylaxis as a high priority (90 % of moderate and severe hemophilia boys suffer joint disease by age 6 - 9). 11 studies were successfully conducted and published results showing evidence of the benefits of low dose prophylaxis to reduce joint bleeding. This new knowledge has been implemented into clinical practice in China. However the long-term outcome of arthropathy remains unclear and obstacles in execution exist. Expert commentary: In 2016, the first phenotype-based individualized prophylaxis study using four escalating low dose regimens on severe Chinese hemophilia A boys (China Individualized Prophylaxis Study (CHIP China)) launched. Using the previously published and imminent CHIP data, the goal for China is to establish an effective escalating low dose prophylaxis protocol for use in China as a standard of care.

  14. Inhibitor development in nonsevere hemophilia A

    NARCIS (Netherlands)

    Eckhardt, C.L.

    2014-01-01

    Hemophilia A is an X-linked inherited bleeding disorder that affects approximately 1 in 5000 male live births. It is caused by a deficient plasma level of clotting factor VIII and can be treated by the intravenous administration of factor VIII concentrates. A severe complication of the treatment

  15. Bruising and Hemophilia: Accident or Child Abuse?

    Science.gov (United States)

    Johnson, Charles F.; Coury, Daniel L.

    1988-01-01

    Two case histories illustrate the difficulty in evaluating abuse/neglect in children with bleeding problems such as hemophilia. Discussed are guidelines for diagnosis and prevention of abuse, including: screening techniques, the need for protection from environmental trauma, parental stress, evaluation of parents' disciplinary methods, and the…

  16. Hemophilia: The Role of the School Nurse.

    Science.gov (United States)

    Damiano, Mary Lou; And Others

    1980-01-01

    Care of the school student with hemophilia requires a cooperative effort by the health care team. A multidisciplinary approach is suggested for the team, whose members include a hematologist, orthopedist, oral surgeon, geneticist, physical therapist, social worker, and school nurse. (JD)

  17. Immunobiology of inhibitor development in hemophilia A

    NARCIS (Netherlands)

    Fijnvandraat, Karin; Bril, Wendy S.; Voorberg, Jan

    2003-01-01

    After treatment with factor (F) VIII concentrate a significant number of patients with hemophilia A develop inhibitory antibodies that neutralize FVIII. Epitope mapping revealed that antibodies bind to selected regions within the A2, A3, and C2 domains of FVIII. Anti-A2 and anti-A3 antibodies

  18. Interventions for treating acute bleeding episodes in people with acquired hemophilia A.

    Science.gov (United States)

    Zeng, Yan; Zhou, Ruiqing; Duan, Xin; Long, Dan; Yang, Songtao

    2014-08-28

    Acquired hemophilia A is a rare bleeding disorder caused by autoantibodies to coagulation factor VIII (FVIII). In most cases, bleeding episodes are spontaneous and severe at presentation. The optimal hemostatic therapy is controversial. To determine the efficacy of hemostatic therapies for acute bleeds in people with acquired hemophilia A; and to compare different forms of therapy for these bleeds. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2014, Issue 4) and MEDLINE (Ovid) (1948 to 30 April 2014). We searched the conference proceedings of the: American Society of Hematology; European Hematology Association; International Society on Thrombosis and Haemostasis (ISTH); and the European Association for Haemophilia and Allied Disorders (EAHAD) (from 2000 to 30 April 2014). In addition to this we searched clinical trials registers. All randomised controlled trials and quasi-randomised trials of hemostatic therapies for people with acquired hemophilia A, with no restrictions on gender, age or ethnicity. No trials matching the selection criteria were eligible for inclusion. No trials matching the selection criteria were eligible for inclusion. No randomised clinical trials of hemostatic therapies for acquired hemophilia A were found. Thus, we are not able to draw any conclusions or make any recommendations on the optimal hemostatic therapies for acquired hemophilia A based on the highest quality of evidence. GIven that carrying out randomized controlled trials in this field is a complex task, the authors suggest that, while planning randomised controlled trials in which patients can be enrolled, clinicians treating the disease continue to base their choices on alternative, lower quality sources of evidence, which hopefully, in the future, will also be appraised and incorporated in a Cochrane Review.

  19. An extra X does not prevent acquired hemophilia - Pregnancy-associated acquired hemophilia A.

    Science.gov (United States)

    Barg, Assaf A; Livnat, Tami; Kenet, Gili

    2017-03-01

    Acquired hemophilia A (AHA) is a severe bleeding disorder caused by autoantibodies against clotting factor VIII (FVIII). With an estimated annual incidence of 1.3 to 1.5 per million, AHA is a rare disease. An extremely rare form of AHA has been described among women in the peripartum period, and may present with peripartum hemorrhage. Notably, although hemorrhagic symptoms commonly present 1-4 months around delivery, they may occur up to 1 year after parturition. When caring for a mother with AHA it is important to note that Factor VIII inhibitor may be transferred via the placenta from the mother to the fetus. Hence the newborn may also be affected. It is important to increase the awareness of Gynecologists for clinical symptoms and laboratory signs of AHA in order to avoid delayed diagnosis. Treatment may involve use of bypass agents to control hemorrhage, despite the risk of thrombosis, while immunomodulation (with increasing role for Rituximab) may be required to eradicate the inhibiting antibodies. Our review will evaluate the epidemiology, diagnosis, clinical course and treatment of peripartum AHA, focusing upon mother and infant care. © 2017 Elsevier Ltd. All rights reserved.

  20. Idiopathic Acquired Hemophilia A with Undetectable Factor VIII Inhibitor

    Directory of Open Access Journals (Sweden)

    Nicholas B. Abt

    2014-01-01

    Full Text Available Objective. We present the case of a 73-year-old female, with no family or personal history of a bleeding disorder, who had a classic presentation for acquired hemophilia A. Factor VIII activity was low but detectable and a factor VIII inhibitor was undetectable. Methods. The patient’s plasma was comprehensively studied to determine the cause of the acquired coagulopathy. Using the Nijmegen modification of the Bethesda assay, no factor VIII autoantibody was measureable despite varying the incubation time from 1 to 3 hours. Results. The aPTT was prolonged at 46.8 seconds, which did not correct in the 4 : 1 mix but did with 1 : 1 mix. Using a one stage factor VIII activity assay, the FVIII activity was 16% and chromogenic FVIII activity was also 16%. The patient was treated with recombinant FVII and transfusion, significantly reducing bleeding. Long-term therapy was initiated with cyclophosphamide and prednisone with normalization of FVIII activity. Conclusions. Physicians can be presented with the challenging clinical picture of an acquired factor VIII inhibitor without a detectable inhibitor by the Bethesda assay. Standard therapy for an acquired hemophilia A should be considered.

  1. New developments in the management of moderate-to-severe hemophilia B

    Directory of Open Access Journals (Sweden)

    Nazeef M

    2016-04-01

    Full Text Available Moniba Nazeef,1,2 John P Sheehan1,2 1Department of Medicine, Division of Hematology/Oncology, 2UW Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA Abstract: Hemophilia B is an X-linked genetic deficiency of coagulation factor IX (FIX activity associated with recurrent deep tissue and joint bleeding that may lead to long-term disability. FIX replacement therapy using plasma-derived protein or recombinant protein has significantly reduced bleeding and disability from hemophilia B, particularly when used in a prophylactic fashion. Although modern factor replacement has excellent efficacy and safety, barriers to the broader use of prophylaxis remain, including the need for intravenous (IV access, frequent dosing, variability in individual pharmacokinetics, and cost. To overcome the requirement for frequent factor dosing, novel forms of recombinant FIX have been developed that possess extended terminal half-lives. Two of these products (FIXFc and rIX-FP represent fusion proteins with the immunoglobulin G1 (IgG1 Fc domain and albumin, respectively, resulting in proteins that are recycled in vivo by the neonatal Fc receptor. The third product has undergone site-specific PEGylation on the activation peptide of FIX, similarly resulting in a long-lived FIX form. Clinical trials in previously treated hemophilia B patients have demonstrated excellent efficacy and confirmed less-frequent dosing requirements for the extended half-life forms. However, gaps in knowledge remain with regard to the risk of inhibitor formation and allergic reactions in previously untreated patient populations, safety in elderly patients with hemophilia, effects on in vivo FIX distribution, and cost-effectiveness. Additional strategies designed to rebalance hemostasis in hemophilia patients include monoclonal-antibody-mediated inhibition of tissue factor pathway inhibitor activity and siRNA-mediated reduction in antithrombin

  2. Progress and challenges in the development of a cell-based therapy for hemophilia A.

    Science.gov (United States)

    Fomin, M E; Togarrati, P P; Muench, M O

    2014-12-01

    Hemophilia A results from an insufficiency of factor VIII (FVIII). Although replacement therapy with plasma-derived or recombinant FVIII is a life-saving therapy for hemophilia A patients, such therapy is a life-long treatment rather than a cure for the disease. In this review, we discuss the possibilities, progress, and challenges that remain in the development of a cell-based cure for hemophilia A. The success of cell therapy depends on the type and availability of donor cells, the age of the host and method of transplantation, and the levels of engraftment and production of FVIII by the graft. Early therapy, possibly even prenatal transplantation, may yield the highest levels of engraftment by avoiding immunological rejection of the graft. Potential cell sources of FVIII include a specialized subset of endothelial cells known as liver sinusoidal endothelial cells (LSECs) present in the adult and fetal liver, or patient-specific endothelial cells derived from induced pluripotent stem cells that have undergone gene editing to produce FVIII. Achieving sufficient engraftment of transplanted LSECs is one of the obstacles to successful cell therapy for hemophilia A. We discuss recent results from transplants performed in animals that show production of functional and clinically relevant levels of FVIII obtained from donor LSECs. Hence, the possibility of treating hemophilia A can be envisioned through persistent production of FVIII from transplanted donor cells derived from a number of potential cell sources or through creation of donor endothelial cells from patient-specific induced pluripotent stem cells. © 2014 International Society on Thrombosis and Haemostasis.

  3. Progress and challenges in the development of a cell-based therapy for hemophilia A

    Science.gov (United States)

    Fomin, Marina E.; Togarrati, Padma Priya; Muench, Marcus O.

    2015-01-01

    Hemophilia A results from an insufficiency of factor VIII (FVIII). Although replacement therapy with plasma-derived or recombinant FVIII is a life-saving therapy for hemophilia A patients, such therapy is a life-long treatment rather than a cure for the disease. In this review we discuss the possibilities, progress and challenges that remain in the development of a cell-based cure for hemophilia A. The success of cell therapy depends on the type and availability of donor cells, the age of the host and method of transplantation, and the levels of engraftment and production of FVIII by the graft. Early therapy, possibly even prenatal transplantation, may yield the highest levels of engraftment by avoiding immunological rejection of the graft. Potential cell sources of FVIII include a specialized subset of endothelial cells known as liver sinusoidal endothelial cells (LSECs) present in the adult and fetal liver, or patient-specific endothelial cells derived from induced pluripotent stem cells (iPSCs) that have undergone gene editing to produce FVIII. Achieving sufficient engraftment of transplanted LSECs is one of the obstacles to successful cell therapy for hemophilia A. We discuss recent results from transplants performed in animals that show production of functional and clinically relevant levels of FVIII obtained from donor LSECs. Hence, the possibility of treating hemophilia A can be envisioned through persistent production of FVIII from transplanted donor cells derived from a number of potential cell sources or through creation of donor endothelial cells from patient-specific iPSCs. PMID:25297648

  4. Case report 475: Hemophilic arthropathy of the hip in a woman with hemophilia A

    International Nuclear Information System (INIS)

    Farsoe Nielsen, F.; Christensen, S.E.; Carvalho, A. de

    1988-01-01

    In summary, a case has been presented of a 31-year-old woman with a history of mild trauma at the age of 14 years and recurrent periods of pain in the hip becoming increasingly more severe. The radiological features were those of marked arthropathy of the affected hip with suggested features of ischemic necrosis. The patient was an example of hemophilia A which occurs rarely in females. The nature of the laboratory and clinical features of deficiency in hemophilia was considered and the clinical and radiological manifestations were described. The differential diagnosis was discussed. The radiological features in the background of the clinical information strongly suggest that the diagnosis of hemophilic arthropathy of the hip is justified. (orig./SHA)

  5. Case report 475: Hemophilic arthropathy of the hip in a woman with hemophilia A

    Energy Technology Data Exchange (ETDEWEB)

    Farsoe Nielsen, F.; Christensen, S.E.; Carvalho, A. de

    1988-04-01

    In summary, a case has been presented of a 31-year-old woman with a history of mild trauma at the age of 14 years and recurrent periods of pain in the hip becoming increasingly more severe. The radiological features were those of marked arthropathy of the affected hip with suggested features of ischemic necrosis. The patient was an example of hemophilia A which occurs rarely in females. The nature of the laboratory and clinical features of deficiency in hemophilia was considered and the clinical and radiological manifestations were described. The differential diagnosis was discussed. The radiological features in the background of the clinical information strongly suggest that the diagnosis of hemophilic arthropathy of the hip is justified. (orig./SHA).

  6. Science, Passion & Compassion vs. Cancer: Tania Crombet MD PhD, Director of Clinical Research. Molecular Immunology Center, Havana.

    Science.gov (United States)

    Gory, Conner

    2016-10-01

    Soon after the Molecular Immunology Center (CIM) was established in 1994 (a founding institution of Havana's biotechnology and pharmaceutical campus known as the scientific pole), Dr Crombet completed her master's thesis there. She joined CIM's team in 1998 and in 2004 was designated Director of Clinical Research. She has participated in the research, development and clinical trials of some of Cuba's most innovative therapies and vaccines, including CIMAvax-EGF for non-small cell lung cancer patients. In 2015, this therapy completed Phase IV clinical trials in Cuba and is now used in primary health care services throughout the country's national health system. CIM and Roswell Park Cancer Institute (Buffalo, New York) received US Department of Treasury approval in 2015 to test CIMAvax-EGF and other CIM products in the United States, opening the way for the Food and Drug Administration (FDA) to consider joint ground-breaking Phase I and II clinical trials in the USA. Recent regulatory changes introduced by President Barack Obama may make applying for such licenses a thing of the past-at least that is what researchers hope. In any case, the work of Dr Crombet and the teams at CIM is making headway in cancer immunotherapy, within the broader goals of the institution's mandate…the subject of our interview.

  7. Assessment of the frequency of regulatory T cells (CD4+CD25+CD127-) in children with hemophilia A: relation to factor VIII inhibitors and disease severity.

    Science.gov (United States)

    El-Asrar, Mohamed Abo; Hamed, Ahmed El-Saeed; Darwish, Yasser Wagih; Ismail, Eman Abdel Rahman; Ismail, Noha Ali

    2016-01-01

    A rapidly growing evidence showed that regulatory T cells (Tregs) play a crucial role in tolerance to coagulation factors and may be involved in the pathogenesis of inhibitor formation in patients with hemophilia. We determined the percentage of Tregs (CD4CD25CD127) in 45 children with hemophilia A compared with 45 healthy controls, and assessed their relation to the clinical characteristics of patients and factor VIII (FVIII) inhibitors. Patients were studied stressing on frequency of bleeding attacks, joint pain, history of viral hepatitis, and the received therapy (FVIII precipitate/cryotherapy). FVIII activity and FVIII inhibitors were assessed with flow cytometric analysis of CD4CD25CD127 Tregs. According to residual FVIII activity levels, 30 patients (66.7%) had mild/moderate hemophilia A, whereas 15 (33.3%) patients had severe hemophilia A. The frequency of Tregs was significantly lower among all patients with hemophilia A compared with controls (2.59 ± 1.1 versus 3.73 ± 1.12%; P = 0.002). Tregs were significantly decreased among patients with FVIII inhibitors compared with the inhibitor-negative group (P hemophilia A had lower Tregs levels than those without (P = 0.34 and P = 0.011, respectively). A significant positive correlation was found between the percentage of Tregs and FVIII among hemophilia A patients. ROC curve analysis revealed that the cut-off value of Tregs at 1.91% could differentiate patients with and without FVIII inhibitors, with a sensitivity of 100% and a specificity of 91.3%. We suggest that alteration in the frequency of Tregs in young patients with hemophilia A may contribute to inhibitor formation and disease severity.

  8. Effects of recombinant human prothrombin on thrombin generation in plasma from patients with hemophilia A and B.

    Science.gov (United States)

    Hansson, K M; Gustafsson, D; Skärby, T; Frison, L; Berntorp, E

    2015-07-01

    The present study was carried out to investigate the impact of FII levels, and their increase, on the hemostatic potential in plasma from hemophilia A and B patients with and without inhibitors. Recombinant human factor (F) II (rhFII) was added ex vivo to plasma from 68 patients with hemophilia A and B, with or without inhibitors. The hemostatic potential as measured by thrombin generation (calibrated automated thrombogram [CAT]) was focused on the endogenous thrombin potential (ETP) as it has been shown to correlate with the clinical phenotype of bleeding in hemophilia patients and has also been used to guide bypassing therapy in hemophilia patients with inhibitors before elective surgery. The factor eight inhibitor bypassing agent (FEIBA(®) ) was used as a reference to the clinical situation. The study shows that rhFII concentration-dependently increased ETP by a similar magnitude in hemophilia A and B, both with and without inhibitors. Compared with FEIBA, rhFII showed a shallower concentration-response curve. In both types of hemophilia 100 mg L(-1) of rhFII roughly doubled the ETP. A corresponding response was obtained by 0.5 U mL(-1) of FEIBA. These data support the theory that FII is one of the major components responsible for the efficacy of FEIBA. The data also indicate that rhFII may be useful, alone or in combination with other coagulation factors, in some of the conditions for which FEIBA is used today, although more data are needed to substantiate this. © 2015 International Society on Thrombosis and Haemostasis.

  9. Mesenchymal stem cell treatment for hemophilia: a review of current knowledge.

    Science.gov (United States)

    Sokal, E M; Lombard, C; Mazza, G

    2015-06-01

    Hemophilia remains a non-curative disease, and patients are constrained to undergo repeated injections of clotting factors. In contrast, the sustained production of endogenous factors VIII (FVIII) or IX (FIX) by the patient's own cells could represent a curative treatment. Gene therapy has thus provided new hope for these patients. However, the issues surrounding the durability of expression and immune responses against gene transfer vectors remain. Cell therapy, involving stem cells expanded in vitro, can provide de novo protein synthesis and, if implanted successfully, could induce a steady-state production of low quantities of factors, which may keep the patient above the level required to prevent spontaneous bleeding. Liver-derived stem cells are already being assessed in clinical trials for inborn errors of metabolism and, in view of their capacity to produce FVIII and FIX in cell culture, they are now also being considered for clinical application in hemophilia patients. © 2015 International Society on Thrombosis and Haemostasis.

  10. Step Up-Not On-The Step 2 Clinical Skills Exam: Directors of Clinical Skills Courses (DOCS) Oppose Ending Step 2 CS.

    Science.gov (United States)

    Ecker, David J; Milan, Felise B; Cassese, Todd; Farnan, Jeanne M; Madigosky, Wendy S; Massie, F Stanford; Mendez, Paul; Obadia, Sharon; Ovitsh, Robin K; Silvestri, Ronald; Uchida, Toshiko; Daniel, Michelle

    2018-05-01

    Recently, a student-initiated movement to end the United States Medical Licensing Examination Step 2 Clinical Skills and the Comprehensive Osteopathic Medical Licensing Examination Level 2-Performance Evaluation has gained momentum. These are the only national licensing examinations designed to assess clinical skills competence in the stepwise process through which physicians gain licensure and certification. Therefore, the movement to end these examinations and the ensuing debate merit careful consideration. The authors, elected representatives of the Directors of Clinical Skills Courses, an organization comprising clinical skills educators in the United States and beyond, believe abolishing the national clinical skills examinations would have a major negative impact on the clinical skills training of medical students, and that forfeiting a national clinical skills competency standard has the potential to diminish the quality of care provided to patients. In this Perspective, the authors offer important additional background information, outline key concerns regarding the consequences of ending these national clinical skills examinations, and provide recommendations for moving forward: reducing the costs for students, exploring alternatives, increasing the value and transparency of the current examinations, recognizing and enhancing the strengths of the current examinations, and engaging in a national dialogue about the issue.

  11. Optimization of prophylaxis for hemophilia A.

    Directory of Open Access Journals (Sweden)

    Robert D Herbert

    Full Text Available Prophylactic injections of factor VIII reduce the incidence of bleeds and slow the development of joint damage in people with hemophilia. The aim of this study was to identify optimal person-specific prophylaxis regimens for children with hemophilia A.Analytic and numerical methods were used to identify prophylaxis regimens which maximize the time for which plasma factor VIII concentrations exceed a threshold, maximize the lowest plasma factor VIII concentrations, and minimize risk of bleeds.It was demonstrated analytically that, for any injection schedule, the regimen that maximizes the lowest factor VIII concentration involves sharing doses between injections so that all of the trough concentrations in a prophylaxis cycle are equal. Numerical methods were used to identify optimal prophylaxis schedules and explore the trade-offs between efficacy and acceptability of different prophylaxis regimens. The prophylaxis regimen which minimizes risk of bleeds depends on the person's pattern of physical activity and may differ greatly from prophylaxis regimens that optimize pharmacokinetic parameters. Prophylaxis regimens which minimize risk of bleeds also differ from prophylaxis regimens that are typically prescribed. Predictions about which regimen is optimal are sensitive to estimates of the effects on risk of bleeds of factor VIII concentration and physical activity.The methods described here can be used to identify optimal, person-specific prophylaxis regimens for children with hemophilia A.

  12. Break-through bleeding in relation to predicted factor VIII levels in patients receiving prophylactic treatment for severe hemophilia A

    NARCIS (Netherlands)

    Collins, P. W.; Blanchette, V. S.; Fischer, K.; Bjorkman, S.; Oh, M.; Fritsch, S.; Schroth, P.; Spotts, G.; Astermark, J.; Ewenstein, B.

    Background: The role of prophylactic factor VIII (FVIII) to decrease hemophilic bleeding and arthropathy is well established. The rationale for this strategy is to convert patients with severe hemophilia A to a moderate clinical phenotype by reducing time spent with a FVIII level <1 IU dL(-1).

  13. The current state of adverse event reporting in hemophilia

    NARCIS (Netherlands)

    van Vulpen, Lize F D; Saccullo, Giorgia; Iorio, Alfonso; Makris, Michael

    INTRODUCTION: Replacement of the missing clotting factor is the mainstay of hemophilia treatment. Whilst historically many hemophilia patients were infected with blood-borne viruses transmitted via plasma-derived products, nowadays the formation of alloantibodies against the missing clotting factor

  14. Hemophilia and Sports: Guidelines for Participation. Case Report.

    Science.gov (United States)

    McLain, Larry G.; Heldrich, Fred T.

    1990-01-01

    Presents a case report of a 15-year-old boy with severe hemophilia who played soccer 1 school year but was denied continued participation following another screening examination. Before deciding about participation, physicians must assess the type and severity of hemophilia and risk factors for injury. Appropriate sports for hemophiliacs are…

  15. Treatment of hemophilia: A qualitative study of mothers' perspectives.

    Science.gov (United States)

    von der Lippe, Charlotte; Frich, Jan C; Harris, Anna; Solbraekke, Kari Nyheim

    2017-01-01

    In Norway, boys with hemophilia usually begin treatment after their first bleeding episode. Boys with severe hemophilia usually start prophylactic treatment around 18-24 months. Health professionals administer factor concentrate initially, but when boys are around 4 years old most parents start treating their children at home. There is a lack of research on how parents, and especially how carrier mothers, experience the medical treatment for their sons' hemophilia. Our aim was to investigate how carrier mothers experience this treatment in the hospital setting and at home. In this qualitative study, we interviewed 16 mothers of boys or men with hemophilia A or B. Data were collected via semistructured interviews and analyzed using an inductive thematic analytical approach. Mothers experienced both practical and emotional challenges in relation to their sons' treatment, and repeated venipuncture was especially difficult emotionally. Parents preferred home treatment to hospital treatment because it was less time-consuming, less disruptive to family life, and provided a greater sense of control. Encountering healthcare professionals who were unfamiliar with hemophilia was a second major stress factor, especially when parents felt that health professionals lacked competence and were unwilling to seek advice. While home treatment for hemophilia enables freedom, flexibility, and autonomy for the boys as well as for the family, mothers may experience treatment of hemophilia as a burden. Health professionals should provide tailored practical and emotional support to parents by probing into their experiences with treating their sons' hemophilia. © 2016 Wiley Periodicals, Inc.

  16. A qualitative evaluation of foundation dentists' and training programme directors' perceptions of clinical audit in general dental practice.

    Science.gov (United States)

    Thornley, P; Quinn, A; Elley, K

    2015-08-28

    This study reports on an investigation into clinical audit (CA) educational and service delivery outcomes in a dental foundation training (DFT) programme. The aim was to investigate CA teaching, learning and practice from the perspective of foundation dentists (FDs) and to record suggestions for improvement. A qualitative research methodology was used. Audio recordings of focus group interviews with FDs were triangulated by an interview with a group of training programme directors (TPDs). The interviews were transcribed and thematically analysed using a 'Framework' approach within Nvivo Data Analysis Software. FDs report considerable learning and behaviour change. However, TPDs have doubts about the long-term effects on service delivery. There can be substantial learning in the clinical, managerial, communication and professionalism domains, and in the development of time management, organisational and team-working skills. Information is provided about use of resources and interaction with teachers and colleagues. CA provides learning opportunities not produced by other educational activities including 'awkward conversations' with team-members in the context of change management and providing feedback. This is relevant when applying the recommendations of the Francis report. This paper should be useful to any dentist conducting audit or team training. Suggestions are made for improvements to resources and support including right touch intervention. Trainers should teach in the 'Goldilocks Zone'.

  17. Myelofibrosis and acquired hemophilia A: a case report.

    Science.gov (United States)

    Wrobel, Marie; Comio, Emilie; Gay, Valerie; Baroudi, Noureddine; Meyer, Pascal; Chuniaud-Louche, Christine; Hacini, Maya; Pica, Gian Matteo

    2016-05-07

    Myelofibrosis and acquired hemophilia A is a rare association. To the best of our knowledge only one case of myelofibrosis and acquired hemophilia A has been previously described. A 66-year-old Caucasian man diagnosed with myelofibrosis evolving in acute myeloid leukemia was referred to us for postoperative bleeding. Hemostatic studies showed prolonged activated partial thromboplastin time, decreased factor VIII coagulation, and a high factor VIII inhibitor titer; these findings led to a diagnosis of acquired hemophilia A for which he was treated with methylprednisolone and recombinant activated factor VII on admission. Due to a lack of response he was subsequently treated with rituximab combined with activated prothrombin complex concentrates. Furthermore, he received azacytidine to treat the underlying hematological malignancies. Immunosuppressive rituximab therapy resolved acquired hemophilia A with marked efficacy. Rapid and accurate diagnosis, effective hemostatic therapy, and timely treatment for underlying disease are important in the management of acquired hemophilia A secondary to hematological malignancy.

  18. Antihemophilic factor (recombinant plasma/albumin-free method for the management and prevention of bleeding episodes in patients with hemophilia A

    Directory of Open Access Journals (Sweden)

    Steven Pipe

    2009-02-01

    Full Text Available Steven PipeDepartment of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI, USAAbstract: Hemophilia is a rare genetic bleeding disorder that, if not adequately controlled, is associated with life-threatening bleeding events and serious and costly complications, primarily from joint damage. The advent of effective clotting factor replacement therapy for patients with hemophilia is considered one of the foremost medical advances of the 20th century. The last 3 decades of experience in hemophilia care have witnessed the effectiveness of the care of patients with hemophilia within specialized comprehensive care centers, advances in factor replacement therapies, the benefits of prophylaxis over on-demand replacement therapy, and the role of aggressive management of joint disease to prevent dysfunction. Ongoing challenges, including the management of inhibitors to factor therapies and the consequences of thousands of patients with hemophilia becoming infected with human immunodeficiency virus and hepatitis C virus in the 1980s from contaminated plasma-derived factor concentrates, have highlighted the need for vigilance with respect to clotting factor product safety, access to care, and a full complement of choice of factor replacement therapies. Advate® (antihemophilic factor [recombinant] plasma/albumin-free method [rAHF-PFM] is the first recombinant factor VIII therapy manufactured without human or animal protein additives to eliminate the risk of pathogen transmission that could be carried by these additives. Preclinical studies established bioequivalence with recombinant antihemophilic factor (Recombinate®, a product with 16 years of clinical experience. Currently licensed in 44 countries worldwide, rAHF-PFM has over 7 years of clinical research within 5 global studies supporting its safety and efficacy in the treatment of patients with hemophilia A.Keywords: factor VIII, hemophilia A, recombinant proteins, clinical

  19. Innovative Approaches for Immune Tolerance to Factor VIII in the Treatment of Hemophilia A

    Science.gov (United States)

    Sherman, Alexandra; Biswas, Moanaro; Herzog, Roland W.

    2017-01-01

    Hemophilia A (coagulation factor VIII deficiency) is a debilitating genetic disorder that is primarily treated with intravenous replacement therapy. Despite a variety of factor VIII protein formulations available, the risk of developing anti-dug antibodies (“inhibitors”) remains. Overall, 20–30% of patients with severe disease develop inhibitors. Current clinical immune tolerance induction protocols to eliminate inhibitors are not effective in all patients, and there are no prophylactic protocols to prevent the immune response. New experimental therapies, such as gene and cell therapies, show promising results in pre-clinical studies in animal models of hemophilia. Examples include hepatic gene transfer with viral vectors, genetically engineered regulatory T cells (Treg), in vivo Treg induction using immune modulatory drugs, and maternal antigen transfer. Furthermore, an oral tolerance protocol is being developed based on transgenic lettuce plants, which suppressed inhibitor formation in hemophilic mice and dogs. Hopefully, some of these innovative approaches will reduce the risk of and/or more effectively eliminate inhibitor formation in future treatment of hemophilia A. PMID:29225598

  20. Inhibitor Risk Stratification and Individualized Treatment in Patients With Nonsevere Hemophilia A: A Single-Institution Practice Audit.

    Science.gov (United States)

    Sun, Haowei Linda; Chan, Stella; Yenson, Paul; Jackson, Shannon

    2018-03-01

    Inhibitor risk in nonsevere hemophilia A increases with cumulative factor VIII (FVIII) exposure days and high-risk mutations. A standardized approach to minimize inhibitor risk is warranted. Following establishment of a systematic approach to reduce inhibitor risk in nonsevere hemophilia, we evaluated the uptake of these strategies into clinical practice. All adult males with nonsevere hemophilia A followed by British Columbia Adult Hemophilia Program from 2004 to 2016 were included in this retrospective audit. Quality-of-care indicators on inhibitor prevention were examined. Of 108 patients, 18 patients had high-risk FVIII mutations for inhibitor development. Rates of FVIII genotyping and 1-deamino-8-d-arginine-vasopressin (DDAVP) testing in mild patients without contraindications were both over 90%, although DDAVP was used for surgical prophylaxis in only 70% of procedures. Inhibitor testing and clinic visits occurred at a median interval of 22 months. Over 80% of patients with high-risk mutations had documentation and education on their inhibitor risk. Our practice audit demonstrated a high level of recognition and patient education of individual inhibitor risk. Impact of our standardized approach on the incidence of inhibitor development is yet to be determined.

  1. Independent Directors

    DEFF Research Database (Denmark)

    Ringe, Wolf-Georg

    2013-01-01

    This paper re-evaluates the corporate governance concept of ‘board independence’ against the disappointing experiences during the 2007-08 financial crisis. Independent or outside directors had long been seen as an essential tool to improve the monitoring role of the board. Yet the crisis revealed...... that they did not prevent firms' excessive risk taking; further, these directors sometimes showed serious deficits in understanding the business they were supposed to control, and remained passive in addressing structural problems. A closer look reveals that under the surface of seemingly unanimous consensus...

  2. Case Management Directors

    Science.gov (United States)

    Bankston White, Cheri; Birmingham, Jackie

    2015-01-01

    that include payer, provider, and regulatory agencies. At the same time, they must also develop the skills to positively influence the revenue cycle and financial health of both the organization for which they work and those to whom they transition patients. Implications for Case Management: A director of case management with responsibility for transitions of care has more power and influence over patient safety than is commonly known. Few of the directors who are drawn from clinical case management or other leadership positions and thrust into this role are prepared to navigate within the organization, much less across the whole spectrum of payer, provider, and monitoring organizations. Yet the external focus of the director's role continues to grow in importance as the health care industry evolves and more focus is placed on population management and relationships with payers and community providers. PMID:25700135

  3. Knee and Ankle Arthroplasty in Hemophilia

    Directory of Open Access Journals (Sweden)

    Luigi Piero Solimeno

    2017-11-01

    Full Text Available Today, major surgical procedures can be safely performed in hemophilic patients with chronic arthropathy, using available factor concentrates. In this setting, total knee replacement is considered the “gold standard”, while the use of total ankle replacement is still debated. Indeed, the unsatisfactory results obtained with the previous available design of implants did not raise enthusiasm as knee or hip replacement. Recently, the introduction of new implant designs and better reported outcomes have renewed the interest in total ankle replacement in people with hemophilia. In this review, the role of replacement surgery in the treatment of chronic hemophilic arthropathy will be described.

  4. Validation of a new pediatric joint scoring system from the International Hemophilia Prophylaxis Study Group: validity of the hemophilia joint health score

    NARCIS (Netherlands)

    Feldman, Brian M.; Funk, Sharon M.; Bergstrom, Britt-Marie; Zourikian, Nichan; Hilliard, Pamela; van der Net, Janjaap; Engelbert, Raoul; Petrini, Pia; van den Berg, H. Marijke; Manco-Johnson, Marilyn J.; Rivard, Georges E.; Abad, Audrey; Blanchette, Victor S.

    2011-01-01

    Repeated hemarthrosis in hemophilia causes arthropathy with pain and dysfunction. The Hemophilia Joint Health Score (HJHS) was developed to be more sensitive for detecting arthropathy than the World Federation of Hemophilia (WFH) physical examination scale, especially for children and those using

  5. Targeting of Antithrombin in Hemophilia A or B with RNAi Therapy.

    Science.gov (United States)

    Pasi, K John; Rangarajan, Savita; Georgiev, Pencho; Mant, Tim; Creagh, Michael D; Lissitchkov, Toshko; Bevan, David; Austin, Steve; Hay, Charles R; Hegemann, Inga; Kazmi, Rashid; Chowdary, Pratima; Gercheva-Kyuchukova, Liana; Mamonov, Vasily; Timofeeva, Margarita; Soh, Chang-Heok; Garg, Pushkal; Vaishnaw, Akshay; Akinc, Akin; Sørensen, Benny; Ragni, Margaret V

    2017-08-31

    Current hemophilia treatment involves frequent intravenous infusions of clotting factors, which is associated with variable hemostatic protection, a high treatment burden, and a risk of the development of inhibitory alloantibodies. Fitusiran, an investigational RNA interference (RNAi) therapy that targets antithrombin (encoded by SERPINC1), is in development to address these and other limitations. In this phase 1 dose-escalation study, we enrolled 4 healthy volunteers and 25 participants with moderate or severe hemophilia A or B who did not have inhibitory alloantibodies. Healthy volunteers received a single subcutaneous injection of fitusiran (at a dose of 0.03 mg per kilogram of body weight) or placebo. The participants with hemophilia received three injections of fitusiran administered either once weekly (at a dose of 0.015, 0.045, or 0.075 mg per kilogram) or once monthly (at a dose of 0.225, 0.45, 0.9, or 1.8 mg per kilogram or a fixed dose of 80 mg). The study objectives were to assess the pharmacokinetic and pharmacodynamic characteristics and safety of fitusiran. No thromboembolic events were observed during the study. The most common adverse events were mild injection-site reactions. Plasma levels of fitusiran increased in a dose-dependent manner and showed no accumulation with repeated administration. The monthly regimen induced a dose-dependent mean maximum antithrombin reduction of 70 to 89% from baseline. A reduction in the antithrombin level of more than 75% from baseline resulted in median peak thrombin values at the lower end of the range observed in healthy participants. Once-monthly subcutaneous administration of fitusiran resulted in dose-dependent lowering of the antithrombin level and increased thrombin generation in participants with hemophilia A or B who did not have inhibitory alloantibodies. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov number, NCT02035605 .).

  6. Successful Phenotype Improvement following Gene Therapy for Severe Hemophilia A in Privately Owned Dogs.

    Science.gov (United States)

    Callan, Mary Beth; Haskins, Mark E; Wang, Ping; Zhou, Shangzhen; High, Katherine A; Arruda, Valder R

    2016-01-01

    Severe hemophilia A (HA) is an inherited bleeding disorder characterized by dogs, and, like humans, is associated with high morbidity and mortality. In gene therapy using adeno-associated viral (AAV) vectors, the canine model has been one of the best predictors of the therapeutic dose tested in clinical trials for hemophilia B (factor IX deficiency) and other genetic diseases, such as congenital blindness. Here we report our experience with liver gene therapy with AAV-FVIII in two outbred, privately owned dogs with severe HA that resulted in sustained expression of 1-2% of normal FVIII levels and prevented 90% of expected bleeding episodes. A Thr62Met mutation in the F8 gene was identified in one dog. These data recapitulate the improvement of the disease phenotype in research animals, and in humans, with AAV liver gene therapy for hemophilia B. Our experience is a novel example of the benefits of a relevant preclinical canine model to facilitate both translational studies in humans and improved welfare of privately owned dogs.

  7. Leopold: the "bleeder prince" and public knowledge about hemophilia in Victorian Britain.

    Science.gov (United States)

    Rushton, Alan R

    2012-07-01

    Hemophilia is a rare bleeding disorder inherited by males born of unaffected female carriers of the trait. British physicians became knowledgeable about this hereditary disease early in the nineteenth century as they investigated families transmitting the character through several generations. Prince Leopold (b. 1853), the fourth son of Queen Victoria, experienced recurrent bleeding episodes and was diagnosed with hemophilia during childhood. His hemorrhagic attacks were first described in the medical journals during 1868, and subsequently in the London and provincial newspapers. The royal family carefully managed news about health matters, and many newspapers reported widespread public sympathy for the travails of the queen and her children. But the republican press argued that the disaffected working classes resented the hyperbole connecting the health of royal individuals with the political future of the entire nation. Public discussion of hemophilia transformed it from a rare medical phenomenon to a matter of national news. Practicing physicians, the royal family, and the general public all came to understand the clinical features and the hereditary nature of the problem. Members of the royal family subsequently utilized this information to guide the marriages of their own children to prevent the spread of this dreaded bleeding disorder.

  8. Successful Phenotype Improvement following Gene Therapy for Severe Hemophilia A in Privately Owned Dogs.

    Directory of Open Access Journals (Sweden)

    Mary Beth Callan

    Full Text Available Severe hemophilia A (HA is an inherited bleeding disorder characterized by <1% of residual factor VIII (FVIII clotting activity. The disease affects several mammals including dogs, and, like humans, is associated with high morbidity and mortality. In gene therapy using adeno-associated viral (AAV vectors, the canine model has been one of the best predictors of the therapeutic dose tested in clinical trials for hemophilia B (factor IX deficiency and other genetic diseases, such as congenital blindness. Here we report our experience with liver gene therapy with AAV-FVIII in two outbred, privately owned dogs with severe HA that resulted in sustained expression of 1-2% of normal FVIII levels and prevented 90% of expected bleeding episodes. A Thr62Met mutation in the F8 gene was identified in one dog. These data recapitulate the improvement of the disease phenotype in research animals, and in humans, with AAV liver gene therapy for hemophilia B. Our experience is a novel example of the benefits of a relevant preclinical canine model to facilitate both translational studies in humans and improved welfare of privately owned dogs.

  9. MR imaging of arthropathies of juvenile arthritis and hemophilia

    International Nuclear Information System (INIS)

    Yulish, B.S.; Lieberman, J.; Mulopoulos, G.P.; Strandjord, S.; Newman, A.; Goodfellow, D.; Bryan, P.J.; Modic, M.T.

    1986-01-01

    The arthropathies of juvenile arthritis and hemophilia have in common abnormal hyperplastic synovium leading to marginal bone erosion, articular cartilage destruction, subchondral bone exposure, and dissolution and ultimately collapse of the affected joint. The authors examined children and young adults with juvenile arthritis and hemophilia by MR imaging and found that they could identify hyperplastic synovium, articular cartilage lesions, bone erosions, and joint effusions. This has therapeutic implications since identification of progressive synovial hyperplasia and/or early cartilage or marginal bone erosion may lead to earlier synovectomy in patients with hemophilia or switch to second line drugs in patients with juvenile arthritis, in an attempt to prevent progressive joint destruction

  10. Relationships between high-stakes clinical skills exam scores and program director global competency ratings of first-year pediatric residents

    Directory of Open Access Journals (Sweden)

    Erik E. Langenau

    2011-09-01

    Full Text Available Responding to mandates from the Accreditation Council for Graduate Medical Education (ACGME and American Osteopathic Association (AOA, residency programs have developed competency-based assessment tools. One such tool is the American College of Osteopathic Pediatricians (ACOP program directors’ annual report. High-stakes clinical skills licensing examinations, such as the Comprehensive Osteopathic Medical Licensing Examination Level 2-Performance Evaluation (COMLEX-USA Level 2-PE, also assess competency in several clinical domains.The purpose of this study is to investigate the relationships between program director competency ratings of first-year osteopathic residents in pediatrics and COMLEX-USA Level 2-PE scores from 2005 to 2009.The sample included all 94 pediatric first-year residents who took COMLEX-USA Level 2-PE and whose training was reviewed by the ACOP for approval of training between 2005 and 2009. Program director competency ratings and COMLEX-USA Level 2-PE scores (domain and component were merged and analyzed for relationships.Biomedical/biomechanical domain scores were positively correlated with overall program director competency ratings. Humanistic domain scores were not significantly correlated with overall program director competency ratings, but did show moderate correlation with ratings for interpersonal and communication skills. The six ACGME or seven AOA competencies assessed empirically by the ACOP program directors’ annual report could not be recovered by principal component analysis; instead, three factors were identified, accounting for 86% of the variance between competency ratings.A few significant correlations were noted between COMLEX-USA Level 2-PE scores and program director competency ratings. Exploring relationships between different clinical skills assessments is inherently difficult because of the heterogeneity of tools used and overlap of constructs within the AOA and ACGME core competencies.

  11. Relationships between high-stakes clinical skills exam scores and program director global competency ratings of first-year pediatric residents

    Science.gov (United States)

    Langenau, Erik E.; Pugliano, Gina; Roberts, William L.

    2011-01-01

    Background Responding to mandates from the Accreditation Council for Graduate Medical Education (ACGME) and American Osteopathic Association (AOA), residency programs have developed competency-based assessment tools. One such tool is the American College of Osteopathic Pediatricians (ACOP) program directors’ annual report. High-stakes clinical skills licensing examinations, such as the Comprehensive Osteopathic Medical Licensing Examination Level 2-Performance Evaluation (COMLEX-USA Level 2-PE), also assess competency in several clinical domains. Objective The purpose of this study is to investigate the relationships between program director competency ratings of first-year osteopathic residents in pediatrics and COMLEX-USA Level 2-PE scores from 2005 to 2009. Methods The sample included all 94 pediatric first-year residents who took COMLEX-USA Level 2-PE and whose training was reviewed by the ACOP for approval of training between 2005 and 2009. Program director competency ratings and COMLEX-USA Level 2-PE scores (domain and component) were merged and analyzed for relationships. Results Biomedical/biomechanical domain scores were positively correlated with overall program director competency ratings. Humanistic domain scores were not significantly correlated with overall program director competency ratings, but did show moderate correlation with ratings for interpersonal and communication skills. The six ACGME or seven AOA competencies assessed empirically by the ACOP program directors’ annual report could not be recovered by principal component analysis; instead, three factors were identified, accounting for 86% of the variance between competency ratings. Discussion A few significant correlations were noted between COMLEX-USA Level 2-PE scores and program director competency ratings. Exploring relationships between different clinical skills assessments is inherently difficult because of the heterogeneity of tools used and overlap of constructs within the AOA

  12. Break-through bleeding in relation to predicted factor VIII levels in patients receiving prophylactic treatment for severe hemophilia A.

    Science.gov (United States)

    Collins, P W; Blanchette, V S; Fischer, K; Björkman, S; Oh, M; Fritsch, S; Schroth, P; Spotts, G; Astermark, J; Ewenstein, B

    2009-03-01

    The role of prophylactic factor VIII (FVIII) to decrease hemophilic bleeding and arthropathy is well established. The rationale for this strategy is to convert patients with severe hemophilia A to a moderate clinical phenotype by reducing time spent with a FVIII level break-through bleeding in patients with severe hemophilia A on prophylaxis. This study analysed data from 44 patients aged 1-6 and 99 patients aged 10-65 years with severe hemophilia A (FVIII safety and efficacy of a recombinant FVIII (Advate). Each patient had pharmacokinetic measurements and FVIII infusions recorded, and these were used to calculate time spent with a FVIII below 1, 2 and 5 IU dL(-1). The data demonstrate that increasing time with a FVIII below 1 IU dL(-1) is associated with increased total bleeds and hemarthroses. Lack of adherence to the intended frequency of FVIII infusion was the most important determinant of low FVIII and increased bleeding. In children aged 1-6 years, the rate of bleeding was also influenced by FVIII half-life and clearance. These data have important implications for the management of patients with severe hemophilia.

  13. Strategies to encourage physical activity in patients with hemophilia to improve quality of life

    Directory of Open Access Journals (Sweden)

    Goto M

    2016-05-01

    Full Text Available Miwa Goto,1 Hideyuki Takedani,2 Kazuhiko Yokota,1 Nobuhiko Haga3 1Rehabilitation Center, The University of Tokyo Hospital, 2Department of Joint Surgery, Research Hospital of the Institute of Medical Science, The University of Tokyo, 3Department of Rehabilitation Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan Abstract: Hemophilia is a bleeding disorder caused by a congenital abnormality of blood coagulation. Until the mid-1970s, patients with hemophilia (PWH were advised to refrain from physical activity (PA because of a perceived increased risk of bleeding. Since then, PA, which is recognized as being essential for health maintenance, is now recommended by the World Federation of Hemophilia. Moreover, a number of studies reported that PA can improve treatment efficacy and prevent bleeding in PWH. Physical assessment and intervention in PA are currently used in clinical practice. However, the necessity of PA is not emphasized, and many PWH generally have low- to- no PA. Therefore, a behavior change approach to encourage patient motivation is becoming ever more important. In this article, we review articles addressing PA in PWH and discuss strategies to encourage PA through a behavior change approach by focusing on factors relevant to hemophilia, such as benefits and bleeding risk of PA, risk management of bleeding, PA characteristics, and difficulty with exercise adherence. The trust relationship between clinicians and patients, a transtheoretical model of behavior change, and motivation theory as approaches to promote PA are introduced. Finally, we review a case report of the clinical success of a behavior change approach to promote PA. Many PWH find it difficult to continue PA because of aging, fear of bleeding, insufficient recognition of PA benefits, and psychological problems. Therefore, it is essential and important to perform prophylaxis with PWH and to heighten their understanding of the benefits and risks of

  14. Social participation of patients with hemophilia in the Netherlands

    NARCIS (Netherlands)

    Plug, Iris; Peters, Marjolein; Mauser-Bunschoten, Eveline P.; de Goede-Bolder, Arja; Heijnen, Lily; Smit, Cees; Willemse, Jose; Rosendaal, Frits R.; van der Bom, Johanna G.

    2008-01-01

    The introduction of replacement therapy in the 1960s has improved medical and social circumstances gradually. The availability of prophylactic treatment has further increased the possibilities of a "normal" life for patients with hemophilia. We examined whether social participation and

  15. An Open-label, Single-dose, Pharmacokinetic Study of Factor VIII Activity After Administration of Moroctocog Alfa (AF-CC) in Male Chinese Patients With Hemophilia A.

    Science.gov (United States)

    Liu, Hongzhong; Wu, Runhui; Hu, Pei; Sun, Feifei; Xu, Lihong; Liang, Yali; Nepal, Sunil; Qu, Peng Roger; Huard, Francois; Korth-Bradley, Joan M

    2017-07-01

    Hemophilia A represents up to 80% of all hemophilia cases in China. In patients with this condition, bleeding can be prevented and controlled by administering clotting factor VIII (FVIII). Since their initial availability, recombinant FVIII products have undergone several iterations to enhance their safety. Moroctocog alfa albumin-free cell culture (AF-CC) is among the third generation of recombinant FVIII products and received regulatory approval in China in August 2012. The present study characterizes the single-dose pharmacokinetic parameters of FVIII activity (FVIII:C) after administration of moroctocog alfa (AF-CC) in male Chinese patients with hemophilia A. This multicenter, open-label, single-dose study enrolled 13 male Chinese patients diagnosed with severe hemophilia A (FVIII:C hemophilia A. The pharmacokinetic profile in older patients was similar to that previously reported with recombinant FVIII products in studies with a predominantly white population; younger patients had reduced exposure to FVIII:C. The single doses of moroctocog alfa (AF-CC) were well tolerated; 2 cases of transient, low-titer FVIII inhibitor development were observed. ClinicalTrials.gov identifier: NCT02461992. Copyright © 2017 Elsevier HS Journals, Inc. All rights reserved.

  16. 4 cases of iliopsoas hematoma associated with hemophilia

    International Nuclear Information System (INIS)

    Oishi, Yukiyoshi; Iwata, Hisashi; Inoda, Kunio

    1984-01-01

    Four patients were diagnosed as having iliopsoas hematoma associated with hemophilia by CT scanning. The site and disappearance of hematoma were observed on CT. It was suggested that hematoma occurs inside the iliacus or posoas muscle in cases of iliopsoas hematoma complicated by hemophilia or coagulation and that it occurs in the pelvic wall of the iliacus muscle in cases of iliopsoas hematoma uncomplicated by coagulation abnormality. (Namekawa, K.)

  17. 4 cases of iliopsoas hematoma associated with hemophilia

    Energy Technology Data Exchange (ETDEWEB)

    Oishi, Yukiyoshi; Iwata, Hisashi; Inoda, Kunio (Nagoya Univ. (Japan). Faculty of Medicine)

    1984-03-01

    Four patients were diagnosed as having iliopsoas hematoma associated with hemophilia by CT scanning. The site and disappearance of hematoma were observed on CT. It was suggested that hematoma occurs inside the iliacus or posoas muscle in cases of iliopsoas hematoma complicated by hemophilia or coagulation and that it occurs in the pelvic wall of the iliacus muscle in cases of iliopsoas hematoma uncomplicated by coagulation abnormality.

  18. Chromogenic Factor VIII Assays for Improved Diagnosis of Hemophilia A.

    Science.gov (United States)

    Rodgers, Susan; Duncan, Elizabeth

    2017-01-01

    Hemophilia A is an inherited bleeding disorder caused by a reduced level of factor VIII coagulant activity (FVIII:C) in blood. Bleeding episodes may occur spontaneously in the severe form of hemophilia or after trauma in the milder forms. It is important that patients are diagnosed correctly, which includes placing them into the correct severity category of the disorder so that appropriate treatment can be given. Diagnosis is made by determination of the amount of FVIII:C in the blood, usually using a one-stage factor VIII:C assay. However, approximately one third of patients with mild or moderate hemophilia will have much lower results by the chromogenic assay, with some of them having normal results by the one-stage assay. The chromogenic factor VIII assay is used in some specialized hemophilia reference centers and is recommended for the diagnosis of mild hemophilia A, as this assay is considered to better reflect the severity status of hemophilia patients than the one-stage assay.

  19. Costs and utilization of hemophilia A and B patients with and without inhibitors.

    Science.gov (United States)

    Armstrong, Edward P; Malone, Daniel C; Krishnan, Sangeeta; Wessler, Maj Jacob

    2014-11-01

    To evaluate the health system costs among patients with hemophilia A and B with and without inhibitors over 5 years. This was a retrospective, observational study utilizing medical and pharmacy electronic medical records and administrative encounters/claims data tracking US patients between 2006-2011. Patients with diagnosis codes for hemophilia A and B were identified. Patients with inhibitors were characterized by utilization of bypassing agents activated prothrombin complex concentrate or factor VIIa on two or more distinct dates. Severity was classified as mild, moderate, or severe based on laboratory tests of clotting factor. There were 160 hemophilia A patients and 54 hemophilia B patients identified. From this group, seven were designated as patients with inhibitors (five with hemophilia A and two with hemophilia B). Hemophilia A patients without inhibitors reported 65 (41.9%) as being severe, 19 (12.3%) as moderate, and 71 (45.8%) as mild. Hemophilia B patients without inhibitors reported nine (17.3%) had severe, 13 (25.0%) had moderate, and 30 (57.7%) had mild hemophilia. All patients with inhibitors had been hospitalized in the previous 5 years compared to 64 (41.3%) with hemophilia A without inhibitors and 22 (42.3%) with hemophilia B without inhibitors. The median aggregate cost per year (including factor and health resource use) was $325,780 for patients with inhibitors compared to $98,334 for hemophilia A patients without inhibitors and $23,265 for hemophilia B patients without inhibitors. The results suggest that, while the frequency of inhibitors within the hemophilia cohort was low, there was a higher frequency of hospitalizations, and the associated median aggregate costs per year were 3-fold higher than those patients without inhibitors. In contrast, hemophilia B patients experience less severe disease and account for lower aggregate yearly costs compared to either patients with hemophilia A or patients with inhibitors.

  20. Mortality caused by intracranial bleeding in non-severe hemophilia A patients

    NARCIS (Netherlands)

    Loomans, Janneke I.; Eckhardt, Corien L.; Reitter-Pfoertner, Sylvia E.; Holmstrom, Mats; Van Gorkom, B. Laros; Leebeek, F. W. G.; Santoro, C.; Haya, Saturnino; Meijer, K.; Nijziel, M. R.; Van Der Bom, J. G.; Fijnvandraat, K.

    Background: Non-severe hemophilia (factor VIII concentration [FVIII: C] of 2-40 IU dL(-1)) is characterized by a milder bleeding phenotype than severe hemophilia A. However, some patients with non-severe hemophilia A suffer from severe bleeding complications that may result in death. Data on

  1. 78 FR 57868 - Prospective Grant of Exclusive Patent License: Oral Treatment of Hemophilia

    Science.gov (United States)

    2013-09-20

    ... Exclusive Patent License: Oral Treatment of Hemophilia AGENCY: National Institutes of Health, HHS. ACTION...), entitled respectively, ``Oral Treatment of Hemophilia'' and ``Induction of Tolerance by Oral administration of Factor VIII and Treatment of Hemophilia''. The patent rights in these inventions have been...

  2. [Analysis of individualized primary prophylactic treatment of 19 cases of children with severe hemophilia A].

    Science.gov (United States)

    Liu, G Q; Tang, L; Wu, X Y; Zhen, Y Z; Li, G; Chen, Z P; Wang, Y; Zhang, N N; Zhang, J S; Yu, G X; Wu, R H

    2016-12-02

    Objective: To study the current situation of primary prophylaxis in severe hemophilia A children and to explore rational regimen in order to provide evidence for the development of primary prophylaxis in China. Method: A retrospective clinical data collection and analysis was conducted for 19 severe hemophilia A children who received primary prophylaxis in Beijing Children's Hospital outpatient clinic between February 2011 and September 2015 and evaluated the regimen and efficacy. Result: (1) Primary prophylaxis regimen: the median beginning age 1.8 (range 0.5-2.9) years, the median FⅧ preparation using dosage 16.7 (8.0-23.5) U/(kg·time), the median using frequency was 1.0 (1.0-3.0) time/week. Eight cases among the patients received escalation of treatment intensity because of the poor bleeding control. (2) Efficacy: the median annual bleeding rate (ABR) was 1.9 (0-6.0) times/year, the median annual joint bleeding rate (AJBR) was 0 (0-3.3) times/year, without life threatening bleeding. All of them kept in 4th scale of Beijing Children Hospital daily activity level. The median annual factor consumption was 1 844 (840-5 040) U/kg. Conclusion: Low-dose primary prophylaxis regimen which were in low-dose /low frequencies and adjusted by bleeding frequency could decrease bleeding and joint bleeding frequency significantly, maintained the normal daily activity capacity and saved the factor consumption compared to standard regimen in severe hemophilia A children.

  3. Director's report.

    Science.gov (United States)

    Pathak, K B

    1993-07-01

    The director's report for the International Institute for Population Sciences in Bombay, India, provides descriptions of the Institute's teaching programs, research, publications, seminars, library collection, visitors, faculty and staff, and special events. The teaching programs include regular instruction in one-year diploma courses in population studies and a masters and a masters in philosophy in population studies; a diploma is also available in health education. Student represent a variety of countries for the diploma programs, while the other certificate programs draw on the national population. A listing is provided of those receiving certificates. Research programs are listed by whether the program was completed during 1992-93 or earlier or is a new project. The Institute conducts a National Family Welfare Survey among 23 states. This household survey is directed to women and supplies village level data. The Institute publishes a quarterly newsletter about ongoing activities and a biennial compendium of research findings. The Institute observes World Population Day and organized the 10th Annual Convention on Medical Statistics and other conferences. The Institute held the first meeting of the National Council of Population Research on September 21, 1992, and the designated subcommittee members met on November 14, 1992. The library recently added 1117 volumes, which contributed to the total library collection of 55,539 volumes, including 8000 bound periodicals and 12,615 reprints. Several high government officials visited the Institute in 1992. Other visitors came from the US, Bangladesh, and the UN. The Institute is comprised of six academic departments with computer and library resources. Staff were involved a few overseas tours of study. Founders day is celebrated as a cultural event.

  4. Hemophilia A. Considerations for dental management of pediatric patients.

    Directory of Open Access Journals (Sweden)

    Sonia López-Villareal

    2016-12-01

    Full Text Available It comes to consulting the Faculty of Dentistry at the University of Nuevo León pediatric male patient of 9 years 10 months, who was admitted with a presumptive diagnosis of hemophilia due to a subsequent persistent bleeding to treatment with steel crowns made in an earlier appointment. Interconsultation is performed with the hematologist who by laboratory examinations notice decreased coagulation factor VIII confirming the diagnosis of hemophilia A. It plans and conducts comprehensive treatment dental team with the hematologist who said that patients in hospitals with the replacement of missing clotting factor is prepared by cryo precipitates or with concentrated factor VIII intravenously before and after his dental intervention. The aim of the article is to highlight that hemophilia can be a disease detected during dental surgery in some patients and for it to be successfully treated with multidisciplinary management protocol is required between hematologists and dentists.

  5. International recommendations on the diagnosis and treatment of patients with acquired hemophilia A

    Science.gov (United States)

    Huth-Kühne, Angela; Baudo, Francesco; Collins, Peter; Ingerslev, Jørgen; Kessler, Craig M.; Lévesque, Hervé; Castellano, Maria Eva Mingot; Shima, Midori; St-Louis, Jean

    2009-01-01

    Acquired hemophilia A (AHA) is a rare bleeding disorder characterized by autoantibodies directed against circulating coagulation factor (F) VIII. Typically, patients with no prior history of a bleeding disorder present with spontaneous bleeding and an isolated prolonged aPTT. AHA may, however, present without any bleeding symptoms, therefore an isolated prolonged aPTT should always be investigated further irrespective of the clinical findings. Control of acute bleeding is the first priority, and we recommend first-line therapy with bypassing agents such as recombinant activated FVII or activated prothrombin complex concentrate. Once the diagnosis has been achieved, immediate autoantibody eradication to reduce subsequent bleeding risk should be performed. We recommend initial treatment with corticosteroids or combination therapy with corticosteroids and cyclophosphamide and suggest second-line therapy with rituximab if first-line therapy fails or is contraindicated. In contrast to congenital hemophilia, no comparative studies exist to support treatment recommendations for patients with AHA, therefore treatment guidance must rely on the expertise and clinical experience of specialists in the field. The aim of this document is to provide a set of international practice guidelines based on our collective clinical experience in treating patients with AHA and contribute to improved care for this patient group. PMID:19336751

  6. Pain Experience in Hemophilia Patients: A Hermeneutic Phenomenological Study

    Science.gov (United States)

    Rambod, Masoume; Sharif, Farkhondeh; Molazem, Zahra; Khair, Kate

    2016-01-01

    ABSTRACT Background: Pain, as a crucial subsequence of joint hemorrhages in hemophilia patients, is chronic, debilitating, and distracting. This study aimed to describe and interpret pain experiences of hemophilia patients in their lives. Methods: This qualitative study with hermeneutic phenomenological approach was conducted on fourteen hemophilia patients who had been referred to a hemophilia center affiliated to Shiraz University of Medical Sciences, Shiraz, Iran. The study question was “what is the meaning of pain in hemophilia patients’ lives? The data were collected through semi-structured interviews and field notes through purposeful sampling. Then, thematic analysis with van Manen’s six-step methodological framework was used. MAX.QDA qualitative software package, 2010, was used to analyze the data. Results: The three main themes that emerged in this study were “alteration in physical health”, “engagement in psychological problems”, and “impairment in social relationships”. Alteration in physical health consisted of three subthemes, namely “impairment of physical function”, “change in body physics”, and “disturbance in sleep quality”. In addition, two subthemes including “nostalgia of pain in adults with hemophilia” and “psychological distress” emerged from engagement in psychological problems. Finally, “loss of social activity” and “change in relationships” were related to impairment in social relationships. Conclusion: The present study highlighted alteration in physical health, engagement in psychological problems, and impairment in social relationship as a result of pain in hemophilia patients. Thus, healthcare providers and family members have to pay special attention to these problems. Besides, providing complementary therapy interventions is suggested for reducing these issues. PMID:27713894

  7. Therapeutic approaches for treating hemophilia A using embryonic stem cells.

    Science.gov (United States)

    Kasuda, Shogo; Tatsumi, Kohei; Sakurai, Yoshihiko; Shima, Midori; Hatake, Katsuhiko

    2016-06-01

    Hemophilia A is an X-linked rescessive bleeding disorder that results from F8 gene aberrations. Previously, we established embryonic stem (ES) cells (tet-226aa/N6-Ainv18) that secrete human factor VIII (hFVIII) by introducing the human F8 gene in mouse Ainv18 ES cells. Here, we explored the potential of cell transplantation therapy for hemophilia A using the ES cells. Transplant tet-226aa/N6-Ainv18 ES cells were injected into the spleens of severe combined immunodeficiency (SCID) mice, carbon tetrachloride (CCl4)-pretreated wild-type mice, and CCl4-pretreated hemophilia A mice. F8 expression was induced by doxycycline in drinking water, and hFVIII-antigen production was assessed in all cell transplantation experiments. Injecting the ES cells into SCID mice resulted in an enhanced expression of the hFVIII antigen; however, teratoma generation was confirmed in the spleen. Transplantation of ES cells into wild-type mice after CCl4-induced liver injury facilitated survival and engraftment of transplanted cells without teratoma formation, resulting in hFVIII production in the plasma. Although CCl4 was lethal to most hemophilia A mice, therapeutic levels of FVIII activity, as well as the hFVIII antigen, were detected in surviving hemophilia A mice after cell transplantation. Immunolocalization results for hFVIII suggested that transplanted ES cells might be engrafted at the periportal area in the liver. Although the development of a safer induction method for liver regeneration is required, our results suggested the potential for developing an effective ES-cell transplantation therapeutic model for treating hemophilia A in the future. Copyright © 2016 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. All rights reserved.

  8. Prevention of the Musculoskeletal Complications of Hemophilia

    Directory of Open Access Journals (Sweden)

    E. C. Rodriguez-Merchan

    2012-01-01

    Full Text Available Hemophilia is an inherited disorder of clotting factor deficiencies resulting in musculoskeletal bleeding, including hemarthroses, leading to musculoskeletal complications. The articular problems of hemophiliac patients begin in infancy. These include: recurrent hemarthroses, chronic synovitis, flexion deformities, hypertrophy of the growth epiphyses, damage to the articular cartilage, and hemophilic arthropathy. The most commonly affected joints are the ankle, the knee, and the elbow. Hematologic prophylactic treatment from ages 2 to 18 years could avoid the development of hemophilic arthropathy if the concentration of the patient's deficient factor is prevented from falling below 1% of normal. Hemarthroses can be prevented by the administration of clotting factor concentrates (prophylaxis. However, high costs and the need for venous access devices in younger children continue to complicate recommendations for universal prophylaxis. Prevention of joint arthropathy needs to focus on prevention of hemarthroses through prophylaxis, identifying early joint disease through the optimal use of cost-effective imaging modalities and the validation of serological markers of joint arthropathy. Screening for effects on bone health and optimal management of pain to improve quality of life are, likewise, important issues. Major hemarthrosis and chronic hemophilic synovitis should be treated aggressively to prevent hemophilic arthropathy.

  9. Report on an Investigation into an Entry Level Clinical Doctorate for the Genetic Counseling Profession and a Survey of the Association of Genetic Counseling Program Directors.

    Science.gov (United States)

    Reiser, Catherine; LeRoy, Bonnie; Grubs, Robin; Walton, Carol

    2015-10-01

    The master's degree is the required entry-level degree for the genetic counseling profession in the US and Canada. In 2012 the Association of Genetic Counseling Program Directors (AGCPD) passed resolutions supporting retention of the master's as the entry-level and terminal degree and opposing introduction of an entry-level clinical doctorate (CD) degree. An AGCPD workgroup surveyed directors of all 34 accredited training programs with the objective of providing the Genetic Counseling Advanced Degrees Task Force (GCADTF) with information regarding potential challenges if master's programs were required to transition to an entry-level CD. Program demographics, projected ability to transition to an entry-level CD, factors influencing ability to transition, and potential effects of transition on programs, students and the genetic counseling workforce were characterized. Two programs would definitely be able to transition, four programs would close, thirteen programs would be at risk to close and fourteen programs would probably be able to transition with varying degrees of difficulty. The most frequently cited limiting factors were economic, stress on clinical sites, and administrative approval of a new degree/program. Student enrollment under an entry-level CD model was projected to decrease by 26.2 %, negatively impacting the workforce pipeline. The results further illuminate and justify AGCPD's position to maintain the master's as the entry-level degree.

  10. Identification of a novel mutation in HPS6 in a patient with hemophilia B and oculocutaneous albinism.

    Science.gov (United States)

    O'Brien, Kevin J; Lozier, Jay; Cullinane, Andrew R; Osorio, Brigitte; Nghiem, Khanh; Speransky, Vladislav; Zein, Wadih M; Mullikin, James C; Neff, Anne T; Simon, Karen L; Malicdan, May Christine V; Gahl, William A; Young, Lisa R; Gochuico, Bernadette R

    2016-11-01

    Hemophilia B, an X-linked disease, manifests with recurrent soft tissue bleeding episodes. Hermansky-Pudlak syndrome, a rare autosomal recessive disorder, is characterized by oculocutaneous albinism and an increased tendency to bleed due to a platelet storage pool defect. We report a novel mutation in HPS6 in a Caucasian man with hemophilia B and oculocutaneous albinism. The patient was diagnosed with hemophilia B at age 4months due to recurrent soft tissue bleeding episodes, and he was also diagnosed with Hermansky-Pudlak syndrome at 32years of age due to unexplained oculocutaneous albinism. His factor IX level was markedly reduced at 13%; whole exome and Sanger sequencing showed the Durham mutation in F9 (NM_000133.3). The diagnosis of Hermansky-Pudlak syndrome subtype 6 was established by demonstrating absence of platelet delta granules on whole mount electron microscopy, an abnormal secondary wave in platelet aggregation studies, and a novel homozygous c.1114 C>T (p.Arg372*) mutation in HPS6 (NM_024747.5) on exome analysis and Sanger sequencing. Clinical phenotyping revealed no evidence of recurrent or unusual infections, interstitial lung disease or pulmonary fibrosis, or neurological disorders. The patient was treated with fresh frozen plasma, recombinant factor IX, and aminocaproic acid. Treatment with desmopressin was added to his regimen after he was diagnosed with Hermansky-Pudlak syndrome. Treatment of bleeding episodes results in effective hemostasis, and the patient has not required platelet or blood product transfusions. This report highlights the need to consider Hermansky-Pudlak syndrome as an etiology of oculocutaneous albinism even in patients with known hematologic disorders associated with bleeding. Identification of a novel mutation in HPS6 in an individual with hemophilia B shows that, although quite rare, patients may be diagnosed with two independent inherited bleeding disorders. No evidence of lung disease was found in this adult patient

  11. Renal Abnormalities Among Egyptian Children With Hemophilia A Using Renal Scintigraphy: Relation to Risk Factors and Disease Severity.

    Science.gov (United States)

    Hamed, Ahmed Alsaeed; Shalaby, Mennatallah Hatem; El-Kinawy, Nihal Saad; Elamawy, Alaa Adel; Abd El-Ghany, Shereen Mohamed

    2017-07-01

    Many risk factors may contribute to renal disease in patients with hemophilia A. We aimed to evaluate functional and structural renal abnormalities among a group of Egyptian children with severe and moderate hemophilia A using technetium-99m diethylene triamine pentaacetic acid ( 99m Tc-DTPA) and technetium-99 m dimercaptusuccinic acid ( 99m Tc-DMSA) scan. We also aimed to determine the relation between these abnormalities and different risk factors and disease severity. Forty male patients, 16 with severe and 24 with moderate hemophilia A, were enrolled in this study. Their mean age was 10.2 ± 4.3 years (range, 5-17 years). Full history taking, clinical examination, laboratory, and radionuclide investigations including serum creatinine, blood urea nitrogen (BUN), urine analysis, creatinine clearance, 24-hour urinary protein, 99m Tc-DTPA scan, and 99m Tc-DMSA scan were performed to all enrolled patients. Serum creatinine and BUN were normal in all patients, and corrected creatinine clearance was diminished in 2 patients. However, 99m Tc-DTPA results yielded 19 (47.5%) patients with diminished glomerular filtration rate (GFR). Moreover, it showed that 14 (35%) had obstructive uropathy, 15 (37.5%) had obstructive nephropathy, while 11 (27.5%) patients showed normal scan. One patient had atrophy of 1 kidney on 99m Tc-DMSA scan. Among our cohort, 5 (12.5%) patients were hypertensive. Microscopic hematuria was detected in 14 (35%) patients while 72.5% had proteinuria. We found an association between hematuria and hypertension with diminished GFR. Despite normal kidney functions (serum creatinine and BUN), we found a high rate of diminished GFR and obstructive uropathy and nephropathy as detected by 99m Tc-DTPA scan among children with hemophilia A.

  12. Hemoaction game: an educational step to improve hemophilia children and nurses self-efficacy

    Directory of Open Access Journals (Sweden)

    NOOASHIN BEHESHTIPOOR

    2016-10-01

    Full Text Available As hemophilia is a chronic bleeding disease and can interfere with daily performance of children, these children require continuous training to prevent bleeding and take timely action (1. Since children nurses play an important role in the education of involved children and their Selfefficacy and also due to today’s approach which is using educational computer games, the use of educational games in respect to teach hemophilia children how to have self-efficacy can be effective (2. Hemoaction game is a computerized educational game designed by the World Federation of Hemophilia to educate hemophilia disease and related procedures to the care of children with hemophilia. By the use of this game children with hemophilia (aged 8-12 and also nursing experts were educated how to increase self efficacy. Nursing School of Shiraz University of Medical Sciences has used this game for the first time after its publishing, in the world (3. The results of the mentioned study demonstrates that after the Hemophilia disease and its related procedures were instructed to children with hemophilia and nursing experts in order to know how to increase patients’ self efficacy by modern approaches, self efficacy of hemophilia children and nurses were both improved. This educational method is a novel way to enhance both Hemophilia children and nursing staff, as major participants in routine and lifelong education process, self-efficacy. Due to nurses’ important role in improving children with hemophilia self-efficacy by different instructions and world leading educational approaches towards use of modern technology in education, using Hemoaction educational game, published by World Federation of Hemophilia and used by Nursing and Midwifery College of Shiraz University of Medical Sciences for the first time, can fulfill hemophilia children needs of care.

  13. Comparing thrombin generation in patients with hemophilia A and patients on vitamin K antagonists.

    Science.gov (United States)

    de Koning, M L Y; Fischer, K; de Laat, B; Huisman, A; Ninivaggi, M; Schutgens, R E G

    2017-05-01

    Essentials It is unknown if hemophilia patients with atrial fibrillation need anticoagulation. Endogenous thrombin potentials (ETP) in hemophilia patients and patients on coumarins were compared. Severe hemophilia patients had comparable ETP to therapeutic international normalized ratio (INR). In non-severe hemophilia, 33% had higher ETP than therapeutic INR and may need anticoagulation. Click to hear Dr Negrier's perspective on global assays for assessing coagulation SUMMARY: Background It is unknown whether patients with hemophilia A with atrial fibrillation require treatment with vitamin K antagonists (VKAs) to the same extent as the normal population. Objective To compare hemostatic potential in hemophilia patients and patients on VKAs using thrombin generation (TG). Methods In this cross-sectional study, TG, initiated with 1pM tissue factor, was measured in 133 patients with severe (FVIII hemophilia A, 97 patients on a VKA with an international normalized ratio (INR) ≥ 1.5 and healthy controls. Endogenous thrombin potential (ETP) (nm*min) was compared according to FVIII level (hemophilia patients and patients on VKAs had lower median ETPs at 304 (196-449) and 176 (100-250), respectively. ETP was quite similar in severe hemophilia patients (185 [116-307]) and patients with a therapeutic INR (156 [90-225]). Compared with patients with therapeutic INR, ETP in patients with FVIII 1-19% and patients with FVIII 20-50% was higher at 296 (203-430) and 397 (219-632), respectively. All patients with therapeutic INR had an ETP hemophilia patients, 70% of patients with FVIII 1-19% and 52% of patients with FVIII 20-50% had an ETP hemophilia patients, TG was comparable to that in patients with a therapeutic INR. In one-third of non-severe hemophilia patients, TG was higher. These results suggest that anticoagulation therapy should be considered in a substantial proportion of non-severe hemophilia patients. © 2017 International Society on Thrombosis and Haemostasis.

  14. Anti-factor IXa/X bispecific antibody ACE910 prevents joint bleeds in a long-term primate model of acquired hemophilia A

    Science.gov (United States)

    Yoshihashi, Kazutaka; Takeda, Minako; Kitazawa, Takehisa; Soeda, Tetsuhiro; Igawa, Tomoyuki; Sampei, Zenjiro; Kuramochi, Taichi; Sakamoto, Akihisa; Haraya, Kenta; Adachi, Kenji; Kawabe, Yoshiki; Nogami, Keiji; Shima, Midori; Hattori, Kunihiro

    2014-01-01

    ACE910 is a humanized anti-factor IXa/X bispecific antibody mimicking the function of factor VIII (FVIII). We previously demonstrated in nonhuman primates that a single IV dose of ACE910 exerted hemostatic activity against hemophilic bleeds artificially induced in muscles and subcutis, and that a subcutaneous (SC) dose of ACE910 showed a 3-week half-life and nearly 100% bioavailability, offering support for effective prophylaxis for hemophilia A by user-friendly SC dosing. However, there was no direct evidence that such SC dosing of ACE910 would prevent spontaneous bleeds occurring in daily life. In this study, we newly established a long-term primate model of acquired hemophilia A by multiple IV injections of an anti-primate FVIII neutralizing antibody engineered in mouse-monkey chimeric form to reduce its antigenicity. The monkeys in the control group exhibited various spontaneous bleeding symptoms as well as continuous prolongation of activated partial thromboplastin time; notably, all exhibited joint bleeds, which are a hallmark of hemophilia. Weekly SC doses of ACE910 (initial 3.97 mg/kg followed by 1 mg/kg) significantly prevented these bleeding symptoms; notably, no joint bleeding symptoms were observed. ACE910 is expected to prevent spontaneous bleeds and joint damage in hemophilia A patients even with weekly SC dosing, although appropriate clinical investigation is required. PMID:25274508

  15. Problems of Hemophilia and the Role of the Rehabilitation Counselor.

    Science.gov (United States)

    Carrai, Edward B.; Handford, H. Allen

    1983-01-01

    Because of the multiple problems associated with hemophilia, optimal treatment is usually provided in a comprehensive care setting by a team of medical and nonmedical professionals. The rehabilitation counselor contributes expertise to that of other team members in development and implementation of an individual rehabilitation plan for…

  16. Chronic spinal epidural hematoma in hemophilia A in a child

    International Nuclear Information System (INIS)

    Stanley, P.; McComb, J.G.; University of Southern California, Los Angeles

    1983-01-01

    A case of chronic spinal epidural hematoma in a thirteen-year-old male, subsequently found to have hemophilia A is reported. Following myelography, surgery was undertaken with clotting factor replacement with relief of cord compression. The patient made an uneventful recovery. (orig.)

  17. Chronic spinal epidural hematoma in hemophilia A in a child

    Energy Technology Data Exchange (ETDEWEB)

    Stanley, P.; McComb, J.G.

    1983-06-01

    A case of chronic spinal epidural hematoma in a thirteen-year-old male, subsequently found to have hemophilia A is reported. Following myelography, surgery was undertaken with clotting factor replacement with relief of cord compression. The patient made an uneventful recovery.

  18. Pain Experience in Hemophilia Patients: A Hermeneutic Phenomenological Study

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    Masoume Rambod

    2016-10-01

    Full Text Available Background: Pain, as a crucial subsequence of joint hemorrhages in hemophilia patients, is chronic, debilitating, and distracting. This study aimed to describe and interpret pain experiences of hemophilia patients in their lives. Methods: This qualitative study with hermeneutic phenomenological approach was conducted on fourteen hemophilia patients who had been referred to a hemophiliacenter affiliated to Shiraz University of Medical Sciences, Shiraz, Iran. The study question was “what is the meaning of pain in hemophilia patients’ lives? The data were collected through semi-structured interviews and field notes through purposeful sampling. Then, thematic analysis with van Manen’s six-step methodological framework was used. MAX.QDA qualitative software package, 2010, was used to analyze the data. Results: The three main themes that emerged in this study were “alteration in physical health”, “engagement in psychological problems”, and “impairment in social relationships”. Alteration in physical health consisted of three subthemes, namely “impairment of physical function”, “change in body physics”, and “disturbance in sleep quality”. In addition, two subthemes including “nostalgia of pain in adults with hemophilia” and “psychological distress” emerged from engagement in psychological problems. Finally, “loss of social activity” and “change in relationships” were related to impairment in social relationships. Conclusion: The present study highlighted alteration in physical health, engagement in psychological problems, and impairment in social relationship as a result of pain in hemophilia patients. Thus, healthcare providers and family members have to pay special attention to these problems. Besides, providing complementary therapy interventions is suggested for reducing these issues.

  19. Cross-cultural adaptation of the CHO-KLAT for boys with hemophilia in rural and urban china

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    Wu Runhui

    2012-09-01

    Full Text Available Abstract Background Quality of life (QoL is increasingly recognized as an important outcome measure in clinical trials. The Canadian Hemophilia Outcomes-Kids Life Assessment Tool (CHO-KLAT shows promise for use in China. Objective To adapt the CHO-KLAT version 2.0 for use in clinical trials in China. Methods Forward and back translations of the CHO-KLAT2.0 were completed in 2008. Between October 2009 and June 2010, a series of 3 focus groups were held with 20 boys and 31 parents in rural and urban China to elicit additional concepts, important to their QoL, for the Chinese CHO-KLAT2.0. All of the items identified by boys and parents were reviewed by a group of experts, resulting in a Chinese version of the CHO-KLAT2.0. This version underwent a detailed cognitive debriefing process between October 2010 and June 2011. Thirteen patient-parent pairs participated in this cognitive debriefing process until a stable and clearly understood Chinese version of the CHO-KLAT2.0 was obtained. Results The initial back translation of the Chinese CHO-KLAT2.0 was slightly discrepant from the original English version on 12 items. These were all successfully adjudicated. The focus groups identified 9 new items that formed an add-on Socio-Economic Context (SEC module for China. Linguistic improvements were made after the 2nd, 5th, 7th and 13th cognitive debriefings pairs and affected a total of 18 items. The result was a 35 item CHO-KLAT2.0 and a SEC module in Simplified Chinese, both of which have good content validity. Conclusion This detailed process proved to be extremely valuable in ensuring the items were accurately interpreted by Chinese boys with hemophilia ages ≤18 years. The need for the additional SEC module highlighted the different context that currently exists in China with regard to hemophilia care as compared to many Western countries, and will be important in tracking progress within both rural and urban China over time. Changes based on the

  20. A Case of Hemophilia A Associated with Spontaneous Hemorrhagic Pleural Effusion and Intracranial Hem

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    Nuri Tutar

    2014-03-01

    Full Text Available Hemophilia A is a sex-linked recessive coagulation disorder almost exclusively occurring in male subjects and caused by a deficiency of factor VIII. It  is a rare disorder characterized by spontaneous hemorrhages. Spontaneous bleeding in the pleural space is very rare in hemophilia both in children and adults. Here in, we present the case of a 56-year-old hemophilia A patient with hemorrhagic pleural effusion and intracranial hematoma.

  1. DESCRIPTIVE EPIDEMIOLOGY OF HEMOPHILIA AND OTHER COAGULATION DISORDERS IN MANSOURA , EGYPT

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    Rasha ElAshry

    2010-08-01

    Full Text Available

    Hemophilia represent the most severe inherited bleeding  disorder (INB , it’s thought to affect inviduals from all geographical areas in equal frequency. In Egypt which has a population of approximately (80million consanguineous marriage are frequent, therefore autosomal recessive coagulation disorders reach a higher prevalence than in many other countries.

    The primary aim of this study was to describe the epidemiological situation of hemophilia in Mansoura, Egypt ,as based on retrospective analysis of clinical records Mansoura University Children Hospital between years 2000 and 2008. The second aim was to assess the orthopedic complications and occurrence of hepatitis C in those patients and relate this status to the type of replacement therapy received prior to the study.

    The study included 72 children with hematological disorders registered from 2000 to 2008 in MUCH. The hemophilic patient was defined as a person with physician-diagnosed hemophilia A or B and a measured factor VIII or IX activity level of 30% or less. Persons with acquired inhibitors of FVIII or FIX excluded. Severity level was categorized as mild if the factor activity level was 6

  2. Hemofilia A adquirida Acquired hemophilia A

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    Delfina Almagro Vázquez

    2010-12-01

    Full Text Available La hemofilia A adquirida (HAA es un trastorno hemorrágico poco frecuente caracterizado por la presencia de autoanticuerpos contra el factor VIII (FVIII circulante. Aproximadamente en la mitad de los casos se ha observado un grupo heterogéneo de procesos patológicos que incluyen, entre otros, enfermedades autoinmunes y malignas y durante el embarazo, parto y puerperio. Las manifestaciones hemorrágicas son variables y fundamentalmente de tipo cutáneo mucoso. El diagnóstico se basa en el hallazgo en un paciente con manifestaciones hemorrágicas, prolongación del tiempo parcial de tromboplastina activado (TPTA, disminución de la actividad del FVIII y presencia de inhibidores del FVIII. El tratamiento de HAA incluye el control de las manifestaciones hemorrágicas y la supresión de la producción del anticuerpo. El concentrado de factor VIIa recombinante (FVIIar y el concentrado de complejo protrombínico (CCPA se consideran el tratamiento antihemorrágico de primera línea. Como terapéutica alternativa, en algunos casos puede utilizarse el concentrado de FVIII, la plasmaféresis y la inmunoadsorción extracorpórea. La prednisona sola o asociada con la ciclofosfamida, constituye el tratamiento inmunosupresor de primera línea. En pacientes refractarios puede administrarse como terapéutica de segunda línea, el rituximab (anti-CD20. Con la azatiopina, la ciclosporina, la vincristina y el micofenolato de mofetil, se han obtenido resultados variables.Acquired hemophilia A (AHA is an uncommon hemorrhagic disorder characterized by presence of autoantibodies to circulating factor VIII. Approximately in half of cases it is noted a heterogeneous group of pathological processes including among others, autoimmune and malignant diseases and during pregnancy, labor and puerperium. Hemorrhagic manifestations are variable and mainly of mucous cutaneous type. Diagnosis is based on the finding of a patient presenting with hemorrhagic manifestations

  3. Advanced therapies for the treatment of hemophilia: future perspectives.

    Science.gov (United States)

    Liras, Antonio; Segovia, Cristina; Gabán, Aline S

    2012-12-13

    Monogenic diseases are ideal candidates for treatment by the emerging advanced therapies, which are capable of correcting alterations in protein expression that result from genetic mutation. In hemophilia A and B such alterations affect the activity of coagulation factors VIII and IX, respectively, and are responsible for the development of the disease. Advanced therapies may involve the replacement of a deficient gene by a healthy gene so that it generates a certain functional, structural or transport protein (gene therapy); the incorporation of a full array of healthy genes and proteins through perfusion or transplantation of healthy cells (cell therapy); or tissue transplantation and formation of healthy organs (tissue engineering). For their part, induced pluripotent stem cells have recently been shown to also play a significant role in the fields of cell therapy and tissue engineering. Hemophilia is optimally suited for advanced therapies owing to the fact that, as a monogenic condition, it does not require very high expression levels of a coagulation factor to reach moderate disease status. As a result, significant progress has been possible with respect to these kinds of strategies, especially in the fields of gene therapy (by using viral and non-viral vectors) and cell therapy (by means of several types of target cells). Thus, although still considered a rare disorder, hemophilia is now recognized as a condition amenable to gene therapy, which can be administered in the form of lentiviral and adeno-associated vectors applied to adult stem cells, autologous fibroblasts, platelets and hematopoietic stem cells; by means of non-viral vectors; or through the repair of mutations by chimeric oligonucleotides. In hemophilia, cell therapy approaches have been based mainly on transplantation of healthy cells (adult stem cells or induced pluripotent cell-derived progenitor cells) in order to restore alterations in coagulation factor expression.

  4. Defining the impact of hemophilia: the Academic Achievement in Children with Hemophilia Study.

    Science.gov (United States)

    Shapiro, A D; Donfield, S M; Lynn, H S; Cool, V A; Stehbens, J A; Hunsberger, S L; Tonetta, S; Gomperts, E D

    2001-12-01

    We characterized a population-based cohort of school-aged children with severe hemophilia with respect to type of treatment, on-demand versus prophylaxis, and frequency of bleeding episodes in the year before enrollment. We also investigated the association between hemophilia-related morbidity, measured by number of bleeding episodes in the year before enrollment, and academic performance after adjustment for other factors known to have an effect on achievement. Finally, we explored the mechanisms for the association between bleeding episodes and academic achievement. This study was a multicenter investigation of boys 6 to 12 years old with severe factor VIII deficiency (clotting factor level 2 months with a goal of preventing bleeding episodes. Academic achievement was measured by the Wechsler Individual Achievement Test. Quality of life was measured by the Child Health Questionnaire. Of particular interest was the Physical Summary (PhS) measure of the Child Health Questionnaire. The type of information captured by the PhS includes limitations in physical activity, limitations in the kind or amount of schoolwork or social activities the child engaged in, and presence of pain or discomfort. One hundred thirty-one children were enrolled, a median center recruitment rate of 77%. The mean age of the participants was 9.6 years, and approximately half of the participants had completed less than the fourth grade at the time of enrollment. Sixty-two percent of the children were on prophylaxis at enrollment, and 9% had previously been on prophylaxis but were currently on on-demand therapy. Two groups were defined: ever treated with prophylaxis and never treated with prophylaxis. For those ever treated, treatment duration ranged from 2.7 months to 7.7 years, with one half of the children treated with prophylaxis for >40% of their lifetimes; 29% had always been on on-demand therapy. Children in both treatment groups were similar with respect to age, clotting factor level

  5. INSIGHT in risk factors and treatment of inhibitors in nonsevere hemophilia A

    NARCIS (Netherlands)

    van Velzen, A.S.

    2016-01-01

    Hemophilia A is an inherited X-linked bleeding disorder that occurs in male offspring of carrier females. In these individuals a mutation in the F8 gene, located on the X-chromosome, causes a deficiency of the factor VIII protein, clotting factor VIII. The worldwide prevalence of hemophilia is 1 in

  6. Mortality caused by intracranial bleeding in non-severe hemophilia A patients: reply

    NARCIS (Netherlands)

    Loomans, J. I.; Fijnvandraat, K.

    2017-01-01

    With great interest we read the letter of Dr. Patil et al. (1) in which they present the number and percentage of hemophilia patients registered in the Mumbai hemophilia center who died from (intracranial) bleeding between 2002 and 2015. We thank Dr. Patil et al. for sharing their data and for

  7. Thirty years of hemophilia treatment in the Netherlands, 1972-2001

    NARCIS (Netherlands)

    Plug, Iris; van der Bom, Johanna G.; Peters, Marjolein; Mauser-Bunschoten, Evelien P.; de Goede-Bolder, Arja; Heijnen, Lily; Smit, Cees; Zwart-van Rijkom, Jeannette E. F.; Willemse, José; Rosendaal, Frits R.

    2004-01-01

    Since the introduction of replacement therapy in the early 1960s by the infusion of plasma-derived factor VIII and IX preparations, important changes have occurred for hemophilia patients. We studied the medical and social developments over 30 years of hemophilia treatment. Since 1972, 5

  8. Hypocoagulability does not protect against atherosclerosis in hemophilia A patients with obesity

    NARCIS (Netherlands)

    Biere-Rafi, S.; Tuinenburg, A.; Haak, B.; Peters, M.; De Groot, E.; Verhamme, P.; Peerlinck, K.; Visseren, F.; Kruip, M.; Gorkom, B.L.-V.; Buller, H.; Gerdes, V.; Schutgens, R.; Kamphuisen, P.

    Introduction: Hemophilia A patients have a 50% lower cardiovascular mortality than the general population. Whether this is caused by less atherosclerosis due to hypocoagulability is unclear. We assessed whether hemophilia A patients with obesity, a major atherosclerotic risk factor, have a lower

  9. Patient and parent preferences for characteristics of prophylactic treatment in hemophilia

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    Furlan R

    2015-11-01

    Full Text Available Roberto Furlan,1 Sangeeta Krishnan,2 Jeffrey Vietri3 1Advanced Methods, Kantar Health, Epsom, Surrey, UK; 2Global Health Economics and Outcomes Research, Biogen, MA, USA; 3Health Outcomes, Kantar Health, Milan, Italy Introduction: New longer-acting factor products will potentially allow for less frequent infusion in prophylactic treatment of hemophilia. However, the role of administration frequency relative to other treatment attributes in determining preferences for prophylactic hemophilia treatment regimens is not well understood. Aim: To identify the relative importance of frequency of administration, efficacy, and other treatment characteristics among candidates for prophylactic treatment for hemophilia A and B. Method: An Internet survey was conducted among hemophilia patients and the parents of pediatric hemophilia patients in Australia, Canada, and the US. A monadic conjoint task was included in the survey, which varied frequency of administration (three, two, or one time per week for hemophilia A; twice weekly, weekly, or biweekly for hemophilia B, efficacy (no bleeding or breakthrough bleeding once every 4 months, 6 months, or 12 months, diluent volume (3 mL vs 2.5 mL for hemophilia A; 5 mL vs 3 mL for hemophilia B, vials per infusion (2 vs 1, reconstitution device (assembly required vs not, and manufacturer (established in hemophilia vs not. Respondents were asked their likelihood to switch from their current regimen to the presented treatment. Respondents were told to assume that other aspects of treatment, such as risk of inhibitor development, cost, and method of distribution, would remain the same. Results: A total of 89 patients and/or parents of children with hemophilia A participated; another 32 were included in the exercise for hemophilia B. Relative importance was 47%, 24%, and 18% for frequency of administration, efficacy, and manufacturer, respectively, in hemophilia A; analogous values were 48%, 26%, and 21% in

  10. Shortened Lifespan and Lethal Hemorrhage in a Hemophilia A Mouse Model.

    Science.gov (United States)

    Staber, Janice M; Pollpeter, Molly J

    2016-01-01

    Hemophilia A animal models have helped advance our understanding of factor VIII deficiency. Previously, factor VIII deficient mouse models were reported to have a normal life span without spontaneous bleeds. However, the bleeding frequency and survival in these animals has not been thoroughly evaluated. To investigate the survival and lethal bleeding frequency in two strains of E-16 hemophilia A mice. We prospectively studied factor VIII deficient hemizygous affected males (n = 83) and homozygous affected females (n = 55) for survival and bleeding frequency. Animals were evaluated for presence and location of bleeds as potential cause of death. Hemophilia A mice had a median survival of 254 days, which is significantly shortened compared to wild type controls (p hemophilia A mice experienced hemorrhage in several tissues. This previously-underappreciated shortened survival in the hemophilia A murine model provides new outcomes for investigation of therapeutics and also reflects the shortened lifespan of patients if left untreated.

  11. Hemodialysis in a patient with severe hemophilia A and factor VIII inhibitor.

    Science.gov (United States)

    Gopalakrishnan, Natarajan; Usha, Thiruvengadam; Thopalan, Balasubramaniyan; Dhanapriya, Jeyachandran; Dineshkumar, Thanigachalam; Thirumalvalavan, Kaliaperumal; Sakthirajan, Ramanathan

    2016-10-01

    Hemophilia A is a hereditary X-linked recessive disease caused by mutations in the gene encoding factor VIII (FVIII), occurring in 1 out of 10,000 persons. Life expectancy and quality of life have dramatically improved recently in patients with hemophilia. Chronic kidney disease and need for renal replacement therapy in these patients are rare. The development of inhibitors to FVIII is the most serious complication of hemophilia and makes treatment of bleeds very challenging. We describe here a 28-year-old male patient with severe hemophilia A with presence of factor VIII inhibitor, who had end stage renal disease. Central venous access device was inserted along with infusion of factor eight inhibitor bypass activity before and after the procedure. He is currently on thrice weekly hemodialysis and doing well for 6 months without bleeding episodes. To our knowledge, hemophilia A with factor VIII inhibitor managed with hemodialysis has not been reported so far. © 2016 International Society for Hemodialysis.

  12. Targeted genome engineering in human induced pluripotent stem cells from patients with hemophilia B using the CRISPR-Cas9 system.

    Science.gov (United States)

    Lyu, Cuicui; Shen, Jun; Wang, Rui; Gu, Haihui; Zhang, Jianping; Xue, Feng; Liu, Xiaofan; Liu, Wei; Fu, Rongfeng; Zhang, Liyan; Li, Huiyuan; Zhang, Xiaobing; Cheng, Tao; Yang, Renchi; Zhang, Lei

    2018-04-06

    Replacement therapy for hemophilia remains a lifelong treatment. Only gene therapy can cure hemophilia at a fundamental level. The clustered regularly interspaced short palindromic repeats-CRISPR associated nuclease 9 (CRISPR-Cas9) system is a versatile and convenient genome editing tool which can be applied to gene therapy for hemophilia. A patient's induced pluripotent stem cells (iPSCs) were generated from their peripheral blood mononuclear cells (PBMNCs) using episomal vectors. The AAVS1-Cas9-sgRNA plasmid which targets the AAVS1 locus and the AAVS1-EF1α-F9 cDNA-puromycin donor plasmid were constructed, and they were electroporated into the iPSCs. When insertion of F9 cDNA into the AAVS1 locus was confirmed, whole genome sequencing (WGS) was carried out to detect the off-target issue. The iPSCs were then differentiated into hepatocytes, and human factor IX (hFIX) antigen and activity were measured in the culture supernatant. Finally, the hepatocytes were transplanted into non-obese diabetic/severe combined immunodeficiency disease (NOD/SCID) mice through splenic injection. The patient's iPSCs were generated from PBMNCs. Human full-length F9 cDNA was inserted into the AAVS1 locus of iPSCs of a hemophilia B patient using the CRISPR-Cas9 system. No off-target mutations were detected by WGS. The hepatocytes differentiated from the inserted iPSCs could secrete hFIX stably and had the ability to be transplanted into the NOD/SCID mice in the short term. PBMNCs are good somatic cell choices for generating iPSCs from hemophilia patients. The iPSC technique is a good tool for genetic therapy for human hereditary diseases. CRISPR-Cas9 is versatile, convenient, and safe to be used in iPSCs with low off-target effects. Our research offers new approaches for clinical gene therapy for hemophilia.

  13. Diagnostic and prognostic value of factor VIII binding antibodies in acquired hemophilia A: data from the GTH-AH 01/2010 study.

    Science.gov (United States)

    Werwitzke, S; Geisen, U; Nowak-Göttl, U; Eichler, H; Stephan, B; Scholz, U; Holstein, K; Klamroth, R; Knöbl, P; Huth-Kühne, A; Bomke, B; Tiede, A

    2016-05-01

    Essentials Factor VIII (FVIII) binding IgG detected by ELISA could be an alternative to the Bethesda assay. We studied the performance of anti-FVIII IgG ELISA in patients with acquired hemophilia and controls. Anti-FVIII IgG > 99th percentile of controls was highly sensitive and specific. Patients with high anti-FVIII IgG have a lower chance of achieving remission. Background Acquired hemophilia A is a severe bleeding disorder that requires fast and accurate diagnosis as it occurs often unexpectedly in previously healthy men and women of every age. The Nijmegen-modified Bethesda assay is the diagnostic reference standard for detecting neutralizing autoantibodies against factor VIII (FVIII), but is not widely available, not ideal for quantifying the complex type 2 inhibitors seen in acquired hemophilia, and suffers from high inter-laboratory variability. Objectives To assess the diagnostic and prognostic value of FVIII-binding antibodies as detected by ELISA compared with the Nijmegen Bethesda assay. Methods Samples from the time of first diagnosis and clinical data were available from 102 patients with acquired hemophilia enrolled in the prospective GTH-AH 01/2010 study. Controls (n = 102) were matched for gender and age. Diagnostic cut-offs were determined by receiver-operator curve analysis. The prognostic value was assessed in 92 of the 102 patients by Cox regression analysis of time to partial remission. Results Anti-FVIII IgG above the 99th percentile (> 15 arbitrary units per mL) revealed high sensitivity and specificity (both 0.99; 95% confidence interval, 0.95-1.0) for diagnosing acquired hemophilia. The likelihood of achieving partial remission was related to anti-FVIII IgG concentration ( 1050, 0.39). The Bethesda titer was only associated with the likelihood of partial remission when analyzed in the central laboratory, but not when data from local GTH study sites were used. Conclusion Although the Nijmegen-modified Bethesda assay is the reference

  14. Genetic Correction and Hepatic Differentiation of Hemophilia B-specific Human Induced Pluripotent Stem Cells.

    Science.gov (United States)

    He, Qiong; Wang, Hui-Hui; Cheng, Tao; Yuan, Wei-Ping; Ma, Yu-Po; Jiang, Yong-Ping; Ren, Zhi-Hua

    2017-09-27

    Objective To genetically correct a disease-causing point mutation in human induced pluripotent stem cells (iPSCs) derived from a hemophilia B patient. Methods First, the disease-causing mutation was detected by sequencing the encoding area of human coagulation factor IX (F IX) gene. Genomic DNA was extracted from the iPSCs, and the primers were designed to amplify the eight exons of F IX. Next, the point mutation in those iPSCs was genetically corrected using CRISPR/Cas9 technology in the presence of a 129-nucleotide homologous repair template that contained two synonymous mutations. Then, top 8 potential off-target sites were subsequently analyzed using Sanger sequencing. Finally, the corrected clones were differentiated into hepatocyte-like cells, and the secretion of F IX was validated by immunocytochemistry and ELISA assay. Results The cell line bore a missense mutation in the 6 th coding exon (c.676 C>T) of F IX gene. Correction of the point mutation was achieved via CRISPR/Cas9 technology in situ with a high efficacy at about 22% (10/45) and no off-target effects detected in the corrected iPSC clones. F IX secretion, which was further visualized by immunocytochemistry and quantified by ELISA in vitro, reached about 6 ng/ml on day 21 of differentiation procedure. Conclusions Mutations in human disease-specific iPSCs could be precisely corrected by CRISPR/Cas9 technology, and corrected cells still maintained hepatic differentiation capability. Our findings might throw a light on iPSC-based personalized therapies in the clinical application, especially for hemophilia B.

  15. Reliability of patient-reported outcome instruments in US adults with hemophilia: the Pain, Functional Impairment and Quality of life (P-FiQ study

    Directory of Open Access Journals (Sweden)

    Kempton CL

    2017-09-01

    Full Text Available Christine L Kempton,1 Michael Wang,2 Michael Recht,3 Anne Neff,4 Amy D Shapiro,5 Amit Soni,6 Roshni Kulkarni,7 Tyler W Buckner,2 Katharine Batt,8 Neeraj N Iyer,9 David L Cooper9 1Departments of Pediatrics and Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA; 2Hemophilia and Thrombosis Center, University of Colorado School of Medicine, Aurora, CO, USA; 3The Hemophilia Center, Oregon Health & Science University, Portland, OR, USA; 4Hematology and Medical Oncology, Cleveland Clinic, Cleveland, OH, USA; 5Indiana Hemophilia & Thrombosis Center, Indianapolis, IN, USA; 6Center for Inherited Blood Disorders and CHOC Children’s Hospital/UC Irvine, Orange, CA, USA; 7MSU Center for Bleeding and Clotting Disorders, Michigan State University, East Lansing, MI, USA; 8Hematology and Oncology, Wake Forest School of Medicine, Winston-Salem, NC, USA; 9Clinical, Medical and Regulatory Affairs, Novo Nordisk Inc., Plainsboro, NJ, USA Background: Hemophilia is marked by frequent joint bleeding, resulting in pain and functional impairment.Objective: This study aimed to assess the reliability of five patient-reported outcome (PRO instruments in people with hemophilia (PWH in a non-bleeding state.Methods: Adult male PWH of any severity and inhibitor status, with a history of joint pain or bleeding, completed a pain history and five PRO instruments (EQ-5D-5L, Brief Pain Inventory v2 [BPI], International Physical Activity Questionnaire [IPAQ], Short Form 36 Health Survey v2 [SF-36v2], and Hemophilia Activities List [HAL] during their routine comprehensive care visit. Patients were approached to complete the PRO instruments again at the end of their visit while in a similar non-bleeding state. Concordance of individual questionnaire items and correlation between domain scores were assessed using intra-class correlation coefficient (ICC.Results: Participants completing the retest (n=164 had a median age of 33.9 years. Median time for

  16. Director`s series on proliferation

    Energy Technology Data Exchange (ETDEWEB)

    Bailey, K.C.; Price, M.E. [eds.

    1994-12-27

    The Director`s Series on Proliferation is an occasional publication of essays on the topics of nuclear, chemical, biological, and missile proliferation. The seven papers presented in this issue cover the following topics: Should the Treaty on the Nonproliferation of Nuclear Weapons (NPT) be amended?; NPT extension - Legal and procedural issues; An Indonesian view of NPT review conference issues; The treaty of Tlatelolco and the NPT - Tools for peace and development; Perspectives on cut-off, weapons dismantlement, and security assurances; Belarus and NPT challenges; A perspective on the chemical weapons convention - Lessons learned from the preparatory commission.

  17. Associations of quality of life, pain, and self-reported arthritis with age, employment, bleed rate, and utilization of hemophilia treatment center and health care provider services: results in adults with hemophilia in the HERO study

    Directory of Open Access Journals (Sweden)

    Forsyth AL

    2015-10-01

    Full Text Available Angela L Forsyth,1 Michelle Witkop,2 Angela Lambing,3 Cesar Garrido,4 Spencer Dunn,5 David L Cooper,6 Diane J Nugent7 1BioRx, Cincinnati, OH, USA; 2Munson Medical Center, Traverse City, MI, USA; 3Henry Ford Hospital, Detroit, MI, USA; 4Asociacion Venezolana para la Hemofilia, Caracas, Venezuela; 5Center for Inherited Blood Disorders, Orange, CA, USA; 6Novo Nordisk Inc., Plainsboro, NJ, USA; 7Children’s Hospital of Orange County, Center for Inherited Blood Disorders, Orange, CA, USA Introduction: Severe hemophilia and subsequent hemophilic arthropathy result in joint pain and impaired health-related quality of life (HRQoL. Assessment of HRQoL in persons with hemophilia (PWH, including underlying factors that drive HRQoL differences, is important in determining health care resource allocation and in making individualized clinical decisions.Aim: To examine potential associations between HRQoL, pain interference, and self-reported arthritis and age, employment, activity, bleed frequency, and hemophilia treatment center and health care professional utilization.Methods: PWH (age ≥18 years from ten countries completed a 5-point Likert scale on pain interference over the previous 4 weeks, the EQ-5D-3L scale (mobility, usual activities, self-care, pain/discomfort, anxiety/depression including a health-related visual analog scale (0–100, coded as an 11-point categorical response.Results: Pain interference (extreme/a lot was higher in PWH aged >40 years (31% compared to those aged 31–40 years (27% or ≤30 years (21%. In an analysis of eight countries with home treatment, PWH who reported EQ-5D mobility issues were less likely to be employed (53% vs 79%, with no mobility issues. Median annual bleed frequency increased with worsening EQ-5D pain or discomfort. The percentage of PWH with inhibitors reporting visual analog scale scores of 80–90–100 was lower (20% than those without inhibitors (34%. Median bleed frequency increased with pain

  18. An examination of the symptoms of anxiety and parental attitude in children with hemophilia.

    Science.gov (United States)

    Abali, Osman; Zülfikar, Osman Bülent; Karakoç Demirkaya, Sevcan; Ayaydin, Hamza; Kircelli, Fuat; Duman, Mehtap

    2014-01-01

    Hemophilia is an inherited disease with serious repercussions. Psychiatric symptoms are frequently seen in children and adolescents with hemophilia. The aim of this study was to assess symptoms of anxiety in children with hemophilia and parental attitude towards children with hemophilia. 42 boys were assessed according to child and adolescent psychiatry. Anxiety symptoms and parental attitude were obtained by the State-Trait Anxiety Scale, the Self-Report for Childhood Anxiety Related Disorders (SCARED) and the Parent Attitude Research Instrument (PARI). The mean age was 11.6 ± 2.5 (range; 7-16). State anxiety scores (44.02 ± 6.9) were higher than trait anxiety scores (32.7 + 7.5). The most interesting results were high scores related to overprotective mothering (47.9 ± 9.7) and the application of strict discipline (39.4 ± 9.1). The total SCARED scores obtained were (23.25 ± 11.3). Assuring a high quality of life is important for children and adolescents with chronic illness. Quality of life is negatively affected by psychiatric symptoms (e.g. anxiety symptoms, depression, intra-familial stress symptoms) in children with hemophilia. This study suggests that high anxiety scores and problems related to parental attitude can be seen in children and adolescents with hemophilia. These problems caused by parental attitude and anxiety symptoms should be considered in the treatment of hemophilia.

  19. Causes of Death Among 379 Patients With Hemophilia: A Developing Country's Report.

    Science.gov (United States)

    Mansouritorghabeh, Hassan; Rahimi, Hossein; Mohades, Seyed Tahereh; Behboudi, Maryam

    2018-05-01

    There are steps to achieve an optimum life for patients with hemophilia in developing countries, and awareness of the pattern of death in patients with hemophilia is a prerequisite for any health-care program. Owing to the lack of any data on the pattern of death in patients with hemophilia from developing countries, the current study was done to address common causes of death, and the spectrum of causes of death among individuals with hemophilia A and B. To address the pattern of death in northeast of Iran, we retrospectively collected demographic data regarding deceased patients with hemophilia A and B. Overall, among 379 people with hemophilia A and B, there were 46 deaths. Thirty-two deaths happened in the severe forms of the diseases. The obtained results show the patterns of death in the patients studied are not as parallel as some reports from the developed countries. Traumatic and spontaneous bleeding events were the main causes of death. The trend of death shows a decrease in the current decade post better therapeutic facilities. Evaluation of causes of death in hemophilia can be a useful indicator for managing the efficacy of health care in the current patients.

  20. Role of bone marrow transplantation for correcting hemophilia A in mice

    Science.gov (United States)

    Follenzi, Antonia; Raut, Sanj; Merlin, Simone; Sarkar, Rita

    2012-01-01

    To better understand cellular basis of hemophilia, cell types capable of producing FVIII need to be identified. We determined whether bone marrow (BM)–derived cells would produce cells capable of synthesizing and releasing FVIII by transplanting healthy mouse BM into hemophilia A mice. To track donor-derived cells, we used genetic reporters. Use of multiple coagulation assays demonstrated whether FVIII produced by discrete cell populations would correct hemophilia A. We found that animals receiving healthy BM cells survived bleeding challenge with correction of hemophilia, although donor BM-derived hepatocytes or endothelial cells were extremely rare, and these cells did not account for therapeutic benefits. By contrast, donor BM-derived mononuclear and mesenchymal stromal cells were more abundant and expressed FVIII mRNA as well as FVIII protein. Moreover, injection of healthy mouse Kupffer cells (liver macrophage/mononuclear cells), which predominantly originate from BM, or of healthy BM-derived mesenchymal stromal cells, protected hemophilia A mice from bleeding challenge with appearance of FVIII in blood. Therefore, BM transplantation corrected hemophilia A through donor-derived mononuclear cells and mesenchymal stromal cells. These insights into FVIII synthesis and production in alternative cell types will advance studies of pathophysiological mechanisms and therapeutic development in hemophilia A. PMID:22368271

  1. The value of HEAD-US system in detecting subclinical abnormalities in joints of patients with hemophilia.

    Science.gov (United States)

    De la Corte-Rodriguez, Hortensia; Rodriguez-Merchan, E Carlos; Alvarez-Roman, M Teresa; Martin-Salces, Mónica; Martinoli, Carlo; Jimenez-Yuste, Víctor

    2018-03-01

    Prevention of hemarthrosis is the key factor in the adequate management of people with hemophilia (PWH). If hemarthrosis occurs, early diagnosis of joint damage is essential to make personalized treatments. This study is aimed at gaining an understanding of the ability of point-of-care ultrasound (US) using the `Hemophilia Early Arthropathy Detection with Ultrasound´ (HEAD-US) protocol to detect abnormalities in joints without history of hemarthrosis and clinically asymptomatic joints of PWH. The sample included 976 joints from 167 PWH (mean age 24.86 years). Data were collected from routine practice over a 3-year period and analyzed based on history of hemarthrosis and results of clinical (HJHS 2.1) and HEAD-US examinations. In our series, 14% of patients exhibited HEAD-US signs of incipient arthropathy in joints with no history of bleeding and with a HJHS 2.1 score of 0. The most severely involved joint was the right ankle. Synovitis, articular cartilage and subchondral bone damage scores in joints with subclinical findings were slower than in joints with previous hemarthroses or HJHS 2.1 > 1 Conclusions: Our study demonstrates that HEAD-US is better than hemarthrosis records and the HJHS 2.1 scale in detecting the early signs of joint damage in PWH.

  2. Prevalent Inhibitors in Hemophilia B Subjects Enrolled in the Universal Data Collection Database

    Science.gov (United States)

    Puetz, John; Soucie, J. Michael; Kempton, Christine L.; Monahan, Paul E.

    2015-01-01

    Summary Background Several risk factors for inhibitors have recently been described for hemophilia A. It has been assumed that similar risk factors are also relevant for hemophilia B, but there is limited data to confirm this notion. Objectives To determine the prevalence of and risk factors associated with inhibitors in hemophilia B Methods The database of the Universal Data Collection (UDC) project of the Centers for Disease Control for the years 1998 – 2011 was queried to determine the prevalence of inhibitors in hemophilia B subjects. In addition, disease severity, race/ethnicity, age, factor exposure, and prophylaxis usage were evaluated to determine their impact on inhibitor prevalence. Results Of the 3800 male subjects with hemophilia B enrolled in the UDC database, 75 (2%) were determined to have an inhibitor at some point during the study period. Severe disease (OR 13.1, 95% CI 6.2-27.7), black race (OR 2.2, 95% CI 1.2-4.1), and age less than 11 (OR 2.5, 95% CI 1.5-4.0) were found to be significantly associated with having an inhibitor. There was insufficient data to determine if type of factor used and prophylaxis were associated with inhibitors. Conclusions Inhibitors in hemophilia B are much less prevalent than hemophilia A, especially in patients with mild disease. Similar factors associated with inhibitors in hemophilia A also seem to be present for hemophilia B. The information collected by this large surveillance project did not permit evaluation of potential risk factors related to treatment approaches and exposures, and additional studies will be required. PMID:23855900

  3. Predictors of retention among HIV/hemophilia health care professionals.

    Science.gov (United States)

    Brown, Larry K; Schultz, Janet R; Forsberg, Ann D; King, Gary; Kocik, Susan M; Butler, Regina B

    2002-01-01

    Health care professionals working with individuals with chronic medical illness, especially those infected with the Human Immunodeficiency Virus (HIV), may be at risk for burnout and departure due to various job stresses such as the death of patients and social stigma. Factors that prevent burnout and employee attrition are seldom studied. Two hundred thirteen staff (doctors, nurses and mental health workers) at a representative sample of Hemophilia Treatment Centers (HTC) completed instruments to measure Burnout (Maslach Burnout Inventory), and perceived job stresses and satisfaction (job tasks, interactions with colleagues and patient care). The staff were surveyed again after two years and their job status determined after 4 years. After 4 years, 35% of the staff had left the field of Hemophilia/HIV care. Univariate tests found that retention was significantly associated with initial job satisfaction, being married and low levels of stress with colleagues. Burnout, as measured by the Maslach Burnout Inventory, at baseline, was unrelated to job retention over 4 years. An adjusted multiple logistic regression of all significant variables found that colleague support was most related to retention (OR=2.8, CI=1.49,5.1). We conclude that attrition of highly trained staff is a significant issue for patients and HTCs. These data suggest the important role that a well-functioning team can have in buffering the inevitable stresses associated with HIV care. Mental Health professionals have considerable expertise in addressing these issues.

  4. Partial correction of a severe molecular defect in hemophilia A, because of errors during expression of the factor VIII gene

    Energy Technology Data Exchange (ETDEWEB)

    Young, M.; Antonarakis, S.E. [Univ. of Geneva (Switzerland); Inaba, Hiroshi [Tokyo Medical College (Japan)] [and others

    1997-03-01

    Although the molecular defect in patients in a Japanese family with mild to moderately severe hemophilia A was a deletion of a single nucleotide T within an A{sub 8}TA{sub 2} sequence of exon 14 of the factor VIII gene, the severity of the clinical phenotype did not correspond to that expected of a frameshift mutation. A small amount of functional factor VIII protein was detected in the patient`s plasma. Analysis of DNA and RNA molecules from normal and affected individuals and in vitro transcription/translation suggested a partial correction of the molecular defect, because of the following: (i) DNA replication/RNA transcription errors resulting in restoration of the reading frame and/or (ii) {open_quotes}ribosomal frameshifting{close_quotes} resulting in the production of normal factor VIII polypeptide and, thus, in a milder than expected hemophilia A. All of these mechanisms probably were promoted by the longer run of adenines, A{sub 10} instead of A{sub 8}TA{sub 2}, after the delT. Errors in the complex steps of gene expression therefore may partially correct a severe frameshift defect and ameliorate an expected severe phenotype. 36 refs., 6 figs.

  5. Bayesian approach to the assessment of the population-specific risk of inhibitors in hemophilia A patients: a case study

    Directory of Open Access Journals (Sweden)

    Cheng J

    2016-10-01

    Full Text Available Ji Cheng,1,2 Alfonso Iorio,2,3 Maura Marcucci,4 Vadim Romanov,5 Eleanor M Pullenayegum,6,7 John K Marshall,3,8 Lehana Thabane1,2 1Biostatistics Unit, St Joseph’s Healthcare Hamilton, 2Department of Clinical Epidemiology and Biostatistics, 3Department of Medicine, McMaster University, Hamilton, ON, Canada; 4Geriatrics, Fondazione Ca’ Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy; 5Baxter HealthCare, Global Medical Affairs, Westlake Village, CA, USA; 6Child Health Evaluation Sciences, Hospital for Sick Children, 7Dalla Lana School of Public Health, University of Toronto, Toronto, 8Division of Gastroenterology, Hamilton Health Science, Hamilton, ON, Canada Background: Developing inhibitors is a rare event during the treatment of hemophilia A. The multifacets and uncertainty surrounding the development of inhibitors further complicate the process of estimating inhibitor rate from the limited data. Bayesian statistical modeling provides a useful tool in generating, enhancing, and exploring the evidence through incorporating all the available information.Methods: We built our Bayesian analysis using three study cases to estimate the inhibitor rates of patients with hemophilia A in three different scenarios: Case 1, a single cohort of previously treated patients (PTPs or previously untreated patients; Case 2, a meta-analysis of PTP cohorts; and Case 3, a previously unexplored patient population – patients with baseline low-titer inhibitor or history of inhibitor development. The data used in this study were extracted from three published ADVATE (antihemophilic factor [recombinant] is a product of Baxter for treating hemophilia A post-authorization surveillance studies. Noninformative and informative priors were applied to Bayesian standard (Case 1 or random-effects (Case 2 and Case 3 logistic models. Bayesian probabilities of satisfying three meaningful thresholds of the risk of developing a clinical

  6. Novel, high incidence exercise-induced muscle bleeding model in hemophilia B mice

    DEFF Research Database (Denmark)

    Tranholm, M.; Kristensen, Annemarie Thuri; Broberg, M. L.

    2015-01-01

    INTRODUCTION: Muscle hematomas are the second most common complication of hemophilia and insufficient treatment may result in serious and even life-threatening complications. Hemophilic dogs and rats do experience spontaneous muscle bleeding, but currently, no experimental animal model is available...... specifically investigating spontaneous muscle bleeds in a hemophilic setting. AIM: The objective of this study was to develop a model of spontaneous muscle bleeds in hemophilia B mice. We hypothesized that treadmill exercise would induce muscle bleeds in hemophilia B mice but not in normal non-hemophilic mice...... and that treatment with recombinant factor IX (rFIX) before treadmill exercise could prevent the occurrence of pathology. METHODS: A total of 203 mice (123 F9-KO and 80 C57BL/6NTac) were included in three separate studies: (i) the model implementation study investigating the bleeding pattern in hemophilia B mice...

  7. Prevention of inhibitor development in hemophilia A in 2016. A glimpse into the future?

    Science.gov (United States)

    Franchini, Massimo; Lippi, Giuseppe

    2016-12-01

    Thanks to considerable progresses made over the last 30years, hemophilia benefits from the most efficacious and safe treatment among the many monogenic inherited disorders. The most challenging complication of replacement therapy in hemophilia A is the occurrence of alloantibodies against infused factor VIII (FVIII), thus predisposing the patients to increased morbidity and disability. Extensive research in this field has definitively unraveled that development of inhibitors in hemophilia A is a complex and multifactorial process, in which inherited and environmental factors dynamically interact. This narrative review, after providing a concise overview about the main genetic and non-genetic risk factors, is aimed to focus on prediction risk models and preventive strategies for minimizing the risk of developing inhibitors in hemophilia A patients. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. Young adults with hemophilia in the U.S.: demographics, comorbidities, and health status.

    Science.gov (United States)

    Curtis, Randall; Baker, Judith; Riske, Brenda; Ullman, Megan; Niu, Xiaoli; Norton, Kristi; Lou, Mimi; Nichol, Michael B

    2015-12-01

    Improvements in hemophilia care over the last several decades might lead to expectations of a near-normal quality of life for young adults with hemophilia. However, few published reports specifically examine health status indicators in this population. To remedy this knowledge gap, we examined the impact of hemophilia on physical and social functioning and quality of life among a national US cohort of 141 young men with hemophilia aged 18-34 years of age who received care at 10 geographically diverse, federally funded hemophilia treatment centers in 11 states between 2005 and 2013 and enrolled in the Hemophilia Utilization Group Studies. Indicators studied included educational achievement, employment status, insurance, health-related quality of life, and prevalence of the following comorbidities: pain, range of motion limitation, overweight/obesity, and viral status. The cohort was analyzed to compare those aged 18-24 to those aged 25-34 years. When compared to the general US adult population, this nationally representative cohort of young US adults with hemophilia experienced significant health and social burdens: more liver disease, joint damage, joint pain, and unemployment as well as lower high-school graduation rates. Nearly half were overweight or obese. Conversely, this cohort had higher levels of health insurance and equivalent mental health scores. While attention has typically focused on newborns, children, adolescents, and increasingly, on older persons with hemophilia, our findings suggest that a specific focus on young adults is warranted to determine the most effective interventions to improve health and functioning for this apparently vulnerable age group. © 2015 Wiley Periodicals, Inc.

  9. Motivational techniques to improve self-care in hemophilia: the need to support autonomy in children.

    Science.gov (United States)

    Bérubé, Sarah; Mouillard, Florine; Amesse, Claudine; Sultan, Serge

    2016-01-11

    In pediatric hemophilia, caregivers are facing unique challenges to adherence and self-care in children and adolescents with hemophilia. Hemophilia treatment requires adequate prophylaxis and on-demand treatment, as well as a clear behavioral strategy to limit risk-taking in terms of physical exercise and diet. Medication adherence rates of hemophilia patients have been reported to decrease during late childhood and adolescence. In the developing child, moving safely from parent-care to self-care is one of the greatest challenges of integrative care within this domain. There is a clear need for initiatives designed to increase an individual's motivation for treatment and self-care activities. Among motivational approaches, the self-determination perspective offers a useful framework to explain how the transition to self-care can be facilitated. We discuss how motivation regarding hemophilia treatment may be increased through parental autonomy support and we offer examples of applied communication techniques to facilitate autonomy-supportive caregiving. Although it has not yet been tested in the context of hemophilia, these communication techniques could potentially help caregivers promote adherence and self-care in children. Confronted by unique challenges to adherence and self-care, caregivers of children with hemophilia should move from an exclusive focus on illness-management education to an integrative strategy, including motivation-enhancing communication. The self-determination perspective provides important proximal objectives (e.g. autonomy support) to maintain optimal adherence in adolescents as they move from parent-care to self-care. Future research initiatives should address the practice of these communication techniques and evaluate them in the context of hemophilia.

  10. Challenges and successes in the treatment of hemophilia: the story of a patient with severe hemophilia A and high-titer inhibitors

    Directory of Open Access Journals (Sweden)

    Saba HI

    2012-05-01

    Full Text Available Hussain I Saba, Duc Quang Tran, JrDepartment of Medicine, University of South Florida Medical Center, Tampa, FL, USAAbstract: In the past, patients with severe hemophilia have suffered a substantially reduced quality of life with frequent bleeding episodes, disabling arthropathy, and shorter life expectancy. In addition, methods of treatment and management have been costly and time-consuming, and have placed a considerable burden on patients' physical and psychological well-being. With the advent of the on-demand therapy and prophylactic treatment paradigm, patients have been able to receive care with less interruption of daily activities. Treatments may be more challenging for hemophiliacs with inhibitors to replacement factor; however, recent advances in the use of bypassing agents and immune tolerance therapy have enabled them to aggressively manage their disease while maintaining their independence. This review focuses on the challenges of treating such a severe hemophiliac through examination of the lifetime experience of a young adult male with a severe form of congenital hemophilia A. At this stage of his life, the patient has minimal disabilities and is inhibitor-free through optimal care and strong family support. His aspiration to pursue a productive life has led him to a career in medicine. After receiving his medical degree, he pursued a specialty in the treatment of hemophilia. By assisting other hemophilia patients, he exemplifies both the rewards of persevering through episodes of bleeding and other complications and the fact that disabilities can be minimized when managed meticulously and in a timely fashion to enable a productive and dignified life.Keywords: hemophilia, quality of life, factor VIII inhibitors, hemophilia treatment center, early treatment, bypassing agent

  11. "Neurologic complications in Hemophilia: A study in 214 cases "

    Directory of Open Access Journals (Sweden)

    Ghaffarpoor M

    2001-08-01

    Full Text Available Intracranial hemorrhage and entrapment neuropathy are the most serious and disabling complications in hemophilia.The occurance of these neurological complications was studied in 214 hemophiliac patients during a 3 month period. Nine patients (4.2% suffered intracranial hemorrhage (One epidural and others intracerebral. All of intracranial hemorrhage patients had the sevee form of disease (<1% factor VIII or IX. 6 out of 9 intracranial hemorrhage cases mentioned a history of head trauma. Entrapment neuropathy was presen in 10 patients (femoral neuropathy 5, ulnar n. 3, radial n. 1 median n. 1 all of entropament neuropathy patients described a history of trauma to the extremities. Eight patients in the latter group had severe disease and two patients had moderate disease (1-5%. The proportion of intracranial hemorrhage following head trauma (20% in this series was greater than other studies. In conclusion, early diagnostic evaluation and replacement therapy may be beneficial in hemophilic patients with trauma.

  12. Special features of total knee replacement in hemophilia.

    Science.gov (United States)

    Rodriguez-Merchan, Emerito Carlos

    2013-12-01

    Total knee replacement is an operation frequently needed by hemophilia patients, which greatly improves their quality of life. This operation, however, carries a higher risk of bleeding and infection for hemophiliacs than it does for osteoarthritis sufferers. It is advisable to implant prosthetic components using antibiotic-loaded cement. It is essential to maintain a level of 100% of the replacement clotting factor for 2 weeks. Hematological treatment must be established, depending on the patient's factor levels and other pharmacokinetic parameters such as recovery and half-life, optimal doses and treatment time. It is preferable to use general anesthesia due to the risk of spinal bleeding. The lifespan of total knee replacement in hemophilic patients is shorter than in patients with osteoarthritis because of the increased risk of infection.

  13. Labeled factor IX kinetics in patients with hemophilia-B

    International Nuclear Information System (INIS)

    Smith, K.J.; Thompson, A.R.

    1981-01-01

    Labeled factor IX was infused five time into four patients with hemophilia-B. Ten-minute plasma recovery average 35% (SD +/- 2) and the mean T 1/2 beta-phase elimination was 23 hr (+/- 5). No alteration in the postinfusion 125I-factor-IX could be detected by radioautography of plasma samples run on polyacrylamide gels or on crossed-immunoelectrophoresis. Label was excreted into the urine as free 125I-iodide. Kinetics were similar when the labeled preparation was infused alone or with a commercial concentrate containing unlabeled factor IX. Infusion of factor IX in man is best described by a two-compartment open pharmacokinetic model where factor IX is distributed in a space larger than the plasma volume

  14. Construct validity of patient-reported outcome instruments in US adults with hemophilia: results from the Pain, Functional Impairment, and Quality of life (P-FiQ study

    Directory of Open Access Journals (Sweden)

    Batt K

    2017-08-01

    Full Text Available Katharine Batt,1 Michael Recht,2 David L Cooper,3 Neeraj N Iyer,3 Christine L Kempton4 1Hematology and Oncology, Wake Forest School of Medicine, Winston-Salem, NC, 2The Hemophilia Center, Oregon Health & Science University, Portland, OR, 3Novo Nordisk Inc., Plainsboro, NJ, 4Departments of Pediatrics and Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA Background: People with hemophilia (PWH experience frequent joint bleeding, resulting in pain and functional impairment. Generic and disease-specific patient-reported outcome (PRO instruments have been used in clinical studies, but rarely in the comprehensive hemophilia care setting. Objective: The objective of this study was to assess construct validity of PRO instruments measuring pain, functional impairment, and health-related quality of life in US PWH with a history of joint pain/bleeding. Methods: Adult male PWH completed 4 PRO instruments (EQ-5D-5L with visual analog scale, Brief Pain Inventory v2 Short Form [BPI], SF-36v2, Hemophilia Activities List [HAL] and underwent a musculoskeletal examination (Hemophilia Joint Health Score v2.1 [HJHS]. Construct validity between index and domain scores was evaluated by Pearson product-moment correlation coefficient. Results: A total of 381 PWH were enrolled. EQ-5D-5L Mobility correlated with BPI, SF-36v2, and HAL domains related to pain, physical function, and activity of the lower extremities. EQ-5D-5L Self-Care correlated only with HAL Self-Care. EQ-5D-5L Usual Activities correlated with BPI Pain Interference and domains within SF-36v2 and HAL related to pain and physical function/activities (particularly those involving the lower extremities. EQ-5D-5L Pain/Discomfort correlated with Bodily Pain and Physical Summary on SF-36v2, HAL Overall Activity, and all BPI pain domains. EQ-5D-5L Anxiety/Depression correlated with social/emotional/mental aspects of SF-36v2. On BPI, most pain domains correlated with Bodily

  15. Genética comunitária e hemofilia em uma população brasileira Community genetics and hemophilia in a Brazilian population

    Directory of Open Access Journals (Sweden)

    Vânia Maria Caio

    2001-06-01

    Full Text Available A hemofilia é uma doença hemorrágica importante no Brasil, afetando cerca de um em cada dez mil indivíduos do sexo masculino. A autopercepção do portador a respeito da hemofilia e a sua interação com a comunidade são relevantes na abordagem clínica dessa doença. Nós investigamos vários aspectos sociais, psicológicos e comunitários da hemofilia em uma população brasileira (Campinas, São Paulo. Entrevistamos trinta portadores adultos da hemofilia, uma amostra-controle composta por 73 de seus irmãos normais do sexo masculino e 641 indivíduos da comunidade. A integração comunitária dos portadores da hemofilia mostrou-se afetada apenas nos aspectos sócio-econômicos, sem alteração no que diz respeito ao casamento, à procriação e à aquisição de melhores níveis educacionais. Observaram-se entre os portadores da hemofilia altos níveis de auto-rotulação, acompanhados de depressão, ansiedade e insegurança. A comunidade apresentou uma alta freqüência de completo desconhecimento a respeito da hemofilia (49%, demonstrando contra os hemofílicos os preconceitos normalmente observados contra os portadores de doenças contagiosas, como a AIDS. O trabalho sugere a estruturação de programa comunitário, visando à melhor adequação psicossocial dos portadores da hemofilia.Hemophilia is an important hemorrhagic disease in Brazil, affecting about 1 out of every 10,000 males. Patient's self-perception of hemophilia and interaction with the community are relevant to the clinical management of this disease. We investigated several social, psychological, and community aspects of hemophilia in a Brazilian population (Campinas, São Paulo State, interviewing 30 hemophiliac males, a control sample comprised of 73 non-hemophiliac brothers, and 641 individuals from the community. According to our results, more severe social disability in the hemophiliac patient was related to economic factors, mainly unemployment; however, no

  16. A Budget Impact Model of Hemophilia Bypassing Agent Prophylaxis Relative to Recombinant Factor VIIa On-Demand.

    Science.gov (United States)

    Mehta, Darshan A; Oladapo, Abiola O; Epstein, Joshua D; Novack, Aaron R; Neufeld, Ellis J; Hay, Joel W

    2016-02-01

    Hemophilia patients use factor-clotting concentrates (factor VIII for hemophilia A and factor IX for hemophilia B) for improved blood clotting. These products are used to prevent or stop bleeding episodes. However, some hemophilia patients develop inhibitors (i.e., the patient's immune system develops antibodies against these factor concentrates). Hence, these patients do not respond well to the factor concentrates. A majority of hemophilia patients with inhibitors are managed on-demand with the following bypassing agents: recombinant factor VIIa (rFVIIa) and activated prothrombin complex concentrate (aPCC). The recently published U.S. registries Dosing Observational Study in Hemophilia (DOSE) and Hemostasis and Thrombosis Research Society (HTRS) reported higher rFVIIa on-demand use for bleed management than previously described. To estimate aPCC and rFVIIa prophylaxis costs relative to rFVIIa on-demand treatment cost based on rFVIIa doses reported in U.S. registries. A literature-based cost model was developed assuming a base case on-demand annual bleed rate (ABR) of 28.7 per inhibitor patient, which was taken from a randomized phase 3 clinical trial. The doses for rFVIIa on-demand were taken from the median dose per bleed reported by the DOSE and HTRS registries. Model inputs for aPCC and rFVIIa prophylaxis (i.e., dosing and efficacy) were derived from respective randomized clinical trials. Cost analysis was from the U.S. payer perspective, and only direct drug costs were considered. The drug cost was based on the Medicare Part B 2014 average sale price (ASP). Two-way sensitivity and threshold analyses were performed by simultaneously varying on-demand ABR, prophylaxis efficacy, and unit drug cost. In addition to studying relative costs associated with on-demand and prophylaxis treatments, relative cost per bleeding episode avoided were also calculated for aPCC and rFVIIa prophylaxis treatments. The prophylaxis efficacy reported in the trials were used to

  17. Culham names new director

    CERN Multimedia

    2003-01-01

    "The United Kingdom Atomic Energy Authority (UKAEA) announced the appointment of Professor Sir Chris Llewellyn Smith FRS (Fellow of the Royal Society) as Director of Culham, responsible for developing and implementing the strategy for the UK's fusion research programme" (1 page).

  18. Ideas for Directors.

    Science.gov (United States)

    Child Care Information Exchange, 1987

    1987-01-01

    Presents child care center directors with a variety of relevant management ideas from business and the child care field. They include translating employee body language; leadership myths; on-the-job teacher training; undesirable bosses; wasting employee talent; voicing disagreement; employee anger; encouraging creativity; and coping with late…

  19. Director Networks and Takeovers

    NARCIS (Netherlands)

    Renneboog, L.D.R.; Zhao, Y.

    2013-01-01

    Abstract: We study the impact of corporate networks on the takeover process. We find that better connected companies are more active bidders. When a bidder and a target have one or more directors in common, the probability that the takeover transaction will be successfully completed augments, and

  20. Director networks and takeovers

    NARCIS (Netherlands)

    Renneboog, L.D.R.; Zhao, Y.

    2014-01-01

    We study the impact of corporate networks on the takeover process. We find that better connected companies are more active bidders. When a bidder and a target have one or more directors in common, the probability that the takeover transaction will be successfully completed augments, and the duration

  1. REGIONAL CUSTOMS DIRECTORATES MANAGEMENT

    Directory of Open Access Journals (Sweden)

    CABA STEFAN

    2009-05-01

    Full Text Available The management of a regional customs directorate is analyzed. A new approach of the managerial system, in the European integration context, is presented. The customs system is one of the first “doors” to a new economic, social and cultural community. For

  2. Director, Platform and Audience.

    Science.gov (United States)

    Meyer, Richard D.

    The open stage is discussed both as architecture and as part of a new theatrical style. In reference to use of the open stage, emphasis is given to specifics with which the director must deal, to special problems of the actor, to the approach to blocking a play, and to the open stage as "theatrical experience". The architectural advantage of the…

  3. User-centered requirements engineering in health information systems: a study in the hemophilia field.

    Science.gov (United States)

    Teixeira, Leonor; Ferreira, Carlos; Santos, Beatriz Sousa

    2012-06-01

    The use of sophisticated information and communication technologies (ICTs) in the health care domain is a way to improve the quality of services. However, there are also hazards associated with the introduction of ICTs in this domain and a great number of projects have failed due to the lack of systematic consideration of human and other non-technology issues throughout the design or implementation process, particularly in the requirements engineering process. This paper presents the methodological approach followed in the design process of a web-based information system (WbIS) for managing the clinical information in hemophilia care, which integrates the values and practices of user-centered design (UCD) activities into the principles of software engineering, particularly in the phase of requirements engineering (RE). This process followed a paradigm that combines a grounded theory for data collection with an evolutionary design based on constant development and refinement of the generic domain model using three well-known methodological approaches: (a) object-oriented system analysis; (b) task analysis; and, (c) prototyping, in a triangulation work. This approach seems to be a good solution for the requirements engineering process in this particular case of the health care domain, since the inherent weaknesses of individual methods are reduced, and emergent requirements are easier to elicit. Moreover, the requirements triangulation matrix gives the opportunity to look across the results of all used methods and decide what requirements are critical for the system success. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  4. Preclinical safety and efficacy of a new recombinant FIX drug product for treatment of hemophilia B.

    Science.gov (United States)

    Dietrich, Barbara; Schiviz, Alexandra; Hoellriegl, Werner; Horling, Frank; Benamara, Karima; Rottensteiner, Hanspeter; Turecek, Peter L; Schwarz, Hans Peter; Scheiflinger, Friedrich; Muchitsch, Eva-Maria

    2013-11-01

    Baxter has developed a new recombinant factor IX (rFIX) drug product (BAX326) for treating patients with hemophilia B, or congenital FIX deficiency. An extensive preclinical program evaluated the pharmacokinetics, efficacy, and safety of BAX326 in different species. The efficacy of BAX326 was tested in three mouse models of primary pharmacodynamics: tail-tip bleeding, carotid occlusion, and thrombelastography. The pharmacokinetics was evaluated after a single intravenous bolus injection in mice, rats, and macaques. Toxicity was assessed in rats and macaques, safety pharmacology in rabbits and macaques, and immunogenicity in mice. BAX326 was shown to be efficacious in all three primary pharmacodynamic studies (P ≤ 0.0076). Hemostatic efficacy was dose related and similar for the three lots tested. Pharmacokinetic results showed that rFIX activity and rFIX antigen concentrations declined in a bi-phasic manner, similar to a previously licensed rFIX product. BAX326 was well tolerated in rabbits and macaques at all dose levels; no thrombogenic events and no adverse clinical, respiratory, or cardiovascular effects occurred. BAX326 was also shown to have a similar immunogenicity profile to the comparator rFIX product in mice. These results demonstrate that BAX326 has a favorable preclinical safety and efficacy profile, predictive of a comparable effect to that of the previously licensed rFIX in humans.

  5. Circumventing furin enhances factor VIII biological activity and ameliorates bleeding phenotypes in hemophilia models

    Science.gov (United States)

    Siner, Joshua I.; Samelson-Jones, Benjamin J.; Crudele, Julie M.; French, Robert A.; Lee, Benjamin J.; Zhou, Shanzhen; Merricks, Elizabeth; Raymer, Robin; Camire, Rodney M.; Arruda, Valder R.

    2016-01-01

    Processing by the proprotein convertase furin is believed to be critical for the biological activity of multiple proteins involved in hemostasis, including coagulation factor VIII (FVIII). This belief prompted the retention of the furin recognition motif (amino acids 1645–1648) in the design of B-domain–deleted FVIII (FVIII-BDD) products in current clinical use and in the drug development pipeline, as well as in experimental FVIII gene therapy strategies. Here, we report that processing by furin is in fact deleterious to FVIII-BDD secretion and procoagulant activity. Inhibition of furin increases the secretion and decreases the intracellular retention of FVIII-BDD protein in mammalian cells. Our new variant (FVIII-ΔF), in which this recognition motif is removed, efficiently circumvents furin. FVIII-ΔF demonstrates increased recombinant protein yields, enhanced clotting activity, and higher circulating FVIII levels after adeno-associated viral vector–based liver gene therapy in a murine model of severe hemophilia A (HA) compared with FVIII-BDD. Moreover, we observed an amelioration of the bleeding phenotype in severe HA dogs with sustained therapeutic FVIII levels after FVIII-ΔF gene therapy at a lower vector dose than previously employed in this model. The immunogenicity of FVIII-ΔF did not differ from that of FVIII-BDD as a protein or a gene therapeutic. Thus, contrary to previous suppositions, FVIII variants that can avoid furin processing are likely to have enhanced translational potential for HA therapy. PMID:27734034

  6. A patient with hypereosinophilic syndrome that manifested with acquired hemophilia and elevated IgG4: a case report

    Directory of Open Access Journals (Sweden)

    Nagao Yoshiro

    2012-02-01

    Full Text Available Abstract Introduction Hypereosinophilic syndrome is defined as a prolonged state (more than six months of eosinophilia (greater than 1500 cells/μL, without an apparent etiology and with end-organ damage. Hypereosinophilic syndrome can cause coagulation abnormalities. Among hypereosinophilic syndrome types, the lymphocytic variant (lymphocytic hypereosinophilic syndrome is derived from a monoclonal proliferation of T lymphocytes. Here, we describe the case of a patient with lymphocytic hypereosinophilic syndrome who presented with a coagulation abnormality. To the best of our knowledge, this is the first such report including a detailed clinical picture and temporal cytokine profile. Case presentation A 77-year-old Japanese man presented to our facility with massive hematuria and hypereosinophilia (greater than 2600 cells/μl. His eosinophilia first appeared five years earlier when he developed femoral artery occlusion. He manifested with multiple hematomas and prolonged activated partial thromboplastin time. His IgG4 level was remarkably elevated (greater than 2000 mg/dL. Polymerase chain reaction tests of peripheral blood and bone marrow identified lymphocytic hypereosinophilic syndrome. His prolonged activated partial thromboplastin time was found to be due to acquired hemophilia. Glucocorticoids suppressed both the hypereosinophilia and coagulation abnormality. However, tapering of glucocorticoids led to a relapse of the coagulation abnormality alone, without eosinophilia. Tumor necrosis factor α, interleukin-5, and/or eotaxin-3 may have caused the hypereosinophilia, and interleukin-10 was correlated with the coagulation abnormality. Conclusions To the best of our knowledge, this is the first case in which lymphocytic hypereosinophilic syndrome and IgG4-related disease have overlapped. In addition, our patient is only the second case of hypereosinophilic disease that manifested with acquired hemophilia. Our patient relapsed with the

  7. A Case of Heel Reconstruction with a Reverse Sural Artery Flap in a Hemophilia B Patient

    Directory of Open Access Journals (Sweden)

    Byung Kwon Lee

    2012-03-01

    Full Text Available Hemophilia B is a rare blood coagulation disorder. Complications such as bleeding and hematoma can cause necrosis of flaps, wound disruption, and the disturbance of wound healing. In particular, guidelines for flap operations in hemophilia B patients have still not been defined, and case reports are rare. We reconstructed the heel of a 41-year-old male hemophilia B patient using a reverse sural artery flap operation. The patient presented with mild hemophilia, having 27% of the normal value of coagulation factor IX. Coagulation and the changing value of the coagulation factor were regularly measured, and 70% of the normal value of coagulation factor IX was maintained through the injection of recombinant coagulation factors and antihemorrhagics. Hematoma developed twice (postoperative day [POD] 5 and POD 7 and in each case the hematoma was removed. Injections of recombinant coagulation factors and antihemorrhagics were continuously administered until postoperative week 2. When the coagulation factors were within normal ranges. In this article, a hemophilia B patient underwent reverse sural artery flap surgery and the healing progress was analyzed. We conclude that higher than baseline levels of coagulation factors are needed for successful healing in reverse sural artery flap surgery.

  8. Atherosclerotic Heart Disease: Prevalence and Risk Factors in Hospitalized Men with Hemophilia A

    Science.gov (United States)

    Ragni, Margaret V.; Moore, Charity G.

    2011-01-01

    Summary Background Atherosclerotic heart disease (ASHD) is a common cause of morbidity and mortality in Western society. Few studies have determined prevalence and predictors of ASHD in hemophilia (HA), a population whose survival is improving with safer blood products and effective treatments for AIDS and hepatitis C. Objectives The purpose of this study was to determine prevalence and factors associated with ASHD in hemophilia A patients in Pennsylvania. Methods The prevalence of ASHD (myocardial infarction, angina, coronary disease), cardiac catheterization, coronary angiography, co-morbidities, and in-hospital mortality were assessed on statewide ASHD discharge data, 2001–2006, from the Pennsylvania Health Care Cost Containment Council (PHC4). Results The prevalence of hemophilia ASHD admissions fluctuated between 6.5% and 10.5% for 2001 to 2006, p=0.62. Compared to HA without ASHD, HA with ASHD were older and more likely to be hypertensive, hyperlipidemic, and diabetic, all pHemophilia patients with ASHD have similar cardiovascular risk factors, admitting diagnoses, severity of illness, and in-hospital mortality as the general population. These findings suggest cardiovascular prevention measures should be promoted in hemophilia. PMID:21371197

  9. Consensus Review of the Treatment of Cardiovascular Disease in People With Hemophilia A and B

    Science.gov (United States)

    Boral, Leonard I.; Cohen, Alice J.; Smyth, Susan S.; White, Gilbert C.

    2015-01-01

    With advances in care, increasing numbers of people with hemophilia (PWH) achieve near-normal life expectancies and present with typical age-related cardiovascular conditions. Evidence-based guidelines for medical or surgical management of cardiovascular conditions in individuals with hemophilia are limited. Published recommendations exist for the management of some common cardiovascular conditions (eg, ischemic heart disease, atrial fibrillation), but identifying optimal strategies for anticoagulant or antithrombotic therapy constitutes the primary challenge of managing nonoperative cardiovascular disease (CVD) in PWH. In general, as long as factor concentrates or other hemostatic therapies maintain adequate hemostasis, the recommended medical and surgical management of CVD in PWH parallels that in individuals without hemophilia. The presence of factor inhibitors complicates hemophilia management. Published outcomes of CVD treatment in PWH are similar to those in the general population. Specific knowledge about factor replacement, factor inhibitors, and disease-specific treatment distinguishes the cardiovascular care of PWH from similar care of individuals without this rare bleeding disorder. Furthermore, a multidisciplinary approach incorporating a hematologist with an onsite coagulation laboratory, ideally associated with a hemophilia treatment center, is integral to the management of CVD in PWH. PMID:25436468

  10. Human parvovirus B19 and parvovirus 4 among Iranian patients with hemophilia.

    Science.gov (United States)

    Javanmard, Davod; Ziaee, Masood; Ghaffari, Hadi; Namaei, Mohammad Hasan; Tavakoli, Ahmad; Mollaei, Hamidreza; Moghoofei, Mohsen; Mortazavi, Helya Sadat; Monavari, Seyed Hamidreza

    2017-12-01

    Human parvovirus B19 (B19V) is one of the smallest DNA viruses and shows great resistance to most disinfectants. Therefore, it is one of the common contaminant pathogens present in blood and plasma products. Parvovirus 4 (PARV4) is a newly identified parvovirus, which is also prevalent in parenteral transmission. In this study, we aimed to evaluate the prevalence of B19V and PARV4 DNA among patients with hemophilia in Birjand County in eastern Iran. This was a cross-sectional epidemiological study comprising nearly all people with hemophilia in this region. Whole blood samples were taken after patient registration and sent for plasma isolation. After nucleic acid extraction, B19V was detected with real-time polymerase chain reaction, PARV4 DNA was then detected using sensitive semi-nested PCR. In total, there were 86 patients with hemophilia, with mean age 28.5±1.5 years. Of these, 90.7% were men and 9.3% women; 84.9% had hemophilia A and 7.0% had hemophilia B. We found 11 patients (12.8%) were positive for B19V DNA and 8 were positive (9.3%) for PARV4 DNA. The prevalence of B19V was higher in middle-aged groups rather than younger people, whereas PARV4 infection was more common in younger patients ( P B19 virus, imposing more precautionary measures for serum and blood products is recommended.

  11. Message from Fermilab Director

    CERN Multimedia

    2009-01-01

    With this issue’s message, Fermilab Director Pier Oddone opens a new series of occasional exchanges between CERN and other laboratories world-wide. As part of this exchange, CERN Director-General Rolf Heuer, wrote a message in Tuesday’s edition of Fermilab TodayPerspectivesNothing is more important for our worldwide particle physics community than successfully turning on the LHC later this year. The promise for great discoveries is huge, and many of the plans for our future depend on LHC results. Those of us planning national programmes in anticipation of data from the LHC face formidable challenges to develop future facilities that are complementary to the LHC, whatever the physics discoveries may be. At Fermilab, this has led us to move forcefully with a programme at the intensity frontier, where experiments with neutrinos and rare decays open a complementary window into nature. Our ultimate goal for a unified picture of nat...

  12. Beam director design report

    International Nuclear Information System (INIS)

    Younger, F.C.

    1986-08-01

    A design and fabrication effort for a beam director is documented. The conceptual design provides for the beam to pass first through a bending and focusing system (or ''achromat''), through a second achromat, through an air-to-vacuum interface (the ''beam window''), and finally through the vernier steering system. Following an initial concept study for a beam director, a prototype permanent magnet 30 0 beam-bending achromat and prototype vernier steering magnet were designed and built. In volume II, copies are included of the funding instruments, requests for quotations, purchase orders, a complete set of as-built drawings, magnetic measurement reports, the concept design report, and the final report on the design and fabrication project

  13. Bayesian approach to the assessment of the population-specific risk of inhibitors in hemophilia A patients: a case study.

    Science.gov (United States)

    Cheng, Ji; Iorio, Alfonso; Marcucci, Maura; Romanov, Vadim; Pullenayegum, Eleanor M; Marshall, John K; Thabane, Lehana

    2016-01-01

    Developing inhibitors is a rare event during the treatment of hemophilia A. The multifacets and uncertainty surrounding the development of inhibitors further complicate the process of estimating inhibitor rate from the limited data. Bayesian statistical modeling provides a useful tool in generating, enhancing, and exploring the evidence through incorporating all the available information. We built our Bayesian analysis using three study cases to estimate the inhibitor rates of patients with hemophilia A in three different scenarios: Case 1, a single cohort of previously treated patients (PTPs) or previously untreated patients; Case 2, a meta-analysis of PTP cohorts; and Case 3, a previously unexplored patient population - patients with baseline low-titer inhibitor or history of inhibitor development. The data used in this study were extracted from three published ADVATE (antihemophilic factor [recombinant] is a product of Baxter for treating hemophilia A) post-authorization surveillance studies. Noninformative and informative priors were applied to Bayesian standard (Case 1) or random-effects (Case 2 and Case 3) logistic models. Bayesian probabilities of satisfying three meaningful thresholds of the risk of developing a clinical significant inhibitor (10/100, 5/100 [high rates], and 1/86 [the Food and Drug Administration mandated cutoff rate in PTPs]) were calculated. The effect of discounting prior information or scaling up the study data was evaluated. Results based on noninformative priors were similar to the classical approach. Using priors from PTPs lowered the point estimate and narrowed the 95% credible intervals (Case 1: from 1.3 [0.5, 2.7] to 0.8 [0.5, 1.1]; Case 2: from 1.9 [0.6, 6.0] to 0.8 [0.5, 1.1]; Case 3: 2.3 [0.5, 6.8] to 0.7 [0.5, 1.1]). All probabilities of satisfying a threshold of 1/86 were above 0.65. Increasing the number of patients by two and ten times substantially narrowed the credible intervals for the single cohort study (1.4 [0.7, 2

  14. Discussion with CERN Directorate

    CERN Document Server

    CERN. Geneva

    2017-01-01

    Please note that the Discussion with CERN Directorate will be transmitted also in the following rooms: Council Chamber - 503-1-001 IT Amphitheatre - 31-3-004 Prevessin 774-R-013 Simultaneous interpreting into French and English will be available in the Main Auditorium. Une interprétation simultanée en français et en anglais sera disponible dans l'amphithéâtre principal.

  15. Lands directorate publications

    Energy Technology Data Exchange (ETDEWEB)

    1981-01-01

    The directorate has a lead role in providing advice to the federal government on land use policy in Canada. The Canada Land Inventory (CLI) Program has produced significant amounts of data pertaining to the capability of Canadian lands to support agriculture, forestry, recreation, wildlife and sport fish. A list of CLI reports is presented in this publication. In addition, and capability maps have been compiled for agricultural, forestry, recreation and wildlife and are listed and described in this publication. (KRM)

  16. In Vivo Gene Therapy of Hemophilia B: Sustained Partial Correction in Factor IX-Deficient Dogs

    Science.gov (United States)

    Kay, Mark A.; Rothenberg, Steven; Landen, Charles N.; Bellinger, Dwight A.; Leland, Frances; Toman, Carol; Finegold, Milton; Thompson, Arthur R.; Read, M. S.; Brinkhous, Kenneth M.; Woo, Savio L. C.

    1993-10-01

    The liver represents a model organ for gene therapy. A method has been developed for hepatic gene transfer in vivo by the direct infusion of recombinant retroviral vectors into the portal vasculature, which results in the persistent expression of exogenous genes. To determine if these technologies are applicable for the treatment of hemophilia B patients, preclinical efficacy studies were done in a hemophilia B dog model. When the canine factor IX complementary DNA was transduced directly into the hepatocytes of affected dogs in vivo, the animals constitutively expressed low levels of canine factor IX for more than 5 months. Persistent expression of the clotting. factor resulted in reductions of whole blood clotting and partial thromboplastin times of the treated animals. Thus, long-term treatment of hemophilia B patients may be feasible by direct hepatic gene therapy in vivo.

  17. Arthroscintigraphy with sup(99m)Tc in children with hemophilia

    International Nuclear Information System (INIS)

    Boyadzhiev, P.; Ignatov, A.; Nin'o, Sh.

    1976-01-01

    Recurrent haemarthroses are one of the most characteristic features of hemophilia during childhood. With the aid of sup(99m)Tc-pertechnetate arthroscintigraphy was carried out in 30 children with hemophilia between 5 and 15 years of age. The 79 articulations under investigation included 42 knee-, 13 elbow- and 24 ankle-joints. The results were compared with the scanograms of 30 normal joints, the activity of the isotope varying between 89% and 130%. Among 19 joints affected by acute haemarthrosis, 11 revealed severe changes while in chronic arthropathy, 50% of the changes proved to be slight which was disclosed with the aid of scintigraphy. There is some dependence between the severity of the changes, the grade of AHG and the frequence of haemarthroses, the latter correlating with the age factor. Arthroscintigraphy is a valuable diagnostic method above all in establishing the presence of an active inflammatory process among the destructive changes in the joints of children with hemophilia. (author)

  18. The impact of extended half-life versus conventional factor product on hemophilia caregiver burden.

    Science.gov (United States)

    Schwartz, Carolyn E; Powell, Victoria E; Su, Jun; Zhang, Jie; Eldar-Lissai, Adi

    2018-05-01

    Extended half-life factor products have reduced annualized bleeding rates in hemophilia patients. The impact of extended half-life versus conventional factor products on hemophilia caregiver burden has not been investigated. This study aimed to evaluate caregiver burden in extended half-life versus conventional factor products for hemophilia A and B. This cross-sectional web-based study of caregivers of people with hemophilia A or B was recruited from a panel research company and by word of mouth. Participants completed the Hemophilia Caregiver Impact measure, the PedsQL Family Impact Module (PedsQL), and the Work Productivity and Activity Impairment Questionnaire (WPAI). We also collected demographic, insurance coverage, and medical information related to the hemophilia patient(s). Burden differences were assessed using linear regression and matched cohort analyses. The sample (n = 448) included 49 people who were caring for people on extended half-life factor products. Worse caregiver burden was associated with more infusions per week and more bleeds in the past 6 months. Regression analyses suggested that caring for someone who is on a extended half-life factor product is associated with lower emotional impact (β = - 0.11, p factor product had lower Emotional Impact and Practical Impact scores (t = - 2.95 and - 2.94, respectively, p factor product infusions of extended half-life factor products appears to reduce the emotional distress and practical burden of caregiving. Future work should evaluate the longitudinal impact.

  19. The Patient Experience of Hemophilia and Human Immunodeficiency Virus: A Systematic Review of Qualitative Evidence.

    Science.gov (United States)

    Omura, Kayoko; Tsuchiya, Sayaka

    The objective of this review is to describe and synthesize the experiences and perspectives of illness for patients living with both hemophilia and human immunodeficiency virus (HIV). Hemophilia is an inherited bleeding disorder caused by low concentrations of specific coagulation factors. There are two major types of this condition characterized by deficiencies of factor VIII (hemophilia A) and factor IX (hemophilia B). Bleeding occurs in hemophilia owing to failure of secondary hemostasis. The bleeding tendency is related to the measured concentration of the factor and is classified as mild, moderate, or severe. Severe hemophilia A and B is classified as repeated (as often as weekly) bleeds into joints and muscles. The main treatment is to arrest spontaneous and traumatic bleeds by prophylactic injection of factor concentrates or to prevent injury by restriction of exercise. Most people with severe hemophilia are on therapy at home with intravenous infusion of the relevant missing factor. Joint bleeds are painful, and the build up of blood is irritating to the synovial lining and damages joint tissue, so that adherence to hemophilia therapy is important.Global research in 18 countries reported that compliance with therapy by patients with hemophilia was low with self-injection adherence under 75% with as few as 53-65% of adults complying with therapy. Some of the most frequently cited factors affecting patients' compliance to therapy are as follows; inability to understand potential benefits (75%); denial (67%); interference with life style (62%); and lack of time (42%).The self-injection method of administering coagulation products became popular in the 1970s. In the early 1980s, 1,432 patients with hemophilia in Japan were infected with HIV (human immunodeficiency virus) because of the use of untreated blood products contaminated with the HIV virus. In addition commercial factor concentrates, which are prepared from pools of 2 to 6000 liters of plasma obtained

  20. Identification and Genetic Analysis of a Factor IX Gene Intron 3 Mutation in a Hemophilia B Pedigree in China

    Directory of Open Access Journals (Sweden)

    Dong Hua Cao

    2014-09-01

    Full Text Available OBJECTIVE: Hemophilia B is caused by coagulation defects in the factor IX gene located in Xq27.1 on the X chromosome. A wide range of mutations, showing extensive molecular heterogeneity, have been described in hemophilia B patients. Our study was aimed at genetic analysis and prenatal diagnosis of hemophilia B in order to further elucidate the pathogenesis of the hemophilia B pedigree in China. METHODS: Polymerase chain reaction amplification and direct sequencing of all the coding regions was conducted in hemophilia B patients and carriers. Prenatal diagnosis of the proband was conducted at 20 weeks. RESULTS: We identified the novel point mutation 10.389 A>G, located upstream of the intron 3 acceptor site in hemophilia B patients. The fetus of the proband’s cousin was identified as a carrier. CONCLUSION: Our identification of a novel mutation in the F9 gene associated with hemophilia B provides novel insight into the pathogenesis of this genetically inherited disorder and also represents the basis of prenatal diagnosis.

  1. Fc-fusion technology and recombinant FVIII and FIX in the management of the hemophilias.

    Science.gov (United States)

    Mancuso, Maria Elisa; Mannucci, Pier Mannuccio

    2014-01-01

    Prophylaxis with regular infusions of factor VIII (FVIII)- or factor IX (FIX)- containing products is the mainstay of modern hemophilia care. However, this therapeutic regimen is inconvenient, requiring repeated intravenous injections from childhood. Approaches meant to prolong the half-life of FVIII and FIX in plasma have been developed in order to improve the feasibility and acceptability of replacement therapy, extending protection from bleeding, reducing infusion frequency and hence the need for venous access devices in young children. Several strategies have been implemented to enhance the pharmacokinetics of clotting factors, including conjugation with polyethylene glycol and the production by genetic engineering of fusion proteins containing the coagulation factors linked to a long-lived plasma protein such as albumin or the Fc fragment of immunoglobulin (Ig)G. The latter technology is one of the most promising, since the prolongation of FVIII and FIX half-life is obtained by exploiting the physiological binding of the Fc domain to the neonatal Fc receptor. Fc fusion monomers have been obtained with both recombinant FVIII (rFVIIIFc) and FIX (rFIXFc), and data from preclinical and clinical studies showed improved pharmacokinetics for both factors, which are produced in human embryonic kidney (HEK) 293 cells, thus ensuring full human post-translational modifications. In Phase I/IIa studies, rFVIIIFc and rFIXFc showed 1.5-1.7 fold and 3.0-4.0 fold longer elimination half-life, respectively. Similar data have been obtained in the Phase III clinical studies with rFVIIIFc and rFIX-Fc published recently. Both drugs were satisfactorily safe, particularly with respect to immunogenicity, and no serious adverse event was observed.

  2. Directors General appointed

    CERN Multimedia

    1975-01-01

    At a special session on 21 March, presided over by P. Levaux, the Council of the European Organization for Nuclear Research appointed J . B. Adams and L . Van Hove as Directors General of the Organization for a period of five years beginning 1 January 1976. Dr. Adams will be responsible for the administration of CERN, for the operation of the equipment and services and for the construction of buildings and major equipment. Professor Van Hove will be responsible for the research activities of the Organization.

  3. Long-term efficacy and safety of prophylaxis with recombinant factor VIII in Chinese pediatric patients with hemophilia A: a multi-center, retrospective, non-interventional, phase IV (ReCARE) study.

    Science.gov (United States)

    Li, Changgang; Zhang, Xinsheng; Zhao, Yongqiang; Wu, Runhui; Hu, Qun; Xu, Weiqun; Sun, Jing; Yang, Renchi; Li, Xiaojing; Zhou, Rongfu; Lian, Shinmei; Gu, Jian; Wu, Junde; Hou, Qingsong

    2017-07-01

    The first recombinant factor VIII (rFVIII) product was launched in China in 2007. However, until now, no study has been conducted to describe the efficacy and safety of prophylaxis with rFVIII in Chinese pediatric patients with hemophilia A (HA). To summarize the efficacy and safety data on prophylaxis with rFVIII in Chinese pediatric patients with HA. ReCARE (Retrospective study in Chinese pediatric hemophilia A patients with rFVIII contained regular prophylaxis) was a retrospective study conducted in 12 hemophilia treatment centers (HTCs) across China. The primary endpoints included reduction in annualized bleeding rate (ABR); the secondary endpoints included evaluation of joint function (number and sites of target joints) using Gilbert score and Hemophilia Joint Health Score (HJHS), quality of life (QoL) and factors affecting treatment choices. Safety assessment of rFVIII was also conducted. We analyzed a total of 183 male pediatric patients (mean age, 7.1 ± 4.23 years) who received prophylaxis between 1 November 2007 and 31 May 2013. Compared with baseline, prophylaxis with rFVIII significantly reduced overall annualized joint bleed rate (AJBR) (p < .001) and ABR (p < .001). Inhibitor formation was reported in 5 (2.7%) patients and hemarthrosis was reported in 1 patient. The mean number of target joints was positively related to age (p < .001) and weight (p = .003) at baseline. Responses from survey questionnaires reported that effective bleeding control, joint protection, improvement in quality of life, favorable medical insurance policies, and economic capability were reasons for choosing prophylaxis. Prophylaxis with rFVIII reduced bleeding and number of target joints, even with a low-dose regimen, in Chinese pediatric patients with HA. Other than the efficacy and safety, factors such as poor disease control, improved economic stability and stable financial support made prophylaxis as an attractive treatment option. ClinicalTrials.gov ID

  4. Recombinant factor VIII Fc fusion protein for the prevention and treatment of bleeding in children with severe hemophilia A.

    Science.gov (United States)

    Young, G; Mahlangu, J; Kulkarni, R; Nolan, B; Liesner, R; Pasi, J; Barnes, C; Neelakantan, S; Gambino, G; Cristiano, L M; Pierce, G F; Allen, G

    2015-06-01

    Prophylactic factor replacement, which prevents hemarthroses and thereby reduces the musculoskeletal disease burden in children with hemophilia A, requires frequent intravenous infusions (three to four times weekly). Kids A-LONG was a phase 3 open-label study evaluating the safety, efficacy and pharmacokinetics of a longer-acting factor, recombinant factor VIII Fc fusion protein (rFVIIIFc), in previously treated children with severe hemophilia A (endogenous FVIII level of hemophilia A. © 2015 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.

  5. Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia a

    NARCIS (Netherlands)

    C.L. Eckhardt (Corien); A.S. van Velzen (Alice); M.A.D. Peters (Marjolein); J. Astermark (Jan); P.P. Brons; G. Castaman (Giancarlo); M.H. Cnossen (Marjon); N. Dors (N.); C. Escuriola-Ettingshausen (Carmen); K. Hamulyák (K.); D.P. Hart (Daniel); C.R.M. Hay (Charles R.); S. Haya (Saturnino); W.L. van Heerde; C. Hermans (Cédric); M. Holmström (Margareta); V. Jimenez-Yuste (Victor); R.D. Keenan (Russell); R. Klamroth (Robert); B.A.P. Laros-Van Gorkom (Britta); F.W.G. Leebeek (Frank); R. Liesner (Ri); A. Mäkipernaa (Anne); C. Male (Christoph); E.P. Mauser-Bunschoten (Eveline); M.G. Mazzucconi (Maria); S. McRae (Simon); K. Meijer (K.); M. Mitchell (Michael); M. Morfini (Massimo); M.R. Nijziel (Marten); J. Oldenburg (Jan); K. Peerlinck; P. Petrini (Pia); H. Platokouki (Helena); S.E. Reitter-Pfoertner (Sylvia); E. Santagostino (Elena); P. Schinco (Piercarla); F.J.W. Smiers (Frans); K.D. Siegmund (Kimberly); A. Tagliaferri (Annarita); T.T. Yee (Thynn); P.W. Kamphuisen (Pieter Willem); J.G. van der Bom (Anske); K. Fijnvandraat

    2013-01-01

    textabstractNeutralizing antibodies (inhibitors) toward factor VIII form a severe complication in nonsevere hemophilia A, profoundly aggravating the bleeding pattern. Identification of high-risk patients is hampered by lack of data that take exposure days to therapeutic factor VIII concentrates into

  6. Assessment of Musculoskeletal Function and its Correlation with Radiological Joint Score in Children with Hemophilia A.

    Science.gov (United States)

    Gupta, Samriti; Garg, Kapil; Singh, Jagdish

    2015-12-01

    To evaluate the functional independence of children with hemophilia A and its correlation to radiological joint score. The present cross sectional study was conducted at SPMCHI, SMS Medical College, Jaipur, India. Children in the age group of 4-18 y affected with severe, moderate and mild hemophilia A and with a history of hemarthrosis who attended the OPD, emergency or got admitted in wards of SPMCHI, SMS Medical College were examined. Musculoskeletal function was measured in 98 patients using Functional Independence Score in Hemophilia (FISH) and index joints (joints most commonly affected with repeated bleeding) were assessed radiologically with plain X rays using Pettersson score. The mean FISH score was 28.07 ± 3.90 (range 17-32) with squatting, running and step climbing as most affected tasks. The mean Pettersson score was 3.8 ± 3.2. A significant correlation was found between mean Pettersson score and FISH (r = -0.875, P hemophilia A.

  7. A systematic review of the effects of hemophilia and von Willebrand disease on arterial trombosis

    NARCIS (Netherlands)

    Biere-Rafi, Sara; Zwiers, M.; Peters, Marjolein; Van Der Meer, Jan; Rosendaal, Frits R; Buller, Harry R; Kamphuisen, Pieter W

    Background: Patients with hemophilia and von Willebrand disease (VWD) may be protected against arterial thrombosis, through a hy-pocoagulable state or atherosclerosis. We performed a systematic review to assess the association between these clotting disorders, arterial thrombosis and the prevalence

  8. Molecular diagnosis of hemophilia A and B. Report of five families from Costa Rica

    Directory of Open Access Journals (Sweden)

    Lizbeth Salazar-Sánchez

    2004-09-01

    Full Text Available Hemophilia Aand B are X-chromosome linked bleeding disorders caused by deficiency of the respective coagulation factor VIII and IX. Affected individuals develop a variable phenotype of hemorrhage caused by a broad range of mutations within the Factor VIII or Factor IX gene. Here, were report the results of the molecular diagnosis in a five Costa Rican families affected with Hemophilia. Methods of indirect and direct molecular diagnosis are applied in three Hemophilia A and two Hemophilia B families from Costa Rica as well as preconditions, practicability and facilities of this diagnosis. In two families with Hemophilia A and both families with Hemophilia B the causative mutation could be detected by Southern blotting, polymerase chain reaction or sequence analysis. One Hemophilia A family could only analyzed by linkage analysis using genomic markers. Rev. Biol. Trop. 52(3: 521-530. Epub 2004 Dic 15.La hemofilia A y B es una enfermedad hemorrágica hereditaria ligada al cromosoma X, producida por la deficiencia del factor VIII o IX, respectivamente. Los individuso afectados presentan un fenotipo de hemorragia variable causada por el amplio espectro de mutacionesdentro del gen del factor VIII o IX. Se reportan los resultados preliminares del diagnóstico molecular de familias hemofilicas costarricenses. Se demuestran los hallazgos obtenidos por medio de diagnóstico molecular directo e indirecto en tres familias con hemofilia A y dos con hemofilia B; así como las precondiciones y facilidad de este diagnóstico. En dos familias con hemofilia A y dos con hemofilia B, la mutación responsable pudo ser detectada por medio de Southern Blot, por la reacción en cadena de la polimerasa o por secuenciación genética. Una familia con hemofilia A pudo ser analizada solamente por medio de análisis indirecto por medio de marcadores genéticos intragénicos y extragénicos.

  9. Validation of the VERITAS-Pro treatment adherence scale in a Spanish sample population with hemophilia

    Directory of Open Access Journals (Sweden)

    Cuesta-Barriuso R

    2017-03-01

    Full Text Available Rubén Cuesta-Barriuso,1–3 Ana Torres-Ortuño,4 Pilar Galindo-Piñana,4 Joaquín Nieto-Munuera,4 Natalie Duncan,5 José Antonio López-Pina6 1Department of Physiotherapy, School of Biomedical and Health Sciences, European University of Madrid, 2Fishemo, Centro Especial de Empleo, Spanish Federation of Hemophilia, 3Royal Foundation Victoria Eugenia, Madrid, 4Department of Psychiatry and Social Psychology, Faculty of Medicine, University of Murcia, Murcia, Spain; 5Indiana Hemophilia & Thrombosis Center, Indianapolis, IN, USA; 6Department of Basic Psychology and Methodology, Faculty of Psychology, University of Murcia, Murcia, Spain Purpose: We aimed to conduct a validation in Spanish of the Validated Hemophilia Regimen Treatment Adherence Scale – Prophylaxis (VERITAS-Pro questionnaire for use in patients with hemophilia under prophylactic treatment.Patients and methods: The VERITAS-Pro scale was adapted through a process of back translation from English to Spanish. A bilingual native Spanish translator translated the scale from English to Spanish. Subsequently, a bilingual native English translator translated the scale from Spanish to English. The disagreements were resolved by agreement between the research team and translators. Seventy-three patients with hemophilia, aged 13–62 years, were enrolled in the study. The scale was applied twice (2 months apart to evaluate the test–retest reliability.Results: Internal consistency reliability was lower on the Spanish VERITAS-Pro than on the English version. Test–retest reliability was high, ranging from 0.83 to 0.92. No significant differences (P>0.05 were found between test and retest scores in subscales of VERITAS-Pro. In general, Spanish patients showed higher rates of nonadherence than American patients in all subscales.Conclusion: The Spanish version of the VERITAS-Pro has high levels of consistency and empirical validity. This scale can be administered to assess the degree of

  10. Magnetic heat pump flow director

    Science.gov (United States)

    Howard, Frank S. (Inventor)

    1995-01-01

    A fluid flow director is disclosed. The director comprises a handle body and combed-teeth extending from one side of the body. The body can be formed of a clear plastic such as acrylic. The director can be used with heat exchangers such as a magnetic heat pump and can minimize the undesired mixing of fluid flows. The types of heat exchangers can encompass both heat pumps and refrigerators. The director can adjust the fluid flow of liquid or gas along desired flow directions. A method of applying the flow director within a magnetic heat pump application is also disclosed where the comb-teeth portions of the director are inserted into the fluid flow paths of the heat pump.

  11. Defining and Selecting Independent Directors

    Directory of Open Access Journals (Sweden)

    Eric Pichet

    2017-10-01

    Full Text Available Drawing from the Enlightened Shareholder Theory that the author first developed in 2011, this theoretical paper with practical and normative ambitions achieves a better definition of independent director, while improving the understanding of the roles he fulfils on boards of directors. The first part defines constructs like firms, Governance system and Corporate governance, offering a clear distinction between the latter two concepts before explaining the four main missions of a board. The second part defines the ideal independent director by outlining the objective qualities that are necessary and adding those subjective aspects that have turned this into a veritable profession. The third part defines the ideal process for selecting independent directors, based on nominating committees that should themselves be independent. It also includes ways of assessing directors who are currently in function, as well as modalities for renewing their mandates. The paper’s conclusion presents the Paradox of the Independent Director.

  12. Nonneutralizing antibodies against factor VIII and risk of inhibitor development in severe hemophilia A.

    Science.gov (United States)

    Cannavò, Antonino; Valsecchi, Carla; Garagiola, Isabella; Palla, Roberta; Mannucci, Pier Mannuccio; Rosendaal, Frits R; Peyvandi, Flora

    2017-03-09

    The development of anti-factor VIII (FVIII) neutralizing antibodies (inhibitors) is the major complication in hemophilia A. Nonneutralizing antibodies (NNAs) have been detected in hemophilia patients and also in unaffected individuals. The aim of this study was to assess the prevalence of NNAs and to evaluate whether their presence is associated with the development of inhibitors in a cohort of previously untreated or minimally treated patients with hemophilia A; plasma samples of 237 patients with severe hemophilia A enrolled in the SIPPET trial were collected before any exposure to FVIII concentrates and analyzed for the presence of anti-FVIII NNAs. Patients were observed for the development of neutralizing antibodies. NNAs were found in 18 (7.6%) of 237 patients at screening, and there was a clear age gradient. Of those with NNAs, 7 patients subsequently developed an inhibitor for a cumulative incidence of 45.4% (95% confidence interval [CI], 19.5% to 71.3%); among the 219 patients without NNAs, 64 (29%) developed an inhibitor (cumulative incidence, 34.0%; 95% CI, 27.1%-40.9%). In Cox regression analyses, patients with NNAs at screening had an 83% higher incidence of inhibitor development than patients without NNAs (hazard ratio [HR], 1.83; 95% CI, 0.84-3.99). For high-titer inhibitors, the incidence rate had an almost threefold increase (HR, 2.74; 95% CI, 1.23-6.12). These associations did not materially change after adjustment. The presence of anti-FVIII NNAs in patients with severe hemophilia A who were not previously exposed to FVIII concentrates is associated with an increased incidence of inhibitors. © 2017 by The American Society of Hematology.

  13. Hemophilia in childhood: the impact of the disease on parent's participation in their child's education

    Directory of Open Access Journals (Sweden)

    Fabiane de Amorim Almeida

    2008-09-01

    Full Text Available Objectives: To identify the limitations faced by the hemophiliac child, according to his/her parents, and how they deal with these limitations, and to verify how parents approach the problem of hemophilia with the child as well as their strategies for disciplining that child and their nonhemophiliac children. Methods: An exploratory descriptive research study with a quantitative approach carried out with 20 parents of hemophiliac children seen at the ambulatory of a medium size public hospital in the city of São Paulo. The data were collected by means of a structured interview, using a form with open-ended and closed questions. Rresults: All the parents (20; 100% reported talking to their children about hemophilia, especially as to the definition of the disease (19; 46,35% and the activities that should be avoided (eight; 19.50%. Most of them (17; 85% also reported talking about hemophilia with their other children. Eighteen parents (90% restricted participation in sports and physical activities for their hemophiliac child, including at school: 11 (55% prohibit participation in physical activities, and 12 (60% ban extracurricular activities. All the parents also reported raising the subject of their child’s hemophilia with the educational professionals at their child’s school. As to discipline, half of them (ten; 50% use different strategies for disciplining their hemophiliac and non-hemophiliac children. Cconclusions: All the parents are concerned with discussing the subject of hemophilia with the child, his/her siblings, and teachers at school, imposing limitations especially as to participation in sports and/or physical activities. Differences were noted as to the strategies used by the parents for the discipline of their hemophiliac and non-hemophiliac children.

  14. Micronucleus evaluation for determining the chromosomal breakages after radionuclide synovectomy in patients with hemophilia

    International Nuclear Information System (INIS)

    Kavakli, K.; Cogulu, O.; Karaca, E.

    2012-01-01

    To investigate the genotoxic effects of 90 Y and 186 Re in patients with hemophilia who were undergoing radionuclide synovectomy (RS) procedure in the last 3 years. Nineteen patients were enrolled in the study. Most of the patients (n=17) were hemophilia-A (mean age 20.6±10.5 years) and 18 patients (mean age 22.6±10.6 years) with hemophilia who were not exposed to RS procedure were included in the study as control group. Most cases in the control group (n=13) were hemophilia-A. 90 Y for knee joints and 186 Re for elbow or ankle joints were used to perform RS in hemophilic patients. We studied the micronucleus (MN) test on peripheral blood lymphocytes as an indicator of radiation-induced cytogenetic damage and calculated nuclear division index. There was no significant difference between the patients with and without RS with respect to MN values. However, both values obtained in RS-exposed patients and control group were much elevated than values reported in literature from healthy controls. The mean MN values of patients below 20 years old were much lower but not significant than those above 20 years old. MN frequencies between 186 Re and 90 Y groups were also analyzed, and no significant difference was observed. Hemophilia patients who were treated with 186 Re showed higher levels of MN compared to patients treated with 90 Y although the difference was not significant. Radioisotope synovectomy (RS) seems to be a safe procedure not causing a significant genotoxic effect on hemophilic patients, however, further studies including larger series of patients are needed to better understand the effects of RS on patients' health. (author)

  15. Genetic variation of rs438601 marker in the Iranian Population: An informative marker for molecular diagnosis of hemophilia B

    Directory of Open Access Journals (Sweden)

    P Dorri

    2014-12-01

    Conclusion: The study findings demonstrated that rs438601 marker due to high heterozygosity could be suggested as an appropriate diagnostic marker in linkage analysis and carrier detection of hemophilia B in regard with a sample of Iranian population.

  16. 75 FR 67380 - Office of the Director; Notice of Meeting

    Science.gov (United States)

    2010-11-02

    ... of Outside Awards for ACD Approval; Biomedical Workforce Issues; ACD Stem Cell Working Group Report...: 8 a.m. to 3 p.m. Agenda: NIH Director's Report, Lasker Clinical Research Program; ACD TRND Working...

  17. Director ownership, outside directors and commitment to corporate social responsibility

    Directory of Open Access Journals (Sweden)

    Chen Ying

    2011-01-01

    Full Text Available This paper examines the effects of director ownership and the proportion of outside directors on firms’ commitment to corporate social responsibility (CSR. Using a sample of 453 Hong Kong listed companies for 2005, we find that there is a non-linear relationship between the level of director ownership and firms’ engagement in CSR behavior. Commitment to CSR first increases as the proportion of director ownership increases up to 50% and then decreases as that proportion of ownership grows higher. Further, the proportion of outside directors on the board exhibits a positive relationship with the level of CSR commitment. These results provide explanations for firms’ commitment to CSR from the corporate governance perspective.

  18. The Director's Work on Himself

    DEFF Research Database (Denmark)

    Kuhlmann, Annelis

    2008-01-01

    A reading of Stanislavsky's major works about the actor's work on himself from the viewpoint of the director's work on himself.......A reading of Stanislavsky's major works about the actor's work on himself from the viewpoint of the director's work on himself....

  19. IT governance guidelines for directors

    CERN Document Server

    Calder, Alan

    2005-01-01

    This important new book – 'IT Governance: Guidelines for Directors' provides directors, executives, managers and professional advisers with clear, pragmatic guidelines for ensuring that IT and the business work together for the same strategic objectives. 

  20. Three directors for one strategy

    CERN Multimedia

    2009-01-01

    Following the interview with the Director General, Rolf-Dieter Heuer, the Bulletin continues its series of interviews with the members of CERN’s new Management team. This week, the Bulletin interviewed the three Directors, who presented their strategies for their respective sectors as a new era begins for CERN.

  1. Object Oriented Programming in Director

    Directory of Open Access Journals (Sweden)

    Marian DARDALA

    2006-01-01

    Full Text Available Director is one of the most popular authoring software. As software for developing multimedia applications, Director is an object oriented programming environment. A very important issue to develop multimedia applications is the designing of their own classes. This paper presents the particular aspects concerning the available facilities offered by Lingo to design classes and to generate objects.

  2. ICU Director Data

    Science.gov (United States)

    Ogbu, Ogbonna C.; Coopersmith, Craig M.

    2015-01-01

    Improving value within critical care remains a priority because it represents a significant portion of health-care spending, faces high rates of adverse events, and inconsistently delivers evidence-based practices. ICU directors are increasingly required to understand all aspects of the value provided by their units to inform local improvement efforts and relate effectively to external parties. A clear understanding of the overall process of measuring quality and value as well as the strengths, limitations, and potential application of individual metrics is critical to supporting this charge. In this review, we provide a conceptual framework for understanding value metrics, describe an approach to developing a value measurement program, and summarize common metrics to characterize ICU value. We first summarize how ICU value can be represented as a function of outcomes and costs. We expand this equation and relate it to both the classic structure-process-outcome framework for quality assessment and the Institute of Medicine’s six aims of health care. We then describe how ICU leaders can develop their own value measurement process by identifying target areas, selecting appropriate measures, acquiring the necessary data, analyzing the data, and disseminating the findings. Within this measurement process, we summarize common metrics that can be used to characterize ICU value. As health care, in general, and critical care, in particular, changes and data become more available, it is increasingly important for ICU leaders to understand how to effectively acquire, evaluate, and apply data to improve the value of care provided to patients. PMID:25846533

  3. Power in the role of the medical director: what it is and how to get more.

    Science.gov (United States)

    Gabel, Stewart

    2011-05-01

    The formal leadership of mental health care organizations commonly resides in an executive director, who may or may not have had clinical training. The medical director is a psychiatrist who reports to the executive director. For some, this arrangement suggests that the medical director lacks or has lost power in the organization. This paper examines more specifically the types of power available to the medical director using French & Raven (1959) and Raven (2008) bases of power framework. The executive director/medical director relationship can be thought of as a relationship between individuals holding formal and informal power, respectively. Although medical directors lack formal or positional power, they potentially have and can gain more informal power based on their recognized clinical/medical expertise, their personal presence and an assertive involvement and focus on the organizational mission.

  4. Assessment of Relative Bioavailability of Moroctocog Alfa and Moroctocog Alfa (AF-CC) in Subjects With Severe Hemophilia A.

    Science.gov (United States)

    Korth-Bradley, Joan; Rupon, Jeremy; Plotka, Anna; Charnigo, Robert; Rendo, Pablo

    2018-05-01

    An open-label, single-dose, randomized, two-period, crossover study comparing the pharmacokinetics of factor VIII activity in plasma (FVIII:C) after administration of an albumin-free presentation of moroctocog alfa (test) and moroctocog alfa manufactured using the previous technique (reference) was conducted in 30 (25 evaluable) male subjects who had severe hemophilia A (FVIII:C < 1 IU/dL). Blood samples were collected for 48 h after administration of each dose. C was assayed using a chromogenic substrate assay. The FVIII:C pharmacokinetic parameters were calculated using noncompartmental analysis. The presentations would be bioequivalent if the 90% confidence limits of the ratio of the geometric mean values of AUC inf and recovery fell within the interval of 80-125%. The bioequivalence criteria were met. A total of 10 treatment-related adverse events were observed in a total of nine subjects. All were mild and none was determined to be related to administration of study medication. © 2018 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

  5. An innovative outcome-based care and procurement model of hemophilia management.

    Science.gov (United States)

    Gringeri, Alessandro; Doralt, Jennifer; Valentino, Leonard A; Crea, Roberto; Reininger, Armin J

    2016-06-01

    Hemophilia is a rare bleeding disorder associated with spontaneous and post-traumatic bleeding. Each hemophilia patient requires a personalized approach to episodic or prophylactic treatment, but self-management can be challenging for patients, and avoidable bleeding may occur. Patient-tailored care may provide more effective prevention of bleeding, which in turn, may decrease the likelihood of arthropathy and associated chronic pain, missed time from school or work, and progressive loss of mobility. A strategy is presented here aiming to reduce or eliminate bleeding altogether through a holistic approach based on individual patient characteristics. In an environment of budget constraints, this approach would link procurement to patient outcome, adding incentives for all stakeholders to strive for optimal care and, ultimately, a bleed-free world.

  6. [Effective immunosuppresive therapies including steroid pulse treatment for intramuscular hematoma in iliopsoas in acquired hemophilia].

    Science.gov (United States)

    Mohri, Hiroshi; Tanabe, Juichi; Takagi, Hiroshi; Murata, Takashi

    2007-12-01

    Acquired hemophilia is a life-threatening bleeding disorder by the development of autoantibody against factor VIII. The therapeutic approach relies on steroid, cyclophosphamide and/or cyclosporine. A 64-year-old man was referred to our hospital with extensive hematoma in both psoas muscles, severe anemia of 6.8 g/dl, prolonged activated partial thromboplastin time over 200 seconds, and factor VIII coagulation activity (FVIII: C) of 1.9%. A factor VIII inhibitor was detected at 118 Bethesda units (BU). The diagnosis of acquired hemophilia was made in the absence of a detectable cause. The inhibitor was IgG with a subclass of IgG4 and reacted with 72 kDa fragment of factor VIII light chain. Steroid pulse therapy following steroid treatment resulted in the resolution of acquired hemophila with marked and prolonged efficacy.

  7. Successful medical management of a neonate with spontaneous splenic rupture and severe hemophilia A.

    Science.gov (United States)

    Badawy, Sherif M; Rossoff, Jenna; Yallapragada, Sushmita; Liem, Robert I; Sharathkumar, Anjali A

    2017-03-01

    Splenic rupture in neonates is a rare event, usually occurring in the setting of underlying predisposing conditions. Here, we present the case of a term neonate who presented with worsening anemia in the setting of known hemolytic disease during the newborn period and was later found to have a spontaneous splenic rupture. He was subsequently diagnosed with severe hemophilia A, and was managed medically with recombinant factor VIII replacement therapy without any surgical intervention. This is the first reported case of a neonate who had spontaneous splenic rupture and severe hemophilia A, and underwent successful medical treatment without any surgical intervention. Copyright © 2016 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. All rights reserved.

  8. Risk Factors for Inhibitor Formation in Hemophilia: A Prevalent Case-Control Study

    Science.gov (United States)

    Ragni, Margaret V.; Ojeifo, Oluseyi; Feng, Jinong; Yan, Jin; Hill, Kathleen A.; Sommer, Steve S.; Trucco, Massimo N.; Brambilla, Donald J.

    2009-01-01

    Background Inhibitor formation is a major complication of hemophilia treatment. Aim In a prevalent case-control study, we evaluated blood product exposure, genotype, and HLA type on hemophilia A inhibitor formation. Methods Product exposure was extracted from medical records. Genotype was determined on stored DNA samples by detection of virtually all mutations-SSCP (DOVAM-S) and subcycling PCR. HLA typing was performed by PCR amplification and exonuclease-released fluorescence. Results Cases experienced higher intensity factor, 455 vs. 200 U per exposure, p0.100. Genotype was not associated with race. Time to immune tolerance was shorter for titers 0.50. Conclusions Inhibitor formation is associated with high intensity product exposure, CNS bleeding, African-American race, and low frequency of missense mutations. The ideal time to initiate prophylaxis to reduce CNS bleeding and inhibitor formation will require prospective studies. PMID:19563499

  9. Neonatal Gene Therapy for Hemophilia B by a Novel Adenovirus Vector Showing Reduced Leaky Expression of Viral Genes.

    Science.gov (United States)

    Iizuka, Shunsuke; Sakurai, Fuminori; Tachibana, Masashi; Ohashi, Kazuo; Mizuguchi, Hiroyuki

    2017-09-15

    Gene therapy during neonatal and infant stages is a promising approach for hemophilia B, a congenital disorder caused by deficiency of blood coagulation factor IX (FIX). An adenovirus (Ad) vector has high potential for use in neonatal or infant gene therapy for hemophilia B due to its superior transduction properties; however, leaky expression of Ad genes often reduces the transduction efficiencies by Ad protein-mediated tissue damage. Here, we used a novel Ad vector, Ad-E4-122aT, which exhibits a reduction in the leaky expression of Ad genes in liver, in gene therapy studies for neonatal hemophilia B mice. Ad-E4-122aT exhibited significantly higher transduction efficiencies than a conventional Ad vector in neonatal mice. In neonatal hemophilia B mice, a single neonatal injection of Ad-E4-122aT expressing human FIX (hFIX) (Ad-E4-122aT-AHAFIX) maintained more than 6% of the normal plasma hFIX activity levels for approximately 100 days. Sequential administration of Ad-E4-122aT-AHAFIX resulted in more than 100% of the plasma hFIX activity levels for more than 100 days and rescued the bleeding phenotypes of hemophilia B mice. In addition, immunotolerance to hFIX was induced by Ad-E4-122aT-AHAFIX administration in neonatal hemophilia B mice. These results indicated that Ad-E4-122aT is a promising gene delivery vector for neonatal or infant gene therapy for hemophilia B.

  10. Detection of hemophilia A carriers by use of frozen plasma samples

    International Nuclear Information System (INIS)

    Yang, H.C.; Hardin, J.; Vaudreuil, C.

    1978-01-01

    The efficacy of using promptly frozen plasma samples in the diagnosis of the carrier state for hemophilia A was evaluated by simultaneous measurement of factor VIII activity and antigen in 20 normal women and 20 obligate carriers. Factor VIII antigen was measured by two methods, electroimmunoassay and immunoradiometric assay. When the factor VIII activity and antigen data were evaluated by regression analysis, 94% of the carriers were correctly identified at the 95% confidence level

  11. Localised prostate cancer and hemophilia A (AHA: Case report and management of the disease

    Directory of Open Access Journals (Sweden)

    Francesco Celestino

    2014-09-01

    Full Text Available Acquired Hemophilia A (AHA is a rare bleeding diathesis characterized by the development of autoantibodies against factor VIII (FVIII. About half of the cases are idiopathic and the other half are associated with autoimmune diseases, postpartum problems, infections, inflammatory bowel disease, drugs, lymphoproliferative disorders or solid tumors . AHA is associated with malignancies in 7-15% of cases. We report a case of AHA in a 65 year old patient with prostatic carcinoma, who underwent retropubic radical prostatectomy (RP.

  12. Considerations in dental treatment of pediatric patients with hemophilia: A case report.

    OpenAIRE

    Lorena Bravo; Daniela Muñoz

    2012-01-01

    A male patient, 7 years old, attends the Regional Hospital of Guillermo Grant Benavente derived by a presumptive diagnosis of hemophilia due to bleeding resulting from extraction of a primary tooth and a family history. A hematologic study was realized, where was observed that the factor VIII was decreased, which confirmed the diagnosis. For dental treatment was coordinated with the treating hematologist for inpatient management and control of hematologic parameters during invasive dental pro...

  13. Considerations in dental treatment of pediatric patients with hemophilia: A case report.

    Directory of Open Access Journals (Sweden)

    Lorena Bravo

    2012-12-01

    Full Text Available A male patient, 7 years old, attends the Regional Hospital of Guillermo Grant Benavente derived by a presumptive diagnosis of hemophilia due to bleeding resulting from extraction of a primary tooth and a family history. A hematologic study was realized, where was observed that the factor VIII was decreased, which confirmed the diagnosis. For dental treatment was coordinated with the treating hematologist for inpatient management and control of hematologic parameters during invasive dental procedures, by the administration of factor VIII.

  14. DESCRIPTIVE EPIDEMIOLOGY OF HEMOPHILIA AND OTHER COAGULATION DISORDERS IN MANSOURA , EGYPT

    Directory of Open Access Journals (Sweden)

    Youssef Al Tonbary

    2010-08-01

    The study included 72 children with hematological disorders registered from 2000 to 2008 in MUCH. The hemophilic patient was defined as a person with physician-diagnosed hemophilia A or B and a measured factor VIII or IX activity level of 30% or less. Persons with acquired inhibitors of FVIII or FIX excluded. Severity level was categorized as mild if the factor activity level was 6–30%, moderate if 1–5% and severe if

  15. Life-threatening hemorrhage from acquired hemophilia A as a presenting manifestation of prostate cancer

    Directory of Open Access Journals (Sweden)

    Chirag Sheth

    2016-09-01

    Full Text Available Acquired factor VIII deficiency (acquired hemophilia A is a rare condition characterized by the acquisition of autoantibodies that affect the clotting activity of factor VIII (fVIII. The most common manifestation in affected patients is a hemorrhagic diathesis. This disorder is associated with autoimmune diseases, pregnancy, postpartum period, drugs, and malignancy. Management of this condition begins with attempts to arrest an acute bleed based on the site and severity of bleeding and inhibitor titer. The next priority is eradication of the fVIII antibodies using immunosuppressive therapies. We report the case of a 66-year-old male who presented with spontaneous right thigh hematoma with prolonged activated partial prothrombin time and normal prothrombin time. Mixing studies confirmed the presence of an inhibitor. Further investigation for the underlying etiology of acquired hemophilia A leads to diagnosis of prostate cancer. Treatment consisted of bypassing agents including activated factor VII and activated prothrombin plasma concentrate to arrest the bleeding. Steroids and cyclophosphamide were added to suppress the fVIII inhibitors. Concomitant treatment of locally advanced prostate cancer with chemotherapy confirmed the eradication of the inhibitors. To our knowledge, this is the first reported case of prostate cancer diagnosed and treated simultaneously with acquired hemophilia A resulting in favorable patient outcome.

  16. Oral Tolerance Induction in Hemophilia B Dogs Fed with Transplastomic Lettuce.

    Science.gov (United States)

    Herzog, Roland W; Nichols, Timothy C; Su, Jin; Zhang, Bei; Sherman, Alexandra; Merricks, Elizabeth P; Raymer, Robin; Perrin, George Q; Häger, Mattias; Wiinberg, Bo; Daniell, Henry

    2017-02-01

    Anti-drug antibodies in hemophilia patients substantially complicate treatment. Their elimination through immune tolerance induction (ITI) protocols poses enormous costs, and ITI is often ineffective for factor IX (FIX) inhibitors. Moreover, there is no prophylactic ITI protocol to prevent anti-drug antibody (ADA) formation. Using general immune suppression is problematic. To address this urgent unmet medical need, we delivered antigen bioencapsulated in plant cells to hemophilia B dogs. Commercial-scale production of CTB-FIX fusion expressed in lettuce chloroplasts was done in a hydroponic facility. CTB-FIX (∼1 mg/g) in lyophilized cells was stable with proper folding, disulfide bonds, and pentamer assembly after 30-month storage at ambient temperature. Robust suppression of immunoglobulin G (IgG)/inhibitor and IgE formation against intravenous FIX was observed in three of four hemophilia B dogs fed with lyophilized lettuce cells expressing CTB-FIX. No side effects were detected after feeding CTB-FIX-lyophilized plant cells for >300 days. Coagulation times were markedly shortened by intravenous FIX in orally tolerized treated dogs, in contrast to control dogs that formed high-titer antibodies to FIX. Commercial-scale production, stability, prolonged storage of lyophilized cells, and efficacy in tolerance induction in a large, non-rodent model of human disease offer a novel concept for oral tolerance and low-cost production and delivery of biopharmaceuticals. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  17. Pharmacokinetics and pharmacodynamics of SCT800, a new recombinant FVIII, in hemophilia A mice

    Science.gov (United States)

    Gu, Ruo-lan; Liu, Liang; Xie, Liang-zhi; Gai, Wen-lin; Cao, Si-shuo; Meng, Zhi-yun; Gan, Hui; Wu, Zhuo-na; Li, Jian; Zheng, Ying; Zhu, Xiao-xia; Dou, Gui-fang

    2016-01-01

    Aim: SCT800 is a new third-generation recombinant FVIII agent that is undergoing promising preclinical study. This study aimed to investigate the pharmacokinetic and pharmacodynamic profiles of SCT800 in hemophilia A mice. Methods: After hemophilia A mice were intravenously injected with single dose of SCT800 (80, 180, and 280 IU/kg) or the commercially available product Xyntha (280 IU/kg), pharmacokinetics profiles were evaluated based on measuring plasma FVIII: C. For pharmacodynamics study, dose-response curves of SCT800 and Xyntha (1–200 IU/kg) were constructed using a tail bleeding model monitoring both bleeding time and blood loss. Results: Pharmacokinetics profile analysis showed a dose independency of SCT800 ranging from 80 to 280 IU/kg and comparable pharmacokinetic profiles between SCT800 and Xyntha at the doses tested. Pharmacodynamics study revealed comparable ED50 values of SCT800 and Xyntha in the tail bleeding model: 14.78 and 15.81 IU/kg for bleeding time, respectively; 13.50 and 13.58 IU/kg for blood loss, respectively. Moreover, at the doses tested, the accompanying dose-related safety evaluation in the tail bleeding model showed lower hypercoagulable tendency and wider dosage range potential for SCT800 than Xyntha. Conclusion: In hemophilia A mice, SCT800 shows comparable pharmacokinetics and pharmacodynamics to Xyntha at the doses tested, and possibly with better safety properties. PMID:26806305

  18. Boards: Independent and Committed Directors?

    OpenAIRE

    Christophe Volonté

    2011-01-01

    Regulators, proxy advisors and shareholders are regularly calling for independent directors. However, at the same time, independent directors commonly engage in numerous outside activities potentially reducing their time and commitment with the particular firm. Using Tobin's Q as an approximation of market valuation and controlling for endogeneity, our empirical analysis reveals that neither is independence positively related to firm performance nor are outside activities negatively related t...

  19. Rationale for a randomized controlled trial comparing two prophylaxis regimens in adults with severe hemophilia A: the Hemophilia Adult Prophylaxis Trial

    Science.gov (United States)

    Ragni, Margaret V

    2011-01-01

    A major goal of comprehensive hemophilia care is to prevent occurrence of bleeds by prophylaxis or regular preventive factor, one or more times weekly. Although prophylaxis is effective in reducing bleeding and joint damage in children, whether it is necessary to continue into adulthood is not known. The purpose of this article is to describe a Phase III randomized controlled trial to evaluate prophylaxis comparing two dose regimens in adults with severe hemophilia A. I hypothesize that adults with mature cartilage and joints are less susceptible to joint bleeds and joint damage, and that once-weekly recombinant factor VIII prophylaxis, with up to two rescue doses per week, is as effective as thrice-weekly prophylaxis in reducing bleeding frequency, but less costly and more acceptable, with higher quality of life. The ultimate goal of this project is to determine whether once-weekly prophylaxis is any worse than thrice-weekly prophylaxis in reducing joint bleeding frequency, while potentially utilizing less factor, at lower cost, leading to a better quality of life. This is an innovative concept, as it challenges the current paradigm of thrice-weekly prophylaxis in adults, which is based on dosing in children. Furthermore, this trial will assess interdose thrombin generation, a novel tissue factor-based assay of hemostasis, to determine if individualized thrombin generation can predict more individualized prophylaxis dosing, which would be practice changing. PMID:21939418

  20. The pharmacokinetics of a B-domain truncated recombinant factor VIII, turoctocog alfa (NovoEight®), in patients with hemophilia A.

    Science.gov (United States)

    Jiménez-Yuste, V; Lejniece, S; Klamroth, R; Suzuki, T; Santagostino, E; Karim, F A; Saugstrup, T; Møss, J

    2015-03-01

    Turoctocog alfa (NovoEight(®)) is a human recombinant coagulation factor VIII (rFVIII) for the treatment of patients with hemophilia A. To evaluate the pharmacokinetics of turoctocog alfa in all age groups across clinical trials. Data from previously treated patients with severe hemophilia A (FVIII activity level of ≤ 1%) with no history of FVIII inhibitors, in a non-bleeding state, were included. The pharmacokinetics were assessed following a wash-out period and a subsequent single intravenous 50 IU kg(-1) dose of turoctocog alfa. Blood was sampled during a 48-h period postdose. Standard pharmacokinetic (PK) parameters were estimated on the basis of plasma FVIII activity vs. time (PK profiles) with non-compartmental methods. Furthermore, a population PK analysis was conducted. Data from 76 patients (aged 1-60 years) enrolled globally across six clinical trials were included, totaling 105 turoctocog alfa PK profiles. Single-dose PK results 3-6 months after the first dose of turoctocog alfa were comparable with the results obtained after the first dose. Similar PK characteristics were shown for different lots and strengths of the drug product. Overall, area under the plasma concentration (activity) curve from administration to infinity (AUC) and t1(/2) tended to increase with increasing age, with lower AUC and shorter t(1/2) being seen in children than in adolescents and adults. The PK profiles of turoctocog alfa and other commercially available plasma-derived FVIII and rFVIII products were similar in all age groups. The PK characteristics of turoctocog alfa have been thoroughly studied, and shown to be consistent over time, reproducible between different lots and strengths of drug product, and similar to those observed for other FVIII products. © 2014 International Society on Thrombosis and Haemostasis.

  1. Declining trends in invasive orthopedic interventions for people with hemophilia enrolled in the Universal Data Collection program (2000–2010)

    Science.gov (United States)

    TOBASE, P.; LANE, H.; SIDDIQI, A.-E-A.; INGRAM-RICH, R.; WARD, R. S.

    2016-01-01

    Introduction Recurrent joint hemarthroses due to hemophilia (Factor VIII and Factor IX deficiency) often lead to invasive orthopedic interventions to decrease frequency of bleeding and/or to alleviate pain associated with end-stage hemophilic arthropathy. Aim Identify trends in invasive orthopedic interventions among people with hemophilia who were enrolled in the Universal Data Collection (UDC) program during the period 2000–2010. Methods Data were collected from 130 hemophilia treatment centers in the United States annually during the period 2000–2010, in collaboration with the Centers for Disease Control and Prevention (CDC). The number of visits in which an invasive orthopedic intervention was reported was expressed as a proportion of the total visits in each year of the program. Invasive orthopedic interventions consisted of arthroplasty, arthrodesis, and synovectomy. Joints included in this study were the shoulder, elbow, hip, knee, and ankle. Results A 5.6% decrease in all invasive orthopedic interventions in all joints of people with hemophilia enrolled in the UDC program over the 11-year study period was observed. Conclusions These data reflect a declining trend in invasive orthopedic interventions in people with hemophilia. Further research is needed to understand the characteristics that may influence invasive orthopedic interventions. PMID:27030396

  2. Comparison of Clot-based, Chromogenic, and Fluorescence Assays for Measurement of Factor VIII Inhibitors in the U.S. Hemophilia Inhibitor Research Study

    Science.gov (United States)

    Miller, Connie H.; Rice, Anne S.; Boylan, Brian; Shapiro, Amy D.; Lentz, Steven R.; Wicklund, Brian M.; Kelly, Fiona M.; Soucie, J. Michael

    2015-01-01

    Summary Background Detection and validation of inhibitors (antibodies) to hemophilia treatment products are important for clinical care, evaluation of product safety, and assessment of population trends. Methods Centralized monitoring for factor VIII (FVIII) inhibitors was conducted for patients in the Hemophilia Inhibitor Research Study using a previously reported modified Nijmegen-Bethesda clotting assay (NBA), a chromogenic Bethesda assay (CBA), and a novel fluorescence immunoassay (FLI). Results NBA and CBA were performed on 1005 specimens and FLI on 272 specimens. CBA was negative on 880/883 specimens (99.7%) with Nijmegen-Bethesda units (NBU)NBA and negative CBA, 58.1% were FLI-negative, 12.9% had evidence of lupus anticoagulant, and 35.5% had non-time-dependent inhibition. CBA and FLI were positive on 72.4% and 100% of 1.0–1.9 NBU specimens and 43.1% and 50.0% of 0.5–0.9 NBU specimens. FLI detected antibodies in 98.0% of CBA-positive and 81.6% of NBA-positive specimens (P=0.004). Among 21 new inhibitors detected by NBA, 5 (23.8%) with 0.7–1.3 NBU did not react in CBA or FLI. Among previously positive patients with 0.5–1.9 NBU, 7/25 (28%) were not CBA or FLI positive. FLI was positive on 36/169 NBU-negative specimens (21.3%). Conclusions FVIII specificity could not be demonstrated by CBA or FLI for 26% of inhibitors of 0.5–1.9 NBU; such results must be interpreted with caution. Low titer inhibitors detected in clot-based assays should always be repeated, with consideration given to evaluating their reactivity with FVIII using more specific assays. PMID:23601690

  3. Cost-utility analysis of immune tolerance induction therapy versus on-demand treatment with recombinant factor VII for hemophilia A with high titer inhibitors in Iran

    Directory of Open Access Journals (Sweden)

    Rasekh HR

    2011-11-01

    Full Text Available Hamid Reza Rasekh1, Ali Imani1, Mehran Karimi2, Mina Golestani11Shahid Beheshti University of Medical Sciences, Department of Pharmaceutical Management and Pharmacoeconomics, School of Pharmacy, Tehran, 2University of Shiraz Medical Sciences, Hematology Research Center, Shiraz, IranBackground: In developing countries, the treatment of hemophilia patients with inhibitors is presently the most challenging and serious issue in hemophilia management, direct costs of clotting factor concentrates accounting for >98% of the highest economic burden absorbed for the health care of patients in this setting. In the setting of chronic diseases, cost-utility analysis, which takes into account the beneficial effects of a given treatment/health care intervention in terms of health-related quality of life, is likely to be the most appropriate approach.Objective: The aim of this study was to assess the incremental cost-effectiveness ratios of immune tolerance induction (ITI therapy with plasma-derived factor VIII concentrates versus on-demand treatment with recombinant-activated FVIIa (rFVIIa in hemophilia A with high titer inhibitors from an Iranian Ministry of Health perspective.Methods: This study was based on the study of Knight et al, which evaluated the cost-effectiveness ratios of different treatments for hemophilia A with high-responding inhibitors. To adapt Knight et al's results to the Iranian context, a few clinical parameters were varied, and cost data were replaced with the corresponding Iranian estimates of resource use. The time horizon of the analysis was 10 years. One-way sensitivity analyses were performed, varying the cost of the clotting factor, the drug dose, and the administration frequency, to test the robustness of the analysis.Results: Comparison of the incremental cost-effectiveness ratios between the three ITI protocols and the on-demand regimen with rFVIIa shows that all three ITI protocols dominate the on-demand regimen with r

  4. Fermilab Education Office - Director's Award

    Science.gov (United States)

    Search The Director's Award Exceptional Service To Fermilab's K-12 Education Programs The many successes of Fermilab's K-12 education programs depend on the talents of the over 200 employees, users, and $1,000, made possible by an anonymous donor to Fermilab Friends for Science Education, recognizes one

  5. The governance of director networks

    NARCIS (Netherlands)

    Renneboog, L.D.R.; Zhou, Y.; Wright, M.; Siegel, D.; Keasey, K.; Filatotchev, I.

    2013-01-01

    This chapter studies director networks, which have gained increasing attention from sociology, finance, and management. It considers the argument that these networks have an interesting role in corporate governance and then reviews their rules in major developed countries. The chapter goes on to

  6. Characterization of genetic defects of hemophilia A in patients of Chinese origin

    Energy Technology Data Exchange (ETDEWEB)

    Lin, Shu-Wha; Lin, Shu-Rung; Shen, Ming-Ching (National Taiwan Univ., Taipei (Taiwan, Province of China))

    1993-12-01

    The molecular characterization of hemophilia A of Chinese origin was carried out by the polymerase chain reaction (PCR) and direct sequencing of patient's factor VIII genes. Single-strand conformation polymorphism (SSCP) and dideoxy fingerprinting (ddF) were used as screening methods to detect mutated DNAs. A total of 102 individuals from 87 different families, including 10 patients (10 families) with mild-to-moderate and 92 patients (77 families) with severe hemophilia A, were analyzed by PCR-SSCP and PCR-ddF. Of the 87 independent cases, 40 revealed a single mutation in the coding regions of their factor VIII genes. These mutations include 21 with single base changes resulting in 8 nonsense and 13 missense codons, 16 with deletion or insertion of 1-11 nucleotides, and 3 with deletion of large DNA fragments. The frequency of 8 of the identified factor VIII polymorphisms or silent mutations was also determined among Chinese. The frequencies for codons 1241, 1269, and 2223 (the numbering system follows J. Gitschier et al., 1984, Nature 312: 326-330) were found to be different from those reported for other populations. As for the 47 severe cases whose mutational events were not readily detected by PCR-SSCP and PCR-ddF, the reverse transcriptase PCR method was applied. In 24 such cases analyzed, 17 were found to be of the [open quotes]intron 22 mutations[close quotes] as described by Naylor et al. (1992, The Lancet, 342: 1066-1067), accounting for 39% of Chinese patients with hemophilia A. 31 refs., 2 figs., 6 tabs.

  7. Direct detection of common and rare inversion mutations in the genetic diagnosis of severe hemophilia A

    Energy Technology Data Exchange (ETDEWEB)

    Windsor, A.S.; Lillicrap, D.P.; Taylor, S.A.M. [Queen`s Univ., Ontario (Canada)

    1994-09-01

    Approximately 50% of the cases of severe hemophilia A (factor VIII:C < 0.01 units/ml) may be due to gross rearrangements of the factor VIII gene. The mutation involves homologous sequences upstream of the factor VIII locus and within intron 22 in an intrachromosomal recombination, inversion, event. The rearrangements can readily be detected on a Southern blot using a probe that is complementary to sequences from within intron 22. We describe here the analysis of this mutation in 71 severe hemophilia A patients. Thirty two of the patients (45%) showed evidence of a rearrangement. Five different patterns of rearrangements were seen, two of which have previously been described and account for the majority of cases (pattern 1, 70% and pattern 2, 16%). Three other abnormal patterns were observed. The inversion mechanism does not usually result in the loss or gain of any genetic material, but in one patient, in whom a unique rearrangement pattern was observed (pattern 3), we have previously documented a gross deletion which removes exons 1-22 of the factor VII gene as well as sequences 5{prime} to the gene. In another individual a fourth pattern in which an extra 19.0 kb band is present was detected. In this case it is unclear as to whether the rearrangement is responsible for the disease or is simply coincident normal variation. A fifth pattern, in which an extra 16.0 kb band was detected, was observed in a family with a new mutation causing hemophilia A. The affected individual and his mother inherited a de novo rearrangement of the factor VIII gene from his unaffected grandfather, implicating it as the cause of the disease. In conclusion, testing for the factor VIII inversion mutation was positive in approximately 45% of severe hemophiliacs, 72% of whom were isolated cases, and as such should constitute the initial stage in the genetic testing protocol for these patients` families.

  8. Mutagenesis in sequence encoding of human factor VII for gene therapy of hemophilia

    Directory of Open Access Journals (Sweden)

    B Kazemi

    2009-12-01

    Full Text Available "nBackground: Current treatment of hemophilia which is one of the most common bleeding disorders, involves replacement therapy using concentrates of FVIII and FIX .However, these concentrates have been associated with viral infections and thromboembolic complications and development of antibodies. "nThe use of recombinant human factor VII (rhFVII is effective  for the treatment of patients with  hemophilia A or B, who develop antibodies ( referred as inhibitors against  replacement therapy , because it induces coagulation independent of FVIII and FIX. However, its short half-life and high cost have limited its use. One potential solution to this problem may be the use of FVIIa gene transfer, which would attain continuing therapeutic levels of expression from a single injection. The aim of this study was to engineer a novel hFVII (human FVII gene containing a cleavage site for the intracellular protease and furin, by PCR mutagenesis "nMethods: The sequence encoding light and heavy chains of hFVII, were amplified by using hFVII/pTZ57R and specific primers, separately. The PCR products were cloned in pTZ57R vector. "nResults and discussion: Cloning was confirmed by restriction analysis or PCR amplification using specific primers and plasmid universal primers. Mutagenesis of sequence encoding light and heavy chain was confirmed by restriction enzyme. "nConclusion: In the present study, it was provided recombinant plasmids based on mutant form of DNA encoding light and heavy chains.  Joining mutant form of DNA encoding light chain with mutant heavy chain led to a new variant of hFVII. This variant can be activated by furin and an increase in the proportion of activated form of FVII. This mutant form of hFVII may be used for gene therapy of hemophilia.

  9. Comparison of radiography, CT and MR imaging in detection of arthropathies in patients with hemophilia

    International Nuclear Information System (INIS)

    Yu Wei; Lin Qiang; Shang Wei; Zhu Haifeng; Meng Wei; Xu Ruiyi; Zhao Yongqiang; Shi Yongsheng

    2007-01-01

    Objective: To compare MR, CT, and radiography in the detection of arthropathies in patients with hemophilia. Methods: Forty-one symptomic joint images in the 14 patients with hemophilia, aged from 11 to 24 years, were used in this study. Each joint had the examinations of radiography, CT and MR within one day. The severity of each joint was staged using conventional radiographic classification. Severe HA patients with stage 5 were excluded from the study. Imaging findings of soft tissue swelling, osteoporosis, epiphyseal overgrowth, joint erosion, cyst, joint space narrowing, bone marrow, joint effusion, hemorrhage, synovial hypertrophy, widened intercondylar notch as well as anterior and posterior cruciate ligaments (only for knee joint) were used for the all imaging comparison. Results: The 41 symptomatic joints in 14 patients with hemophilia were classified by radiographic criteria into stage 0 (n=5), stage 1 (n=7), stage 2 (n=6), stage 3 (n=8) and stage 4 (n=15). Soft tissue swelling or joint effusion was observed in 33 joints by radiographs, in 34 joints by both CT and MR. Joint erosions were demonstrated in 34 joints by MR, in 33 joints by CT and 20 joints by radiographs. Joint cysts were shown in 21 joints by MR, in 18 joints by CT and 9 joints by radiographs. Significant differences in detection of erosion and cyst were found between radiography with either CT (P 0.05). MR showed improvement for detecting more foci of both erosion and cyst than CT and radiography, and also CT showed the improvement than radiography. Bone marrow edema 14 joints, hemorrhage in 34 joints and synovial hypertrophy in 27 joints were revealed on MR images. Conclusion: MRI is superior to CT and conventional radiography in detecting the abnormal changes and should be considered as the first choice among the imaging modalities in evaluating hemophilic arthropathies. (authors)

  10. Potential role of a new PEGylated recombinant factor VIII for hemophilia A

    Directory of Open Access Journals (Sweden)

    Wynn TT

    2016-06-01

    Full Text Available Tung Thanh Wynn,1 Burak Gumuscu,2,3 1Department of Pediatrics, Division of Pediatric Hematology/Oncology, University of Florida, Gainesville, FL, 2Pediatric Hematology-Oncology, Bon Secours Health System, St. Mary’s Hospital, Richmond, VA, 3Department of Pediatrics, Division of Pediatric Hematology/Oncology, University of Virginia, Charlottesville, VA, USA Abstract: Hemophilia A, a deficiency in the activity of coagulation factor (F VIII, is an X-linked bleeding disorder with an approximate incidence of one in 5,000 male infants. Bleeding-related complications often result in greater severity of disease, poor quality of life, surgical interventions for severe joint destruction, and shortened life span. With the availability of plasma-derived and recombinant FVIII products, the benefits of primary prophylaxis were demonstrated and is now the standard of care for patients with severe factor deficiencies. Current hemophilia research is focusing on the creation of new factor replacement therapies with longer half-lives; accessing alternative mechanisms to achieve desired hemostasis and enhance bypassing ­activity; and limiting the immunogenicity of the protein. PEGylation involves the covalent attachment of polyethylene glycol (PEG to a protein, peptide, or a small molecule drug. PEG effectively increases the molecular weight and size of the protein by creating a hydrophilic cloud around the molecule. This molecular change may reduce susceptibility of the molecule to proteolytic activity and degradation. It is also believed that PEGylation changes the surface charge of the protein that ultimately interferes with some receptor-mediated clearance processes. The half-life of PEGylated factor is more prolonged when compared to non-PEGylated full-length recombinant FVIII. The dawn of a new era in the care of hemophilia patients is upon us with the release of recombinant FVIII products with extended half-lives, and products with even more extended half

  11. METHODOLOGY OF THE DRUGS MARKET VOLUME MODELING ON THE EXAMPLE OF HEMOPHILIA A

    OpenAIRE

    N. B. Molchanova

    2015-01-01

    Hemophilia A is a serious genetic disease, which may lead to disability of a patient even in early ages without a required therapy. The only one therapeutic approach is a replacement therapy with drugs of bloodcoagulation factor VIII (FVIII). The modeling of coagulation drugs market volume will allow evaluation of the level of patients’ provision with a necessary therapy. Modeling of a “perfect” market of drugs and its comparison with the real one was the purpose of the study. During the mode...

  12. Acquired hemophilia A: a review of recent data and new therapeutic options.

    Science.gov (United States)

    Franchini, Massimo; Vaglio, Stefania; Marano, Giuseppe; Mengoli, Carlo; Gentili, Sara; Pupella, Simonetta; Liumbruno, Giancarlo Maria

    2017-10-01

    Acquired hemophilia A (AHA) is a rare, but potentially life-threatening, bleeding disorder caused by an autoantibody against factor VIII that interferes with its coagulant function. We performed a narrative review focusing on the diagnostic aspects of AHA and on the current treatment strategies with particular regard to new data and therapeutic developments. The management of this severe hemorrhagic disorder is based on the control of bleeding with the use of bypassing agents and on the utilization of a variety of immunosuppressant agents with the goal of eliminating the autoantibody permanently. The optimal management of AHA should be multidisciplinary and requires a close collaboration between physicians from various specialties.

  13. Patient preferences in the treatment of hemophilia A: impact of storage conditions on product choice

    Directory of Open Access Journals (Sweden)

    Tischer B

    2018-03-01

    Full Text Available Bernd Tischer,1 Renato Marino,2 Mariasanta Napolitano3 1Kantar Health, Munich, Germany; 2Haemophilia and Thrombosis Centre, University Hospital of Bari, Apulia, Italy; 3University of Palermo, Reference Regional Center for Thrombosis and Hemostasis Hematology Unit, Palermo, Italy Objectives: To gain insights into the usage of factor VIII (FVIII products by patients diagnosed with moderate/severe hemophilia A, and to assess the impact and perceived importance of product storage.Methods: In this study, 200 patients diagnosed with moderate or severe hemophilia A across seven countries participated. Data were collected via a 30-minute, face-to-face interview in six countries and via a web-based survey in the seventh country. The questionnaire evaluated the effect of six features associated with FVIII products on the choice of the product; the structure and flow of data collection was designed to eliminate potential bias.Results: Two-thirds of the respondents were using recombinant FVIII products. Only 17% were generally dissatisfied with current FVIII products, whereas >40% of the respondents were dissatisfied with frequency of administration and storage issues when traveling. The majority noted restrictions in their daily activities, particularly travel and sports. Most of them (85%, stored their product in the refrigerator and of these, 88% believed that it should always be stored there. These patients were also less satisfied with the product overall, more concerned about storage temperature, more restricted in daily activities, and spent more time on preparation and injection compared with patients who stored their product at room temperature. Conjoint analysis revealed that origin of FVIII (plasma-derived vs recombinant was the strongest driver of product choice among all respondents, followed by storage flexibility (temperature, reconstitution device, and administration frequency. In this study, we did not investigate the efficacy and safety of

  14. Comparing the Effects of Therapeutic Exercise and Hydrotherapy on Pain Severity and Knee Range of Motion in Patients with Hemophilia: A Randomized Controlled Trial

    Directory of Open Access Journals (Sweden)

    V Mazloum

    2013-10-01

    . Results: Both experimental groups exhibited significant reduction of pain along with improved knee flexion and extension compared with the control group (P<0.001. Pain reduction in subjects treated in water treatment was significantly higher than exercise group in drought (P0.05. Conclusion: The use of therapeutic exercise in water with regular exercise rehabilitation for patients with hemophilia can be helpful to reduce pain and improve range of motion in hemophilia patients. The effect of exercise therapy on pain reduction is more effective compared to traditional pain therapy. Key words: Hydrotherapy, Exercise Therapy, Hemophilia, Knee Range of Motion

  15. In silico evaluation of limited blood sampling strategies for individualized recombinant factor IX prophylaxis in hemophilia B patients

    NARCIS (Netherlands)

    Preijers, T.; Hazendonk, H. C. A. M.; Fijnvandraat, K.; Leebeek, F. W. G.; Cnossen, M. H.; Mathôt, R. A. A.

    2017-01-01

    Background Patients with severe hemophilia B regularly administer prophylactic intravenous doses of clotting factor IX concentrate to maintain a trough level of at least 0.01 IU mL(-1) in order to prevent joint bleeds. Assessment of individual pharmacokinetic (PK) parameters allows individualization

  16. In vitro evidence of a tissue factor-independent mode of action of recombinant factor VIIa in hemophilia.

    Science.gov (United States)

    Augustsson, Cecilia; Persson, Egon

    2014-11-13

    Successful competition of activated factor VII (FVIIa) with zymogen factor VII (FVII) for tissue factor (TF) and loading of the platelet surface with FVIIa are plausible driving forces behind the pharmacological effect of recombinant FVIIa (rFVIIa) in hemophilia patients. Thrombin generation measurements in platelet-rich hemophilia A plasma revealed competition for TF, which potentially could reduce the effective (r)FVIIa:TF complex concentration and thereby attenuate factor Xa production. However, (auto)activation of FVII apparently counteracted the negative effect of zymogen binding; a small impact was observed at endogenous concentrations of FVII and FVIIa but was virtually absent at pharmacological amounts of rFVIIa. Moreover, corrections of the propagation phase in hemophilia A required rFVIIa concentrations above the range where a physiological level of FVII was capable to downregulate thrombin generation. These data strongly suggest that rFVIIa acts independently of TF in hemophilia therapy and that FVII displacement by rFVIIa is a negligible mechanistic component. © 2014 by The American Society of Hematology.

  17. Tranexamic acid combined with recombinant factor VIII increases clot resistance to accelerated fibrinolysis in severe hemophilia A

    DEFF Research Database (Denmark)

    Hvas, Anne-Mette; Sørensen, Hanne Thykjær; Norengaard, Lisbeth

    2007-01-01

    examined whether the clot stability in hemophiliacs could be improved by treatment with tranexamic acid (TXA) in combination with recombinant factor VIII (rFVIII). PATIENTS/METHODS: Baseline blood samples were obtained from eight males with severe hemophilia A. Thereafter, a bolus injection of r...

  18. Gene therapy with adeno-associated virus vector 5-human factor IX in adults with hemophilia B

    DEFF Research Database (Denmark)

    Miesbach, Wolfgang; Meijer, Karina; Coppens, Michiel

    2018-01-01

    Hemophilia B gene therapy aims to ameliorate bleeding risk and provide endogenous factor IX (FIX) activity/synthesis through a single treatment, eliminating the requirement for FIX concentrate. AMT-060 combines an adeno-associated virus-5 (AAV5) vector with a liver-specific promoter driving expre...

  19. Antibody response to recombinant human coagulation factor VIII in a new rat model of severe hemophilia A

    DEFF Research Database (Denmark)

    Löfgren, Karin Maria; Sondergaard, H.; Skov, Søren

    2016-01-01

    Background: Neutralizing antibodies towardFVIII replacement therapy (inhibitors) are the most seri-ous treatment-related complication in hemophilia A(HA). A rat model of severe HA (F8/) has recentlybeen developed, but an immunological characterization isneeded to determine the value of using...

  20. Evaluation of the biological differences of canine and human factor VIII in gene delivery: Implications in human hemophilia treatment

    Science.gov (United States)

    The canine is the most important large animal model for testing novel hemophilia A(HA) treatment. It is often necessary to use canine factor VIII (cFIII) gene or protein for the evaluation of HA treatment in the canine model. However, the different biological properties between cFVIII and human FVII...

  1. Effect of a period of aquatic exercise therapy on the quality of life, anxiety and depression in patients with hemophilia

    Directory of Open Access Journals (Sweden)

    Mehdi Kargarfard

    2011-07-01

    Full Text Available Introduction: Muscle-Skeletal disorders are the most common problems in hemophilia patients that can affect the quality of life and psychological factors in these patients. The aim of this study was to evaluate the effect of a period of aquatic exercise therapy on the quality of life, depression and anxiety in hemophilia patients. Materials and Methods: In a semi-experimental study, 20 patients who referred to Isfahan Sayedo-Shohada hospital voluntarily were selected and then randomly in two experimental (n=10 and control (n=10 groups. Subjects of aquatic exercise therapy group started their activity in water for 8 weeks, 3 sessions per week about45 to 60 minutes, while the control group was only followed-up and during this period they did not experience any exercise. The quality of life, depression and anxiety variables of patients were measured by standard questionnaires in the beginning and end of eight week aquatic exercise therapy. Results: The results showed significant improvement in quality of life, depression and anxiety variables in aquatic exercise therapy group patients, compared with the control group after 8 week aquatic exercise therapy (p<0.05. Conclusion: Results of this study showed that aquatic exercise therapy can be used as an effective and helpful method to prevent and treat hemophilia patients because it leads to improve multi-dimensional variable quality of life, depression and anxiety in hemophilia patients .

  2. Characterization of a genetically engineered mouse model of hemophilia A with complete deletion of the F8 gene.

    Science.gov (United States)

    Chao, B N; Baldwin, W H; Healey, J F; Parker, E T; Shafer-Weaver, K; Cox, C; Jiang, P; Kanellopoulou, C; Lollar, P; Meeks, S L; Lenardo, M J

    2016-02-01

    ESSENTIALS: Anti-factor VIII (FVIII) inhibitory antibody formation is a severe complication in hemophilia A therapy. We genetically engineered and characterized a mouse model with complete deletion of the F8 coding region. F8(TKO) mice exhibit severe hemophilia, express no detectable F8 mRNA, and produce FVIII inhibitors. The defined background and lack of FVIII in F8(TKO) mice will aid in studying FVIII inhibitor formation. The most important complication in hemophilia A treatment is the development of inhibitory anti-Factor VIII (FVIII) antibodies in patients after FVIII therapy. Patients with severe hemophilia who express no endogenous FVIII (i.e. cross-reacting material, CRM) have the greatest incidence of inhibitor formation. However, current mouse models of severe hemophilia A produce low levels of truncated FVIII. The lack of a corresponding mouse model hampers the study of inhibitor formation in the complete absence of FVIII protein. We aimed to generate and characterize a novel mouse model of severe hemophilia A (designated the F8(TKO) strain) lacking the complete coding sequence of F8 and any FVIII CRM. Mice were created on a C57BL/6 background using Cre-Lox recombination and characterized using in vivo bleeding assays, measurement of FVIII activity by coagulation and chromogenic assays, and anti-FVIII antibody production using ELISA. All F8 exonic coding regions were deleted from the genome and no F8 mRNA was detected in F8(TKO) mice. The bleeding phenotype of F8(TKO) mice was comparable to E16 mice by measurements of factor activity and tail snip assay. Similar levels of anti-FVIII antibody titers after recombinant FVIII injections were observed between F8(TKO) and E16 mice. We describe a new C57BL/6 mouse model for severe hemophilia A patients lacking CRM. These mice can be directly bred to the many C57BL/6 strains of genetically engineered mice, which is valuable for studying the impact of a wide variety of genes on FVIII inhibitor formation on a

  3. The CDC Hemophilia B mutation project mutation list: a new online resource.

    Science.gov (United States)

    Li, Tengguo; Miller, Connie H; Payne, Amanda B; Craig Hooper, W

    2013-11-01

    Hemophilia B (HB) is caused by mutations in the human gene F9. The mutation type plays a pivotal role in genetic counseling and prediction of inhibitor development. To help the HB community understand the molecular etiology of HB, we have developed a listing of all F9 mutations that are reported to cause HB based on the literature and existing databases. The Centers for Disease Control and Prevention (CDC) Hemophilia B Mutation Project (CHBMP) mutation list is compiled in an easily accessible format of Microsoft Excel and contains 1083 unique mutations that are reported to cause HB. Each mutation is identified using Human Genome Variation Society (HGVS) nomenclature standards. The mutation types and the predicted changes in amino acids, if applicable, are also provided. Related information including the location of mutation, severity of HB, the presence of inhibitor, and original publication reference are listed as well. Therefore, our mutation list provides an easily accessible resource for genetic counselors and HB researchers to predict inhibitors. The CHBMP mutation list is freely accessible at http://www.cdc.gov/hemophiliamutations.

  4. Knee Fat Pad Volumes in Patients with Hemophilia and Their Relationship with Osteoarthritis

    Directory of Open Access Journals (Sweden)

    Annette von Drygalski

    2017-01-01

    Full Text Available Hemophilic arthropathy is a progressive, disabling condition with poorly understood pathobiology. Since there is an emerging interest to study the role of intra-articular fat pad size and biology in arthritic conditions, we explored fat pad volume changes in hemophilic arthropathy and to what extent they differed from osteoarthritis. We matched a cohort of 13 adult patients with hemophilic arthropathy of the knee with age- and gender-matched cohorts without osteoarthritis (“control cohort” and with the same degree of radiographic osteoarthritis (“OA cohort” in 1 : 2 fashion. Infrapatellar fat pad (IPFP and suprapatellar fat pad (SPFP volumes were calculated based on magnetic resonance imaging and differences in fat pad volumes, demographics, height, weight, and osteoarthritis scores were evaluated. Fat pad volumes were positively associated with body size parameters in all three cohorts but were unaffected by the degree of osteoarthritis. While IPFP volumes did not differ between cohorts, SPFP volumes expanded disproportionally with weight in hemophilia patients. Our observations indicate that IPFPs and SPFPs behave biologically differently in response to different arthritic stimuli. The exaggerated expansion of the SPFP in hemophilia patients highlights the importance of further studying the implications of fat pad biology for progression of hemophilic arthropathy.

  5. A close insight to factor VIII inhibitor in the congenital hemophilia A.

    Science.gov (United States)

    Tabriznia-Tabrizi, Shamsoreza; Gholampour, Marzie; Mansouritorghabeh, Hassan

    2016-09-01

    Hemophilia A (HA) has an X-linked pattern of inheritance and is the most common of the hemorrhagic disorders. HA is caused by a decreased or deficiency of the functional clotting factor VIII (FVIII) and effects 1 in 5000-10,000 male births. The common treatment for hemophilia is replacement therapy by plasma-derived or recombinant FVIII. Approximately 20-30% of people with a severe type of HA develop an inhibitor and this phenomenon is the main challenge in the management of these patients. Genetic factors and environmental determinants contribute to inhibitor development. Here, the roles of various genetic and environmental factors such as the type of FVIII concentrate used, the number of exposure days, and peak treatment time will be discussed in detail. It seems this information is helpful for hematologists. A literature review was done in January 2016 on PubMed and Scopus using the following keywords:' h(a)emophilia A & factor VIII inhibitor', 'h(a)emophilia A & factor VIII alloantibody', 'h(a)emophilia A & inhibitor'. There was no time limitation; however, there was an English language limitation placed on the articles selected. Expert commentary: Influential genetic and environmental factors in developing inhibitors have been discussed. Most of the risk factors are related to previously untreated patients with hemophili.

  6. Severe neonatal subgaleal hemorrhage as the first presentation of hemophilia A.

    Science.gov (United States)

    Radovanović, Tanja; Spasojević, Slobodan; Stojanović, Vesna; Doronjski, Aleksandra

    2016-01-01

    Subgaleal hemorrhage is a rare but potentially fatal birth trauma. It is caused by rupture of the emissary veins (connections between the dural sinuses and scalp veins), followed by the accumulation of blood between the epicranial aponeurosis and the periosteum. Usually, it is associated with instrumental delivery (vacuum extraction, forceps delivery), but it may also occur spontaneously, suggesting the possibility of congenital bleeding disorder. A full term male neonate was born at 40 weeks gestation by spontaneous vaginal delivery, with birth weight of 3,700 g. The Apgar scores were 9 and 10 at 1 and 5 minutes, respectively. At the age of 23 hours, the baby became pale and lethargic. Large fluctuant swelling on his head was noted. He developed severe anemia and hypovolemia as a result of massive subgaleal hemorrhage. After successful treatment, the baby fully recovered. Follow-up and further evaluation revealed hemophilia A as a result of a de novo mutation. This case illustrates that subgaleal hemorrhage may be the first presentation of hemophilia A. Infants without obvious risk factors for developing subgaleal hemorrhage should be evaluated for congenital bleeding disorder. Successful outcome in affected infants requires early diagnosis, careful monitoring and prompt treatment.

  7. Severe neonatal subgaleal hemorrhage as the first presentation of hemophilia A

    Directory of Open Access Journals (Sweden)

    Radovanović Tanja

    2016-01-01

    Full Text Available Introduction. Subgaleal hemorrhage is a rare but potentially fatal birth trauma. It is caused by rupture of the emissary veins (connections between the dural sinuses and scalp veins, followed by the accumulation of blood between the epicranial aponeurosis and the periosteum. Usually, it is associated with instrumental delivery (vacuum extraction, forceps delivery, but it may also occur spontaneously, suggesting the possibility of congenital bleeding disorder. Case Outline. A full term male neonate was born at 40 weeks gestation by spontaneous vaginal delivery, with birth weight of 3,700 g. The Apgar scores were 9 and 10 at 1 and 5 minutes, respectively. At the age of 23 hours, the baby became pale and lethargic. Large fluctuant swelling on his head was noted. He developed severe anemia and hypovolemia as a result of massive subgaleal hemorrhage. After successful treatment, the baby fully recovered. Follow-up and further evaluation revealed hemophilia A as a result of a de novo mutation. Conclusion. This case illustrates that subgaleal hemorrhage may be the first presentation of hemophilia A. Infants without obvious risk factors for developing subgaleal hemorrhage should be evaluated for congenital bleeding disorder. Successful outcome in affected infants requires early diagnosis, careful monitoring and prompt treatment.

  8. Hemofilia: aspectos históricos y genéticos Hemophilia: historical and genetic aspects

    Directory of Open Access Journals (Sweden)

    Dunia Castillo-González

    2012-03-01

    Full Text Available La hemofilia es un trastorno hemorrágico con disminución o ausencia de la actividad procoagulante del factor VIII o del IX. Las primeras descripciones de esta enfermedad son tan antiguas como la propia humanidad. A lo largo de los años, la hemofilia ha sido nombrada "enfermedad real" debido a que la padecieron diversos miembros de las familias reales europeas. En la actualidad, mediante estudios moleculares, se encontró el defecto genético causante de la enfermedad en los varones hemofílicos de la familia de la Reina Victoria y se encontró que sus descendientes padecieron una hemofilia B severa. El fenotipo de esta enfermedad es hemorrágico; se observan sangramientos en diversos sitios de la economía condicionados fundamentalmente por los niveles del factor deficiente. Existen otros factores que intervienen en las características fenotípicas variables de estos pacientes, entre ellos: las características intrínsecas de los factores VIII/IX, la presencia de genes modificadores y factores ambientales que influyen sobre la severidad de la enfermedad. Se revisa la correlación genotipo-fenotipo en esta enfermedad mediante las mutaciones más frecuentes en cada tipo de hemofilia. En cuanto a la presencia de los inhibidores, se destacan las evidencias actuales en relación con los factores de riesgo relacionados con su aparición y los aspectos moleculares presentes en la variante de hemofilia B Leyden.Hemophilia is a hemorrhagic disorder characterized by decreasing or absence of the procoagulant activity in factor VIII or IX. First descriptions of this disease are as old as mankind itself. During time, hemophilia has been called "royal disease" since different members of European royal families suffered from it. Currently, by molecular studies, it was found the causing genetic defect of this disease in hemophilic male members of Queen Victoria´s family; and it was found that her descendants suffered a severe hemophilia B. This disease

  9. Integration of Leadership Styles of School Director

    Science.gov (United States)

    Pavlovic, Nebojsa; Oljaca, Milka; Kostovic, Svetlana

    2012-01-01

    Management style can be defined as a special behavior of directors in the work process that affects the performance in an organization, in this case-school. Management style has two related meanings: first is behavior of directors to employees, second is directors' approach in school regarding management, participation of employees in decision…

  10. 30 CFR 282.11 - Director's authority.

    Science.gov (United States)

    2010-07-01

    ... CONTINENTAL SHELF FOR MINERALS OTHER THAN OIL, GAS, AND SULPHUR Jurisdiction and Responsibilities of Director § 282.11 Director's authority. (a) In the exercise of jurisdiction under § 282.10, the Director is... of two or more OCS mineral leases or portions of two or more OCS mineral leases into a single mining...

  11. 30 CFR 736.14 - Director's decision.

    Science.gov (United States)

    2010-07-01

    ... Director shall publish the decision in the Federal Register, including a statement of the basis and purpose... 30 Mineral Resources 3 2010-07-01 2010-07-01 false Director's decision. 736.14 Section 736.14... Director's decision. (a) After considering all relevant information received under § 736.12 of this part...

  12. 12 CFR 7.2010 - Directors' responsibilities.

    Science.gov (United States)

    2010-01-01

    ... refer to OCC published guidance for additional information regarding responsibilities of directors. ... 12 Banks and Banking 1 2010-01-01 2010-01-01 false Directors' responsibilities. 7.2010 Section 7... OPERATIONS Corporate Practices § 7.2010 Directors' responsibilities. The business and affairs of the bank...

  13. Molecular study in children with hemophilia A in Colombia: analysis of Intron 1 and 22 inversion using long-distance PCR technique

    Directory of Open Access Journals (Sweden)

    María Fernanda Garcés

    2017-04-01

    Conclusions: Inversions of intron 22 and 1 were found in half of this group of patients. These results are reproducible and useful to identify the two most frequent mutations in severe hemophilia A patients.

  14. Core clerkship directors: their current resources and the rewards of the role.

    Science.gov (United States)

    Ephgrave, Kimberly; Margo, Katherine L; White, Christopher; Hammoud, Maya; Brodkey, Amy; Painter, Thomas; Juel, Vern C; Shaw, Darlene; Ferguson, Kristi

    2010-04-01

    To conduct a national multidisciplinary investigation assessing core clinical clerkships and their directors, variances in resources from national guidelines, and the impact of the clerkship director role on faculty members' academic productivity, advancement, and satisfaction. A multidisciplinary working group of the Alliance for Clinical Education (ACE), representing all seven core clinical disciplines, created and distributed a survey to clerkship directors at 125 U.S. MD-granting medical schools, in academic year 2006-2007. A total of 544 clerkship directors from Internal Medicine (96), Family Medicine (91), Psychiatry, (91), Pediatrics (79), Surgery (71), Neurology (60), and Obstetrics-Gynecology (56) responded, representing over 60% of U.S. core clinical clerkships. The clerkship directors were similar across disciplines in demographics and academic productivity, though clinical and clerkship activities varied. Departmental staff support for clerkships averaged 0.69 people, distinctly less than the ACE's 2003 guideline of a full-time coordinator in all disciplines' clerkships. Clerkship directors reported heavy clinical responsibilities, which, as in previous studies, were negatively related to academic productivity. However, many clerkship directors felt the role enhanced their academic advancement; a large majority felt it significantly enhanced their career satisfaction. The resources and rewards of the clerkship director role were similar across disciplines. Expectations of clerkship directors were considerable, including responsibility for clinical material and the learning environment. Resources for many fall short of those stated in the ACE guidelines, particularly regarding support staff. However, the findings indicate that the clerkship director role can have benefits for academic advancement and strongly enhances career satisfaction.

  15. IAEA Director General to Visit Iran

    International Nuclear Information System (INIS)

    2012-01-01

    Full text: The Director General of the IAEA, Yukiya Amano, will travel to Tehran this Sunday, 20 May 2012, to discuss issues of mutual interest with high Iranian officials. In the course of his one-day working visit, on Monday 21 May 2012 the Director General will meet the Secretary of Iran's Supreme National Security Council, His Excellency Saeed Jalili, and other senior representatives of the Iranian government. Herman Nackaerts, Deputy Director General for Safeguards, and Rafael Mariano Grossi, Assistant Director General for Policy, will accompany the Director General. (IAEA)

  16. Papike appointed Director of IOM

    Science.gov (United States)

    James Papike was appointed director of the Institute of Meteoritics in the Department of Geology and Presidential Professor at the University of New Mexico, Albuquerque, on July 1, 1990. Papike succeeded Klaus Keil, who moved to the University of Hawaii to direct the Planetary Geoscience Division at the Hawaii Institute of Geosciences.The newly constituted IOM will emphasize planetary volcanic processes through the study of achondritic meteorites, the Moon, and Earth, and the origin of primitive solar system materials and planetary formation through the study of chondritic meteorites.

  17. Analysis of factor VIII gene inversions in 164 unrelated hemophilia A families

    Energy Technology Data Exchange (ETDEWEB)

    Vnencak-Jones, L.; Phillips, J.A. III; Janco, R.L. [Vanderbilt Univ. School of Medicine, Nashville, TN (United States)] [and others

    1994-09-01

    Hemophilia A is an X-linked recessive disease with variable phenotype and both heterogeneous and wide spread mutations in the factor VIII (F8) gene. As a result, diagnostic carrier or prenatal testing often relies upon laborious DNA linkage analysis. Recently, inversion mutations resulting from an intrachromosomal recombination between DNA sequences in one of two A genes {approximately}500 kb upstream from the F8 gene and a homologous A gene in intron 22 of the F8 gene were identified and found in 45% of severe hemophiliacs. We have analyzed banked DNA collected since 1986 from affected males or obligate carrier females representing 164 unrelated hemophilia A families. The disease was sporadic in 37%, familial in 54% and in 10% of families incomplete information was given. A unique deletion was identified in 1/164, a normal pattern was observed in 110/164 (67%), and 53/164 (32%) families had inversion mutations with 43/53 (81%) involving the distal A gene (R3 pattern) and 10/53 (19%) involving the proximal A gene (R2 pattern). While 19% of all rearrangements were R2, in 35 families with severe disease (< 1% VIII:C activity) all 16 rearrangements seen were R3. In 18 families with the R3 pattern and known activities, 16 (89%) had levels < 1%, with the remaining 2 families having {le} 2.4% activity. Further, 18 referrals specifically noted the production of inhibitors and 8/18 (45%) had the R3 pattern. Our findings demonstrate that the R3 inversion mutation patterns is (1) only seen with VIII:C activity levels of {le} 2.4%, (2) seen in 46% of families with severe hemophilia, (3) seen in 45% of hemophiliacs known to have inhibitors, (4) not correlated with sporadic or familial disease and (5) not in disequilibrium with the Bcl I or Taq I intron 18 or ST14 polymorphisms. Finally, in families positive for an inversion mutation, direct testing offers a highly accurate and less expensive alternative to DNA linkage analysis.

  18. Patient preferences in the treatment of hemophilia A: impact of storage conditions on product choice.

    Science.gov (United States)

    Tischer, Bernd; Marino, Renato; Napolitano, Mariasanta

    2018-01-01

    To gain insights into the usage of factor VIII (FVIII) products by patients diagnosed with moderate/severe hemophilia A, and to assess the impact and perceived importance of product storage. In this study, 200 patients diagnosed with moderate or severe hemophilia A across seven countries participated. Data were collected via a 30-minute, face-to-face interview in six countries and via a web-based survey in the seventh country. The questionnaire evaluated the effect of six features associated with FVIII products on the choice of the product; the structure and flow of data collection was designed to eliminate potential bias. Two-thirds of the respondents were using recombinant FVIII products. Only 17% were generally dissatisfied with current FVIII products, whereas >40% of the respondents were dissatisfied with frequency of administration and storage issues when traveling. The majority noted restrictions in their daily activities, particularly travel and sports. Most of them (85%), stored their product in the refrigerator and of these, 88% believed that it should always be stored there. These patients were also less satisfied with the product overall, more concerned about storage temperature, more restricted in daily activities, and spent more time on preparation and injection compared with patients who stored their product at room temperature. Conjoint analysis revealed that origin of FVIII (plasma-derived vs recombinant) was the strongest driver of product choice among all respondents, followed by storage flexibility (temperature), reconstitution device, and administration frequency. In this study, we did not investigate the efficacy and safety of the product. Not refrigerating FVIII products was associated with greater patient satisfaction and less restriction on daily activities. If efficacy and safety are unaffected, then storing FVIII at room temperature might have a positive impact on product choice. Few patients were aware that FVIII can be stored without

  19. Perioperative treatment of hemophilia A patients: blood group O patients are at risk of bleeding complications.

    Science.gov (United States)

    Hazendonk, H C A M; Lock, J; Mathôt, R A A; Meijer, K; Peters, M; Laros-van Gorkom, B A P; van der Meer, F J M; Driessens, M H E; Leebeek, F W G; Fijnvandraat, K; Cnossen, M H

    2016-03-01

    ESSENTIALS: Targeting of factor VIII values is a challenge during perioperative replacement therapy in hemophilia. This study aims to identify the extent and predictors of factor VIII underdosing and overdosing. Blood group O predicts underdosing and is associated with perioperative bleeding. To increase quality of care and cost-effectiveness of treatment, refining of dosing is obligatory. Perioperative administration of factor VIII (FVIII) concentrate in hemophilia A may result in both underdosing and overdosing, leading to respectively a risk of bleeding complications and unnecessary costs. This retrospective observational study aims to identify the extent and predictors of underdosing and overdosing in perioperative hemophilia A patients (FVIII levels < 0.05 IU mL(-1)). One hundred nineteen patients undergoing 198 elective, minor, or major surgical procedures were included (median age 40 years, median body weight 75 kg). Perioperative management was evaluated by quantification of perioperative infusion of FVIII concentrate and achieved FVIII levels. Predictors of underdosing and (excessive) overdosing were analyzed by logistic regression analysis. Excessive overdosing was defined as upper target level plus ≥ 0.20 IU mL(-1). Depending on postoperative day, 7-45% of achieved FVIII levels were under and 33-75% were above predefined target ranges as stated by national guidelines. A potential reduction of FVIII consumption of 44% would have been attained if FVIII levels had been maintained within target ranges. Blood group O and major surgery were predictive of underdosing (odds ratio [OR] 6.3, 95% confidence interval [CI] 2.7-14.9; OR 3.3, 95% CI 1.4-7.9). Blood group O patients had more bleeding complications in comparison to patients with blood group non-O (OR 2.02, 95% CI 1.00-4.09). Patients with blood group non-O were at higher risk of overdosing (OR 1.5, 95% CI 1.1-1.9). Additionally, patients treated with bolus infusions were at higher risk of excessive

  20. Single-tube tetradecaplex panel of highly polymorphic microsatellite markers hemophilia A.

    Science.gov (United States)

    Zhao, M; Chen, M; Tan, A S C; Cheah, F S H; Mathew, J; Wong, P C; Chong, S S

    2017-07-01

    Essentials Preimplantation genetic diagnosis (PGD) of severe hemophilia A relies on linkage analysis. Simultaneous multi-marker screening can simplify selection of informative markers in a couple. We developed a single-tube tetradecaplex panel of polymorphic markers for hemophilia A PGD use. Informative markers can be used for linkage analysis alone or combined with mutation detection. Background It is currently not possible to perform single-cell preimplantation genetic diagnosis (PGD) to directly detect the common inversion mutations of the factor VIII (F8) gene responsible for severe hemophilia A (HEMA). As such, PGD for such inversion carriers relies on indirect analysis of linked polymorphic markers. Objectives To simplify linkage-based PGD of HEMA, we aimed to develop a panel of highly polymorphic microsatellite markers located near the F8 gene that could be simultaneously genotyped in a multiplex-PCR reaction. Methods We assessed the polymorphism of various microsatellite markers located ≤ 1 Mb from F8 in 177 female subjects. Highly polymorphic markers were selected for co-amplification with the AMELX/Y indel dimorphism in a single-tube reaction. Results Thirteen microsatellite markers located within 0.6 Mb of F8 were successfully co-amplified with AMELX/Y in a single-tube reaction. Observed heterozygosities of component markers ranged from 0.43 to 0.84, and ∼70-80% of individuals were heterozygous for ≥ 5 markers. The tetradecaplex panel successfully identified fully informative markers in a couple interested in PGD for HEMA because of an intragenic F8 point mutation, with haplotype phasing established through a carrier daughter. In-vitro fertilization (IVF)-PGD involved single-tube co-amplification of fully informative markers with AMELX/Y and the mutation-containing F8 amplicon, followed by microsatellite analysis and amplicon mutation-site minisequencing analysis. Conclusions The single-tube multiplex-PCR format of this highly polymorphic

  1. Magnetic resonance imaging of myocardial infarction during prothrombin complex concentrate therapy of hemophilia A

    International Nuclear Information System (INIS)

    Gruen, D.R.; Winchester, P.H.; Brill, P.W.; Ramirez, E.

    1997-01-01

    In patients with hemophilia, prothrombin complex concentrates (PCCs) have been successfully used to bypass inhibitors to fctor VIII during bleeding episodes. The use of PCCS, including FEIBA (factor eight inhibitor bypassing activity), has been associated with thromboembolic complications. Myocardial infarction (MI) is a rare but serious complication, reported in 13 previous cases, six in the pediatric age group. In all four patients who died during the acute MI, autopsy revealed extensive myocardial hemorrhage. The hearts of three other patients examined at least 5 months after the acute MI showed no evidence of prior hemorrhage. Magnetic resonance (MR) imaging has been shown to be able to evaluate the sequelae of myocardial infarction in adults with coronary artery disease and in children with Kawasaki syndrome. We report the first case of the used of MR imaging in the evaluation of myocardial damage during the acute stage of a FEIBA-associated MI in a 10-year-old boy. (orig.)

  2. Genetic diagnosis in Hemophilia A from southern China: five novel mutations and one preimplantation genetic analysis.

    Science.gov (United States)

    Chen, J; Wang, J; Lin, X Y; Xu, Y W; He, Z H; Li, H Y; Chen, S Q; Jiang, W Y

    2017-04-01

    As there is currently no complete cure for hemophilia A (HA), the identification of pathogenic mutations in factor VIII (FVIII) gene from HA patients and carriers, which can contribute to genetic counseling prenatal diagnosis, and preimplantation genetic diagnosis (PGD), is an important step to prevent HA. A total of 14 unrelated Chinese HA subjects (FVIII activity C, c.304_305insA, c.1594T>A, c.6045G>A, and c.2645_2646insG) were found. The real-time PCR showed that the expression of FVIII mRNAs was lower in HA patients than in normal subjects. Prenatal diagnosis and PGD were successfully performed: Two of three fetuses and four of eight blastomeres were confirmed to be normal. In conclusion, genetic diagnosis of 14 unrelated HA subjects, 20 carrier subjects, three fetuses, and one PGD was successfully performed in our study. © 2016 John Wiley & Sons Ltd.

  3. Magnetic resonance imaging of myocardial infarction during prothrombin complex concentrate therapy of hemophilia A

    Energy Technology Data Exchange (ETDEWEB)

    Gruen, D.R. [Dept. of Radiology, The New York Hospital-Cornell Medical Center, New York, NY (United States); Winchester, P.H. [Dept. of Radiology, The New York Hospital-Cornell Medical Center, New York, NY (United States); Brill, P.W. [Dept. of Radiology, The New York Hospital-Cornell Medical Center, New York, NY (United States); Ramirez, E. [Dept. of Radiology, The New York Hospital-Cornell Medical Center, New York, NY (United States)

    1997-03-01

    In patients with hemophilia, prothrombin complex concentrates (PCCs) have been successfully used to bypass inhibitors to fctor VIII during bleeding episodes. The use of PCCS, including FEIBA (factor eight inhibitor bypassing activity), has been associated with thromboembolic complications. Myocardial infarction (MI) is a rare but serious complication, reported in 13 previous cases, six in the pediatric age group. In all four patients who died during the acute MI, autopsy revealed extensive myocardial hemorrhage. The hearts of three other patients examined at least 5 months after the acute MI showed no evidence of prior hemorrhage. Magnetic resonance (MR) imaging has been shown to be able to evaluate the sequelae of myocardial infarction in adults with coronary artery disease and in children with Kawasaki syndrome. We report the first case of the used of MR imaging in the evaluation of myocardial damage during the acute stage of a FEIBA-associated MI in a 10-year-old boy. (orig.)

  4. Analysis of inversions in the factor VIII gene in Spanish hemophilia A patients and families

    Energy Technology Data Exchange (ETDEWEB)

    Domenech, M.; Tizzano, E.; Baiget, M. [Hospital de Sant Pau, Barcelona (Spain); Altisent, C. [Hospital Vall d`Hebron, Barcelona (Spain)

    1994-09-01

    Intron 22 is the largest intron of the factor VIII gene and contains a CpG island from which two additional transcripts originate. One of these transcripts corresponds to the F8A gene which have telomeric extragenic copies in the X chromosome. An inversion involving homologous recombination between the intragenic and the distal or proximal copies of the F8A gene has been recently described as a common cause of severe hemophilia A (HA). We analyzed intron 22 rearrangements in 195 HA patients (123 familial and 72 sporadic cases). According to factor VIII levels, our sample was classified as severe in 114 cases, moderate in 29 cases and mild in 52 cases. An intron 22 (F8A) probe was hybridized to Southern blots of BcII digested DNA obtained from peripheral blood. A clear pattern of altered bands identifies distal or proximal inversions. We detected an abnormal pattern identifying an inversion in 49 (25%) of the analyzed cases. 43% of severe HA patients (49 cases) showed an inversion. As expected, no inversion was found in the moderate and mild group of patients. We found a high proportion (78%) of the distal rearrangement. From 49 identified inversions, 33 were found in familial cases (27%), while the remaining 15 were detected in sporadic patients (22%) in support that this mutational event occurs with a similar frequency in familial or sporadic cases. In addition, we detected a significant tendency of distal inversion to occur more frequently in familial cases than in sporadic cases. Inhibitor development to factor VIII was documented in approximately 1/3 of the patients with inversion. The identification of such a frequent molecular event in severe hemophilia A patients has been applied in our families to carrier and prenatal diagnosis, to determine the origin of the mutation in the sporadic cases and to detect the presence of germinal mosaicism.

  5. Spectrum of mutations in CRM-positive and CRM-reduced hemophilia A

    Energy Technology Data Exchange (ETDEWEB)

    McGinniss, M.J.; Kazazian, H.H. Jr.; Bi, L.; Antonarakis, S.E. (John Hopkins Univ., Baltimore, MD (United States)); Hoyer, L.W. (American Red Cross Blood Services, Rockville, MD (United States)); Inaba, H. (Tokyo Medical College (Japan))

    1993-02-01

    Hemophilia A is due to the functional deficiency of factor VIII (FVIII, gene locus F8C). Although half the patients have no detectable FVIII protein in their plasma, the more rare patients ([approximately]5%) have normal levels of a dysfunctional FVIII and are termed cross-reacting material (CRM)-positive. More commonly ([approximately]45%), patients have plasma FVIII protein reduced to an extent roughly comparable to the level of FVIII activity and are designated CRM-reduced. We used denaturing gradient gel electrophoresis to screen for mutations within the F8C gene of 11 patients (6CRM-positive, 5 CRM-reduced) and identified 9 different mutations in 9 patients after analyses of all 26 exons, the promoter region, and the polyadenylation site. Six mutations have not been described previously. Five weree missense (Ser289Leu, Ser558Phe, Val634Ala, Val634Met, Asn1441Lys), and the sixth was a 3-bp deletion ([Delta]Phe652). A review of the literature and the assay of FVIII antigen in 5 hemophilia A patients with previously identified missense mutations from this laboratory yielded a total of 20 other unique CRM-reduced and CRM-positive mutations. Almost all CRM-positive/reduced mutations (24/26) were missense, and many (12/26) occurred at CpG dinucleotides. We examined 19 missense mutation for evolutionary conservation using the portions of the porcine and murine F8C sequences that are known, and 18/19 amino acid residue altered by mutation in these patients wer conserved. Almost 50% of mutations (11/26) clustered in the A2 domain, suggesting that this region is critical for the function of FVIII. The results indicate a nonrandom distribution of mutations and suggest that mutations in a limited number of FVIII regions may cause CRM-positive and CRM-reduced heomphilia A. 48 refs., 1 fig., 1 tab.

  6. Prevention and Reversal of Antibody Responses Against Factor IX in Gene Therapy for Hemophilia B

    Directory of Open Access Journals (Sweden)

    Sushrusha eNayak

    2011-12-01

    Full Text Available Intramuscular (IM administration of an adeno-associated viral (AAV vector represents a simple and safe method of gene transfer for treatment of the X-linked bleeding disorder hemophilia B (factor IX, F.IX, deficiency. However, the approach is hampered by an increased risk of immune responses against F.IX. Previously, we demonstrated that the drug cocktail of immune suppressants rapamycin, IL-10, and a specific peptide (encoding a dominant CD4+ T cell epitope caused an induction of regulatory T cells (Treg with a concomitant apoptosis of antigen-specific effector T cells (J. Thromb. Haemost. 7:1523, 2009. This protocol was effective in preventing inhibitory antibody formation against human F.IX (hF.IX in muscle gene transfer to C3H/HeJ hemophilia B mice (with targeted F9 gene deletion. Here, we show that this protocol can also be used to reverse inhibitor formation. IM injection of AAV1-hF.IX vector resulted in inhibitors of on average 8-10 BU within 1 month. Subsequent treatment with the tolerogenic cocktail accomplished a rapid reduction of hF.IX-specific antibodies to <2 BU, which lasted for >4.5 months. Systemic hF.IX expression increased from undetectable to >200 ng/ml, and coagulation times improved. In addition, we developed an alternative prophylactic protocol against inhibitor formation that did not require knowledge of T cell epitopes, consisting of daily oral administration of rapamycin for 1-month combined with frequent, low-dose intravenous injection of hF.IX protein. Experiments in T cell receptor transgenic mice showed that the route and dosing schedule of drug administration substantially affected Treg induction. When combined with intravenous antigen administration, oral delivery of rapamycin had to be performed daily in order to induce Treg, which were suppressive and phenotypically comparable to natural Treg.

  7. MicroRNA-15b Modulates Molecular Mediators of Blood Induced Arthropathy in Hemophilia Mice

    Directory of Open Access Journals (Sweden)

    Dwaipayan Sen

    2016-04-01

    Full Text Available The development of arthropathy is a major co-morbidity in patients with hemophilia. The present study was designed to study the role of a microRNA biomarker (miR-15b in the development of joint disease. To investigate the expression profile of miR-15b during the development of arthropathy, we first isolated and studied small RNA from the acute and chronic hemarthrosis model of hemophilia A mice. We observed that miR-15b was consistently repressed (~1- to 4-fold from the onset of joint bleeding (1, 3, 7 and 24 h until six bleeding episodes (up to 90 days. To test if reconstitution of miR-15b modulates biomarkers of joint damage in a chronic hemarthrosis model, we administered an adeno-associated virus (AAV 5-miR-15b vector intra-articularly alone or in combination with systemic administration of AAV2-factor VIII. miR-15b overexpression downregulated markers of angiogenesis and hypoxia (vascular epithelial growth factor α (VEGF-α and hypoxia inducing factor 2α (HIF-2α, ~70% and ~34%, respectively in the affected joints. In addition, the co-administration of miR-15b and factor VIII vectors reduced the levels of the chondrodegenerative matrix-metalloproteinases (MMPs 1, 3, 9 and 14 (~14% to 60% in the injured joints. These data demonstrate for the first time the role of a miR-15b in the development of hemophilic arthropathy and has implications in development of miR based therapies for joint disease.

  8. The program director and accreditation

    International Nuclear Information System (INIS)

    Tristan, T.A.; Capp, M.P.; Krabbenhoft, K.L.; Armbruster, J.S.

    1987-01-01

    Field Survey is contrasted with the Specialist Site Visitor. The discussion addresses the reasons for different types of surveys and how the surveys and the Hospital Information Form are used in evaluating a graduate residency program in radiology for accreditation. The Residency Review Committee for Radiology (RRC) and the staff of the Accreditation Council for Graduate Medical Education (ACGME) of Residencies in Radiology offer a program for program directors and other interested leaders in graduate programs in radiology. The authors explain the review and accreditation process for residencies in radiology with special emphasis on the preparation for inspection by accurate and full completion of the Hospital Information Form on which the program is judged, and the nature of the inspection procedures

  9. Director general presentation to personnel

    CERN Multimedia

    2016-01-01

    Dear Colleagues, Many important discussions are scheduled for the upcoming Council Week (13-17 June) on topics including the Medium-Term Plan, the Pension Fund and other matters of great relevance to us.   I would therefore like to share the main outcome of the week with you and I invite you to join me and the Directors in the Main Auditorium at 10 a.m. on Thursday 23 June. The meeting will last about one hour and a webcast will also be available. Best regards, Fabiola Gianotti DG presentation to personnel Thursday 23 June at 10 am Main Auditorium Retransmission in Council Chamber, IT Auditorium, Kjell Jonhsen Auditorium, Prevessin 864-1-C02 Webcast on cern.ch/webcast More information on the event page.

  10. Institutional directors and board compensation: Spanish evidence

    Directory of Open Access Journals (Sweden)

    Felix López-Iturriaga

    2015-07-01

    Full Text Available We address the influence of directors who represent institutional investors in three aspects of board compensation policies: level of compensation, composition, and performance sensitivity. We differentiate pressure-sensitive directors (i.e., with business links and pressure-resistant directors (i.e., without business links. Our results show that pressure-resistant directors decrease total board compensation and its fixed proportion, whereas they increase the variable proportion of total remuneration and the pay-for-performance sensitivity. By contrast, pressure-sensitive directors offer the opposite results. These findings are consistent with the view that institutional investors are not a homogeneous group and that pressure-resistant directors fulfill a more thorough monitoring role.

  11. Bentall Operation in a Patient With Severe Hemophilia A and Marfan Syndrome by Use of a Biologic Composite Graft.

    Science.gov (United States)

    Yildirim, Funda; Ozbakkaloglu, Alper; Ozturk, Tulun; Tetik, Omer

    2016-03-01

    We describe a patient with severe hemophilia A and Marfan syndrome who underwent an elective Bentall operation. Because of the severe hemophilia, anticoagulation could not be given postoperatively; thus, a biologic Valsalva conduit graft was used. During the procedure, factor VIII was given as a bolus dose just before incision, then by continous infusion intraoperatively to maintain the factor VIII activity level between 200% and 300%. Minimal postoperative bleeding occurred. The infusion was continued postoperatively at a lower dose until all chest tubes, pacing wires, and invasive catheters were removed. The patient was discharged on postoperative day 7 without adverse events. Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

  12. Characterization of the factor VIII defect in 147 patients with sporadic hemophilia A: Family studies indicate a mutation type-dependent sex ratio of mutation frequencies

    Energy Technology Data Exchange (ETDEWEB)

    Becker, J.; Schmidt, W.; Olek, K. [Univ. of Bonn (Germany)] [and others

    1996-04-01

    The clinical manifestation of hemophilia A is caused by a wide range of different mutations. In this study the factor VIII genes of 147 severe hemophilia A patients-all exclusively from sporadic families-were screened for mutations by use of the complete panel of modern DNA techniques. The pathogenous defect could be characterized in 126 patients (85.7%). Fifty-five patients (37.4%) showed a F8A-gene inversion, 47 (32.0%) a point mutation, 14 (9.5%) a small deletion, 8 (5.4%) a large deletion, and 2 (1.4%) a small insertion. Further, four (2.7%) mutations were localized but could not be sequenced yet. No mutation could be identified in 17 patients (11.6%). Sixteen (10.9%) of the P identified mutations occurred in the B domain. Four of these were located in an adenosine nucleotide stretch at codon 1192, indicating a mutation hotspot. Somatic mosaicisms were detected in 3 (3.9%) of 76 patients` mothers, comprising 3 of 16 de novo mutations in the patients` mothers. Investigation of family relatives allowed detection of a de novo mutation in 16 of 76 two-generation and 28 of 34 three-generation families. On the basis of these data, the male:female ratio of mutation frequencies (k) was estimated as k = 3.6. By use of the quotients of mutation origin in maternal grandfather to patient`s mother or to maternal grandmother, k was directly estimated as k = 15 and k = 7.5, respectively. Considering each mutation type separately, we revealed a mutation type-specific sex ratio of mutation frequencies. Point mutations showed a 5-to-10-fold-higher and inversions a >10-fold- higher mutation rate in male germ cells, whereas deletions showed a >5-fold-higher mutation rate in female germ cells. Consequently, and in accordance with the data of other diseases like Duchenne muscular dystrophy, our results indicate that at least for X-chromosomal disorders the male:female mutation rate of a disease is determined by its proportion of the different mutation types. 68 refs., 1 fig., 5 tabs.

  13. Severe Hemophilia A in a Male Old English Sheep Dog with a C→T Transition that Created a Premature Stop Codon in Factor VIII

    Science.gov (United States)

    Lozier, Jay N; Kloos, Mark T; Merricks, Elizabeth P; Lemoine, Nathaly; Whitford, Margaret H; Raymer, Robin A; Bellinger, Dwight A; Nichols, Timothy C

    2016-01-01

    Animals with hemophilia are models for gene therapy, factor replacement, and inhibitor development in humans. We have actively sought dogs with severe hemophilia A that have novel factor VIII mutations unlike the previously described factor VIII intron 22 inversion. A male Old English Sheepdog with recurrent soft-tissue hemorrhage and hemarthrosis was diagnosed with severe hemophilia A (factor VIII activity less than 1% of normal). We purified genomic DNA from this dog and ruled out the common intron 22 inversion; we then sequenced all 26 exons. Comparing the results with the normal canine factor VIII sequence revealed a C→T transition in exon 12 of the factor VIII gene that created a premature stop codon at amino acid 577 in the A2 domain of the protein. In addition, 2 previously described polymorphisms that do not cause hemophilia were present at amino acids 909 and 1184. The hemophilia mutation creates a new TaqI site that facilitates rapid genotyping of affected offspring by PCR and restriction endonuclease analyses. This mutation is analogous to the previously described human factor VIII mutation at Arg583, which likewise is a CpG dinucleotide transition causing a premature stop codon in exon 12. Thus far, despite extensive treatment with factor VIII, this dog has not developed neutralizing antibodies (‘inhibitors’) to the protein. This novel mutation in a dog gives rise to severe hemophilia A analogous to a mutation seen in humans. This model will be useful for studies of the treatment of hemophilia. PMID:27780008

  14. High-affinity, noninhibitory pathogenic C1 domain antibodies are present in patients with hemophilia A and inhibitors

    Science.gov (United States)

    Batsuli, Glaivy; Deng, Wei; Healey, John F.; Parker, Ernest T.; Baldwin, W. Hunter; Cox, Courtney; Nguyen, Brenda; Kahle, Joerg; Königs, Christoph; Li, Renhao; Lollar, Pete

    2016-01-01

    Inhibitor formation in hemophilia A is the most feared treatment-related complication of factor VIII (fVIII) therapy. Most inhibitor patients with hemophilia A develop antibodies against the fVIII A2 and C2 domains. Recent evidence demonstrates that the C1 domain contributes to the inhibitor response. Inhibitory anti-C1 monoclonal antibodies (mAbs) have been identified that bind to putative phospholipid and von Willebrand factor (VWF) binding epitopes and block endocytosis of fVIII by antigen presenting cells. We now demonstrate by competitive enzyme-linked immunosorbent assay and hydrogen-deuterium exchange mass spectrometry that 7 of 9 anti-human C1 mAbs tested recognize an epitope distinct from the C1 phospholipid binding site. These mAbs, designated group A, display high binding affinities for fVIII, weakly inhibit fVIII procoagulant activity, poorly inhibit fVIII binding to phospholipid, and exhibit heterogeneity with respect to blocking fVIII binding to VWF. Another mAb, designated group B, inhibits fVIII procoagulant activity, fVIII binding to VWF and phospholipid, fVIIIa incorporation into the intrinsic Xase complex, thrombin generation in plasma, and fVIII uptake by dendritic cells. Group A and B epitopes are distinct from the epitope recognized by the canonical, human-derived inhibitory anti-C1 mAb, KM33, whose epitope overlaps both groups A and B. Antibodies recognizing group A and B epitopes are present in inhibitor plasmas from patients with hemophilia A. Additionally, group A and B mAbs increase fVIII clearance and are pathogenic in a hemophilia A mouse tail snip bleeding model. Group A anti-C1 mAbs represent the first identification of pathogenic, weakly inhibitory antibodies that increase fVIII clearance. PMID:27381905

  15. Factor IX expression in skeletal muscle of a severe hemophilia B patient 10 years after AAV-mediated gene transfer

    OpenAIRE

    Buchlis, George; Podsakoff, Gregory M.; Radu, Antonetta; Hawk, Sarah M.; Flake, Alan W.; Mingozzi, Federico; High, Katherine A.

    2012-01-01

    In previous work we transferred a human factor IX–encoding adeno-associated viral vector (AAV) into skeletal muscle of men with severe hemophilia B. Biopsy of injected muscle up to 1 year after vector injection showed evidence of gene transfer by Southern blot and of protein expression by IHC and immunofluorescent staining. Although the procedure appeared safe, circulating F.IX levels remained subtherapeutic (< 1%). Recently, we obtained muscle tissue from a subject injected 10 years earlier ...

  16. 78 FR 68466 - BLM Director's Response to the Idaho Governor's Appeal of the BLM Idaho State Director's Governor...

    Science.gov (United States)

    2013-11-14

    ... Bureau of Land Management (BLM) is publishing this notice to explain why the BLM Director is denying the...] BLM Director's Response to the Idaho Governor's Appeal of the BLM Idaho State Director's Governor's... (Finding) to the BLM Idaho State Director (State Director). The State Director determined the Governor's...

  17. The value of usability testing for Internet-based adolescent self-management interventions: "Managing Hemophilia Online".

    Science.gov (United States)

    Breakey, Vicky R; Warias, Ashley V; Ignas, Danial M; White, Meghan; Blanchette, Victor S; Stinson, Jennifer N

    2013-10-04

    As adolescents with hemophilia approach adulthood, they are expected to assume responsibility for their disease management. A bilingual (English and French) Internet-based self-management program, "Teens Taking Charge: Managing Hemophilia Online," was developed to support adolescents with hemophilia in this transition. This study explored the usability of the website and resulted in refinement of the prototype. A purposive sample (n=18; age 13-18; mean age 15.5 years) was recruited from two tertiary care centers to assess the usability of the program in English and French. Qualitative observations using a "think aloud" usability testing method and semi-structured interviews were conducted in four iterative cycles, with changes to the prototype made as necessary following each cycle. This study was approved by research ethics boards at each site. Teens responded positively to the content and appearance of the website and felt that it was easy to navigate and understand. The multimedia components (videos, animations, quizzes) were felt to enrich the experience. Changes to the presentation of content and the website user-interface were made after the first, second and third cycles of testing in English. Cycle four did not result in any further changes. Overall, teens found the website to be easy to use. Usability testing identified end-user concerns that informed improvements to the program. Usability testing is a crucial step in the development of Internet-based self-management programs to ensure information is delivered in a manner that is accessible and understood by users.

  18. Program Director Survey: Attitudes Regarding Child Neurology Training and Testing.

    Science.gov (United States)

    Valencia, Ignacio; Feist, Terri B; Gilbert, Donald L

    2016-04-01

    As a result of major clinical and scientific advances and changes in clinical practice, the role of adult neurology training for Child Neurology and Neurodevelopmental Disability (NDD) certification has become controversial. The most recently approved requirements for board eligibility for child neurology and neurodevelopmental disability residents still include 12 months in adult neurology rotations. The objective of this study was to assess United States child neurology and neurodevelopmental disability residency program directors' opinions regarding optimal residency training. The authors developed an 18-item questionnaire and contacted all 80 child neurology and neurodevelopmental disability program directors via e-mail, using SurveyMonkey. A total of 44 program directors responded (55%), representing programs that train 78 categorical and 94 total resident positions, approximately 70% of those filled in the match. Respondents identified multiple areas where child neurology residents need more training, including genetics and neuromuscular disease. A substantial majority (73%) believed child neurology and neurodevelopmental disability residents need less than 12 adult neurology training months; however, most (75%) also believed adult hospital service and man-power needs (55%) and finances (34%) would pose barriers to reducing adult neurology. Most (70%) believed reductions in adult neurology training should be program flexible. A majority believed the written initial certification examination should be modified with more child neurology and fewer basic neuroscience questions. Nearly all (91%) felt the views of child neurology and neurodevelopmental disability program directors are under-represented within the Accreditation Council for Graduate Medical Education Residency Review Committee. The requirement for 12 adult neurology months for Child Neurology and Neurodevelopmental Disability certification is not consistent with the views of the majority of program

  19. PLAY DIRECTING AND DIRECTORS: AN EVOLUTIONARY ...

    African Journals Online (AJOL)

    While the theatre director can be seen as the `god of the theatre', he/she can also be seen as a priest and a carrier who must coordinate human and material resources a master and a messenger. Drawing from the above, this paper traces the evolution of play directing and the theatre director in different theatres of the world ...

  20. CERN loses two former Directors-General

    CERN Multimedia

    2002-01-01

    Victor Weisskopf, a giant of modern physics and Director General of CERN from 1961-65, died on 21 April. The previous month, Willibald Jentschke, Director General from 1971-75 and founder of the DESY Laboratory in Hamburg, passed away.

  1. Robert Aymar, Director-General of CERN

    CERN Document Server

    Patrice Loïez

    2003-01-01

    Robert Aymar, photographed in 2003 before taking his position as Director-General at CERN, succeeding Luciano Maiani in 2004. At this time, Aymar was director of the International Thermonuclear Experimental Reactor (ITER) although he had already been involved with developments at CERN, chairing the External Review Committee, set up in 2001 in response to the increased cost of the LHC.

  2. Gender Quotas on Board of Directors

    DEFF Research Database (Denmark)

    Smith, Nina

    2013-01-01

    Beside arguments of fairness and equal opportunities, it is often argued that gender diversity on boards of directors may improve firm performance, but the empirical results are mixed and often negative. Based on the available research, gender quotas on boards of directors cannot be justified...

  3. Dr. Francis Collins Is New NIH Director

    Science.gov (United States)

    ... Ph.D., a physician and geneticist, is the new Director of the National Institutes of Health (NIH), part of the U.S. Department of Health and Human Services. President Barack Obama nominated Dr. Collins, who served as Director of ...

  4. J. B. Adams Acting Director-General

    CERN Multimedia

    1960-01-01

    After the tragic death of Prof. C. J. Bakker, the Council of CERN held an emergency meeting on May 3, 1960. Following this session, Mr. F. de Rose, President of the Council of the European Organization for Nuclear Research, announced the appointment of Mr. J. B. Adams, Director of the PS division to the post of acting Director-General.

  5. Director Turnover: An Australian Academic Development Study

    Science.gov (United States)

    Fraser, Kym; Ryan, Yoni

    2012-01-01

    Although it can be argued that directors of central academic development units (ADUs) are critical to the implementation of university teaching and learning strategies, it would appear there is a high director turnover rate. While research in the USA, the UK, and Australia illustrates that ADUs are frequently closed or restructured, that research…

  6. Predictors of Choral Directors' Voice Handicap

    Science.gov (United States)

    Schwartz, Sandra

    2013-01-01

    Vocal demands of teaching are considerable and these challenges are greater for choral directors who depend on the voice as a musical and instructive instrument. The purpose of this study was to (1) examine choral directors' vocal condition using a modified Voice Handicap Index (VHI), and (2) determine the extent to which the major variables…

  7. New project director for Honduras.

    Science.gov (United States)

    1984-01-01

    Miguel Machuca has been installed as project director for the Honduras Contraceptive Social Marketing Program (HCSMP). he was selected from a field of candidates with public and private sector experience in marketing, business management and program development. Machuca will direct the development of the social marketing program and work to establish a marketing function within ASHONPLAFA, the sponsoring organization for HCSMP. A major goal is to correct misinformation or lack of information about family planning methods among consumers and reatilers; for example, consumers worry about the side-effects of oral contraceptives (OCs) and many perceive subsidized products to be either experimental or discards. Easily understandable graphic package naterials are being prepared for OCs distributed through the program. Another goal is sales training. The project is scheduled to be launched in March 1984 with distribution of Perla, a standard dose OC. Radio spots and newspaper ads are being prepared to inform consumers that Perla can be purchased through pharmacies and small rural shops at the cost of US$.75/cycle. A low-dose OC, a condom and a vaginal tablet are scheduled to be added to the product line by December 1984. Market research on brand names, packaging and pricing of these products is currently being conducted. According the Machuca, his biggest challenge will be to maintain a balance between the need to comply with the policies and regulations of the various organizations involved with the HCSMP and the simultaneous need to promote and implement the entrepreneurial activities necessary to project goals.

  8. Postdoctoral periodontal program directors' perspectives of resident selection.

    Science.gov (United States)

    Khan, Saba; Carmosino, Andrew J; Yuan, Judy Chia-Chun; Lucchiari, Newton; Kawar, Nadia; Sukotjo, Cortino

    2015-02-01

    Applications for postdoctoral periodontal programs have recently increased. The National Board Dental Examinations (NBDE) has adopted a pass/fail format. The purpose of this study is to examine the criteria used by accredited postdoctoral periodontal programs in the United States to evaluate potential applicants. A secondary purpose was to determine whether the absence of NBDE scores would change program directors' selection process. Basic demographic information of the program directors was also collected. A questionnaire was sent to all 54 program directors of accredited postdoctoral periodontal programs in the United States. The raw data were compiled, descriptive analyses were performed, and results were tabulated and ranked when applicable. Thirty-five of 54 program directors (64.8%) responded to the survey. The five most important factors in selecting residents were: 1) interview ratings; 2) dental school clinical grades; 3) dental school periodontics grades; 4) personal statement; and 5) letters of recommendation. The majority of the programs (94%; n = 33) require an interview, and many (86%; n = 30) have a committee that makes the final decision on candidate acceptance. More than half of the respondents (56%; n = 17) stated that the pass/fail format of the NBDE would affect the decision-making process. This study describes the criteria used by postdoctoral periodontal programs to help select applicants. Interview ratings, dental school grades, personal statements, and letters of recommendation were found to be the most important factors. Results from this study may be helpful for prospective postdoctoral periodontal program applicants in the United States.

  9. Quality Improvement in Otolaryngology Residency: Survey of Program Directors.

    Science.gov (United States)

    Bowe, Sarah N

    2016-02-01

    The Clinical Learning Environment Review focuses on the responsibility of the sponsoring institution for quality and patient safety. Very little information is known regarding the status of quality improvement (QI) education during otolaryngology training. The purpose of this survey is to evaluate the extent of resident and faculty participation in QI and identify opportunities for both resident curriculum and faculty development. Cross-sectional survey A 15-item survey was distributed to all 106 otolaryngology program directors. The survey was developed after an informal review of the literature regarding education in QI and patient safety. Questions were directed at the format and content of the QI curriculum, as well as barriers to implementation. There was a 39% response rate. Ninety percent of responding program directors considered education in QI important or very important to a resident's future success. Only 23% of responding programs contained an educational curriculum in QI, and only 33% monitored residents' individual outcome measures. Barriers to implementation of a QI program included inadequate number of faculty with expertise in QI (75%) and competing resident educational demands (90%). Every program director considered morbidity and mortality conferences as an integral component in QI education. Program directors recognize the importance of QI in otolaryngology practice. Unfortunately, this survey identifies a distinct lack of resources in support of these educational goals. The results highlight the need to generate a comprehensive and stepwise approach to QI for faculty development and resident instruction. © American Academy of Otolaryngology—Head and Neck Surgery Foundation 2015.

  10. Effectiveness of the Medtep Hemophilia online platform for adherence to prophylactic treatment in haemophilia patients: Results from a 1-year observational study.

    Science.gov (United States)

    Cuesta-Barriuso, R; López-Pina, J A; Nieto-Munuera, J; Sagarra-Valls, G; Panisello-Royo, J M; Torres-Ortuño, A

    2018-03-01

    Medtep Hemophilia platform is an online tool that allows patients with congenital coagulopathies to keep track of their daily condition-related events with the objective of ensuring successful adherence to therapy. To assess the effectiveness of Medtep Hemophilia in improving adherence to prophylactic treatment in haemophilia A and B patients in a 1-year prospective observational study, as well as its impact on the patient's disease status. Patients (>13 years old) received support material to familiarize themselves with Medtep Hemophilia. Adherence to treatment, quality of life (QoL) and illness perception were assessed. Values at baseline, 1, 6 and 12 months, and changes from baseline value were analysed. The Hemophilia Joint Health Score (HJHS) test was applied at baseline and study completion. Forty-six patients were enrolled (43 evaluable). After 1 year, 56.4% patients showed continued use of the platform (100% compliance) whereas 25.6% were inactive. Treatment adherence increased both significantly (P 80% of platform use) tended to score better than noncompliant. The HJHS test values remained similar during the study. The Medtep Hemophilia online platform helped the studied patients with haemophilia to improve their adherence to prophylactic treatment, while increasing their QoL and illness perception, as well as joint arthropathies stabilization. © 2018 John Wiley & Sons Ltd.

  11. Status and trend analysis of prophylactic usage of recombinant factor VIII in Chinese pediatric patients with hemophilia A: ReCare - a retrospective, phase IV, non-interventional study.

    Science.gov (United States)

    Li, Changgang; Zhang, Xinsheng; Zhao, Yongqiang; Wu, Runhui; Hu, Qun; Xu, Vicky; Sun, Jing; Yang, Renchi; Li, Xiaojing; Zhou, Rongfu; Lian, Shinmei; Gu, Jian; Wu, Junde; Hou, Qingsong

    2017-09-01

    No study has reported the status and chronological trend of prophylactic recombinant factor VIII (rFVIII) use in Chinese pediatric patients with hemophilia A (HA). We aimed to analyze the status and trend of rFVIII-containing prophylaxis in Chinese pediatric patients with HA. ReCARE (Retrospective study in Chinese pediatric hemophilia A patients with rFVIII contained REgular prophylaxis) was a retrospective study conducted in 12 hemophilia treatment centers across China. The trend of prophylaxis was evaluated by determining the mean duration of prophylaxis, mean injection frequency (per week), mean dose of each injection (IU/kg), mean total dose injected/week (IU) and proportion of rFVIII consumption relative to factor VIII (FVIII) consumption over the study period. We analyzed 183 male pediatric patients with HA (mean age, 7.1 ± 4.23 years), who received intermittent prophylaxis between 1 November 2007 and 31 May 2013. The mean duration of prophylaxis with rFVIII increased from 16.72 weeks in 2008 to 32.77 in 2012. Per injection dose of rFVIII increased significantly from 2008 to 2013 (25.89 to 28.31 IU/kg, p < .001). An increase was also reported in the mean total FVIII consumed (699.97 ± 173.25 IU in 2008 and 891.30 ± 730.341 in 2013) and mean proportion of rFVIII used (33.33 ± 57.73% in 2008 to 85.50 ± 29.077% in 2013). Our data revealed an overall improvement in treatment dosage and duration with an increase in the number of patients receiving prophylaxis. The total proportion of rFVIII also increased gradually indicating the development of economy and safety awareness. The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT02263066).

  12. Hans Blix appointed Director General

    International Nuclear Information System (INIS)

    1981-01-01

    On 1 December 1981, Dr Hans Blix took office as Director General of the International Atomic Energy Agency in succession to Dr Sigvard Eklund who has headed the IAEA since 1961. The Agency's Board of Governors nominated Dr Blix by acclamation on 26 September. His appointment was unanimously approved by the final session of the 25th regular session of the General Conference of the IAEA the same day. The President of the Conference, Ambassador Manaspas Xuto, administered the oath of office to Dr Blix at the final plenary meeting that day. Hans Blix was born in 1928 in Uppsala He studied at the University of Uppsala, at Columbia University, where he was also a research graduate and at Cambridge, where he received his Ph D In 1959 he became Doctor of Laws at the Stockholm University and in 1960 was appointed associate professor in international law. From 1963 to 1976 Dr Blix was Head of Department at the Ministry for Foreign Affairs and served as Legal Adviser on International Law. In 1976 he became Undersecretary of State at the Ministry for Foreign Affairs in charge of international development co-operation He was appointed Minister for Foreign Affairs in October 1978 In September 1979 he was again appointed Undersecretary of State at the Ministry for Foreign Affairs in charge of international development co-operation. Since 1961 he has been a member of Sweden's delegation to the United Nations General Assembly, and from 1962 to 1978 a member of the Swedish delegation to the Conference on Disarmament in Geneva. He has written several books on subjects associated with international and constitutional law and was leader of the Liberal Campaign Committee in favour of retention of the Swedish nuclear energy program in the referendum in 1980

  13. An Analysis of the hemophilia of the royal families of Europe, its startling implication and dentistry's role in treating the hemophiliac patient.

    Science.gov (United States)

    Maloney, William James; Raymond, George; Hershkowitz, David; Rochlen, Glenn

    2015-03-01

    Hemophilia is an inherited x-linked recessive disorder. It is known popularly as "The Royal Disease," as it has affected many of the royal families of Europe by virtue of Queen Victoria being a carrier for the gene and, subsequently, passing it on to her offspring. They, in turn, married and had children with other royal families of Europe. Hemophilia is certainly not limited to royalty. There are many hemophiliacs living in our communities, and they must receive both proper dental home-care education and dental treatment in order to prevent possibly life-threatening emergency dental episodes. Individuals with hemophilia pose different management issues to the dental professional. The various precautions and modifications that must be taken in order to ensure the safe delivery of dental care to hemophiliac dental patients are discussed.

  14. Hemophilia A Pseudoaneurysm in a Patient with High Responding Inhibitors Complicating Total Knee Arthroplasty: Embolization: A Cost-Reducing Alternative to Medical Therapy

    International Nuclear Information System (INIS)

    Kickuth, Ralph; Anderson, Suzanne; Peter-Salonen, Kristiina; Laemmle, Bernhard; Eggli, Stefan; Triller, Juergen

    2006-01-01

    Joint hemorrhages are very common in patients with severe hemophilia. Inhibitors in patients with hemophilia are allo-antibodies that neutralize the activity of the clotting factor. After total knee replacement, rare intra-articular bleeding complications might occur that do not respond to clotting factor replacement. We report a 40-year-old male with severe hemophilia A and high responding inhibitors presenting with recurrent knee joint hemorrhage after bilateral knee prosthetic surgery despite adequate clotting factor treatment. There were two episodes of marked postoperative hemarthrosis requiring extensive use of subsititution therapy. Eleven days postoperatively, there was further hemorrhage into the right knee. Digital subtraction angiography diagnosed a complicating pseudoaneurysm of the inferior lateral geniculate artery and embolization was successfully performed. Because clotting factor replacement therapy has proved to be excessively expensive and prolonged, especially in patients with inhibitors, we recommend the use of cost-effective early angiographic embolization

  15. What every library director should know

    CERN Document Server

    Curzon, Susan Carol

    2014-01-01

    What Every Library Director Should Know is the insider's view of vital actions, behaviors and strategies to succeed in every type of library. The content is based both on the author's direct experience after a long career in several types of libraries but also on the direct observation of other managers. Inset into the book are pearls of wisdom from other directors, managers and observers who are answering the question, "what is the one piece of management wisdom that you would give to anyone who wishes to become a library director?" This book will help to get you there by explaining and illus

  16. Two-incision laparoscopic appendectomy for a severe hemophilia A child patient with coagulation factor VII deficiency: Case report and review of literature.

    Science.gov (United States)

    He, Jin Peng; Feng, Jie Xiong

    2017-10-01

    The main complication of patients with severe hemophilia is recurrent bleeding events that usually affected musculoskeletal contractures. And replacement therapy methods were continuously improved to minimize adverse impacts brought by those complications. However, only several cases reported about the appendectomy for hemophilia A. We report a case of acute appendicitis treated by two-incision laparoscopy in a boy with hemophilia A and coagulation factor VII deficiency for the first time. An 8y7m-old Chinese boy presented with half a day of right sided abdominal pain, fever, nausea, and vomiting. He received a computed tomography (CT) scan which revealed an enlarged appendix, thickened wall and appendiceal fecalith, and had received a conservative anti-bacterial treatment for his acute appendicitis but failed. He was diagnosed with hemophilia A and coagulation factor VII deficiency. Two-incision laparoscopic appendectomy was made in success with a careful management of perioperative period. We monitored the clotting factor FVIII level and gave him a replacement therapy. The patient had an uneventful recovery. It is important to exclude intraabdominal or retroperitoneal hemorrhage in patients suffering from hemophilia and acute abdominal pain. Pre-operative evaluation of validity of the FVIII replacement therapy is another effective strategy to assess the safety and feasibility of applying an operation procedure. The two-incision laparoscopic appendectomy is an effective treatment for this kind of patients for its minimal trauma and fast recovery characteristics. Our report shows that laparoscopic appendectomy is feasible in a child suffering from hemophilia after adequate blood clotting factor replacement treatment.

  17. 78 FR 4435 - BLM Director's Response to the Alaska Governor's Appeal of the BLM Alaska State Director's...

    Science.gov (United States)

    2013-01-22

    ... Bureau of Land Management (BLM) is publishing this notice to explain why the BLM Director is rejecting... Director's Response to the Alaska Governor's Appeal of the BLM Alaska State Director's Governor's... the BLM Alaska State Director. The State Director determined the Governor's Finding was outside the...

  18. Bypassing agent prophylaxis in people with hemophilia A or B with inhibitors.

    Science.gov (United States)

    Chai-Adisaksopha, Chatree; Nevitt, Sarah J; Simpson, Mindy L; Janbain, Maissaa; Konkle, Barbara A

    2017-09-25

    People with hemophilia A or B with inhibitors are at high risk of bleeding complications. Infusion of bypassing agents, such as recombinant activated FVII (rFVIIa) and plasma-derived activated prothrombin complex concentrate, are suggested as alternative therapies to factor VIII (haemophilia A) or IX (haemophilia B) for individuals who no longer respond to these treatments because they develop inhibitory antibodies. The ultimate goal of treatment is to preserve the individual's joints, otherwise destroyed by recurrent bleeds. To assess the effects of bypassing agent prophylaxis to prevent bleeding in people with hemophilia A or B and inhibitors. We searched for relevant studies from the Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, comprising of references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also searched trial registries (16 February 2017) and bibliographic references of retrieved studies were reviewed for potential articles to be included in the review.Date of the last search of the Cochrane Cystic Fibrosis and Genetic Disorders Coagulopathies Trials Register: 12 December 2016. We included randomized and quasi-randomized controlled studies (cross-over or parallel design) evaluating the effect of prophylaxis treatment with bypassing agents compared with on-demand treatment, or studies evaluating the effects of high-dose compared with low-dose prophylaxis in males of any age with hemophilia with inhibitors. Two authors independently selected studies and extracted data and assessed the risk of bias according to standard Cochrane criteria. They assessed the quality of the evidence using the GRADE criteria. We included four randomized studies (duration 7 to 15 months) involving 116 males. Risk of bias was judged to be high in two studies due to the open-label study design and in one study due to attrition bias.Two studies

  19. Management of bleeding in acquired hemophilia A: results from the European Acquired Haemophilia (EACH2) Registry.

    Science.gov (United States)

    Baudo, Francesco; Collins, Peter; Huth-Kühne, Angela; Lévesque, Hervé; Marco, Pascual; Nemes, László; Pellegrini, Fabio; Tengborn, Lilian; Knoebl, Paul

    2012-07-05

    Acquired hemophilia A is a rare bleeding disorder caused by autoantibodies to coagulation FVIII. Bleeding episodes at presentation are spontaneous and severe in most cases. Optimal hemostatic therapy is controversial, and available data are from observational and retrospective studies only. The EACH2 registry, a multicenter, pan-European, Web-based database, reports current patient management. The aim was to assess the control of first bleeding episodes treated with a bypassing agent (rFVIIa or aPCC), FVIII, or DDAVP among 501 registered patients. Of 482 patients with one or more bleeding episodes, 144 (30%) received no treatment for bleeding; 31 were treated with symptomatic therapy only. Among 307 patients treated with a first-line hemostatic agent, 174 (56.7%) received rFVIIa, 63 (20.5%) aPCC, 56 (18.2%) FVIII, and 14 (4.6%) DDAVP. Bleeding was controlled in 269 of 338 (79.6%) patients treated with a first-line hemostatic agent or ancillary therapy alone. Propensity score matching was applied to allow unbiased comparison between treatment groups. Bleeding control was significantly higher in patients treated with bypassing agents versus FVIII/DDAVP (93.3% vs 68.3%; P = .003). Bleeding control was similar between rFVIIa and aPCC (93.0%; P = 1). Thrombotic events were reported in 3.6% of treated patients with a similar incidence between rFVIIa (2.9%) and aPCC (4.8%).

  20. Neonatal circumcision in severe haemophilia: a survey of paediatric haematologists at United States Hemophilia Treatment Centers.

    Science.gov (United States)

    Kearney, S; Sharathkumar, A; Rodriguez, V; Chitlur, M; Valentino, L; Boggio, L; Gill, J

    2015-01-01

    Neonatal circumcision in patients with severe haemophilia has not been well studied. We performed a survey of paediatric haematologists from Hemophilia Treatment Centers (HTC) across the United States to better understand the attitudes toward and management of neonatal circumcision in haemophilia patients. Response rate to our survey was 40% (n = 64/159). Thirty-eight percent of respondents (n = 24) said that they would allow this procedure in the newborn period but in many cases this was against medical advice. The most reported concern regarding neonatal circumcision in haemophilia patients was the risk of development of an inhibitor (n = 25; 39%) followed by the concern for bleeding (n = 22; 34%) and issues related to vascular access in the neonate (n = 11; 17%). All respondents recommended at least one preprocedure dose of factor replacement. Twenty-two percent (n = 14) of respondents did not use more than one dose of factor replacement but 32% (n = 21) used 1-2 postoperative doses. The remainder of paediatric haematologists surveyed recommended between 3-5 (16%; n = 10) and 6-10 (3%, n = 2) additional days postoperatively. There was wide variation in both techniques of circumcision as well as adjuvant haemostatic agents used. Only 22% of respondents said that they had an established protocol for management of circumcision in the newborn haemophilia patient. These survey results highlight the need for evidence-based guidelines regarding the optimal management of circumcision in neonates with severe haemophilia. © 2014 John Wiley & Sons Ltd.

  1. Immunosuppression for acquired hemophilia A: results from the European Acquired Haemophilia Registry (EACH2).

    Science.gov (United States)

    Collins, Peter; Baudo, Francesco; Knoebl, Paul; Lévesque, Hervé; Nemes, László; Pellegrini, Fabio; Marco, Pascual; Tengborn, Lilian; Huth-Kühne, Angela

    2012-07-05

    Acquired hemophilia A (AHA) is an autoimmune disease caused by an autoantibody to factor VIII. Patients are at risk of severe and fatal hemorrhage until the inhibitor is eradicated, and guidelines recommend immunosuppression as soon as the diagnosis has been made. The optimal immunosuppressive regimen is unclear; therefore, data from 331 patients entered into the prospective EACH2 registry were analyzed. Steroids combined with cyclophosphamide resulted in more stable complete remission (70%), defined as inhibitor undetectable, factor VIII more than 70 IU/dL and immunosuppression stopped, than steroids alone (48%) or rituximab-based regimens (59%). Propensity score-matched analysis controlling for age, sex, factor VIII level, inhibitor titer, and underlying etiology confirmed that stable remission was more likely with steroids and cyclophosphamide than steroids alone (odds ratio = 3.25; 95% CI, 1.51-6.96; P < .003). The median time to complete remission was approximately 5 weeks for steroids with or without cyclophosphamide; rituximab-based regimens required approximately twice as long. Immunoglobulin administration did not improve outcome. Second-line therapy was successful in approximately 60% of cases that failed first-line therapy. Outcome was not affected by the choice of first-line therapy. The likelihood of achieving stable remission was not affected by underlying etiology but was influenced by the presenting inhibitor titer and FVIII level.

  2. Computation Directorate 2007 Annual Report

    Energy Technology Data Exchange (ETDEWEB)

    Henson, V E; Guse, J A

    2008-03-06

    If there is a single word that both characterized 2007 and dominated the thoughts and actions of many Laboratory employees throughout the year, it is transition. Transition refers to the major shift that took place on October 1, when the University of California relinquished management responsibility for Lawrence Livermore National Laboratory (LLNL), and Lawrence Livermore National Security, LLC (LLNS), became the new Laboratory management contractor for the Department of Energy's (DOE's) National Nuclear Security Administration (NNSA). In the 55 years under the University of California, LLNL amassed an extraordinary record of significant accomplishments, clever inventions, and momentous contributions in the service of protecting the nation. This legacy provides the new organization with a built-in history, a tradition of excellence, and a solid set of core competencies from which to build the future. I am proud to note that in the nearly seven years I have had the privilege of leading the Computation Directorate, our talented and dedicated staff has made far-reaching contributions to the legacy and tradition we passed on to LLNS. Our place among the world's leaders in high-performance computing, algorithmic research and development, applications, and information technology (IT) services and support is solid. I am especially gratified to report that through all the transition turmoil, and it has been considerable, the Computation Directorate continues to produce remarkable achievements. Our most important asset--the talented, skilled, and creative people who work in Computation--has continued a long-standing Laboratory tradition of delivering cutting-edge science even in the face of adversity. The scope of those achievements is breathtaking, and in 2007, our accomplishments span an amazing range of topics. From making an important contribution to a Nobel Prize-winning effort to creating tools that can detect malicious codes embedded in commercial

  3. Directors' report and accounts 1991-1992

    International Nuclear Information System (INIS)

    1993-01-01

    This report for Scottish Hydro-Electric PLC contains details of key financial statistics, the financial calendar, the Directors' Report, the Auditors' Report, accounting policies, a Group Profit and Loss Account, balance sheets and a Group Cash Flow Statement. (UK)

  4. Regional Director | IDRC - International Development Research ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    ... its effective utilization in the design and execution of the IDRC strategic plan. ... Provides assistance to Program Managers/Leaders, Directors of Program Areas, ... the Partnership and Business Development Division and Programs Branch.

  5. Leader in Digital Transformation: Director, Information Management ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    As the Deputy Chief Information Officer, the Director is also accountable for developing ... operations and maintenance of key business systems (financial applications, ... Plays a key role in the control of access to personal information in e-mail ...

  6. Selected Publications by the NCI Director

    Science.gov (United States)

    Dr. Norman Sharpless's written work on cancer research appears in many leading scientific journals, as well as a variety of other publications. This page lists some of the articles published by Dr. Sharpless since becoming NCI director.

  7. Wanted: Fermilab director who can build consensus

    CERN Multimedia

    Pierce, G M

    2004-01-01

    "With current Fermilab Director Michael Witherell stepping down in July 2005, an appointed committee has vowed to find a new leader who will keep the Batavia lab at the forefront of the high-energy physics field" (1 page).

  8. Alternative Perspectives on Independence of Directors

    OpenAIRE

    Brennan, Niamh; McDermott, Michael

    2004-01-01

    This paper examines the issue of independence of boards of directors and non-executive directors of companies listed on the Irish Stock Exchange. Based on information published in annual reports, the study found that most Irish listed companies were complying with the Combined Code’s recommendations for a balanced board structure, albeit with only 60 per cent having majority-independent boards. The study found a lack of consistency in interpreting the definition of “independence”, a lack of d...

  9. Board Directors and Corporate Social Responsibility

    Directory of Open Access Journals (Sweden)

    Mariana Nedelcu (Bunea

    2014-08-01

    Full Text Available The boards of directors and corporate social responsibility (CSR have been the subject of much study and debate in the corporate governance circles over the two last decades. With issues ranging from poor corporate reporting to excessive executive compensation often splashed in the headlines, the role of boards comes into the media limelight as never before. Boards of directors are also becoming increasingly aware of corporate social responsibility issues.

  10. Board Directors and Corporate Social Responsibility

    OpenAIRE

    Mariana Nedelcu (Bunea)

    2014-01-01

    The boards of directors and corporate social responsibility (CSR) have been the subject of much study and debate in the corporate governance circles over the two last decades. With issues ranging from poor corporate reporting to excessive executive compensation often splashed in the headlines, the role of boards comes into the media limelight as never before. Boards of directors are also becoming increasingly aware of corporate social responsibility issues.

  11. VMware vCloud director cookbook

    CERN Document Server

    Langenhan, Daniel

    2013-01-01

    VMware vCloud Director Cookbook will adopt a Cookbook-based approach. Packed with illustrations and programming examples, this book explains the simple as well as the complex recipes in an easy-to-understand language.""VMware vCloud Director Cookbook"" is aimed at system administrators and technical architects moving from a virtualized environment to cloud environments. Familiarity with cloud computing platforms and some knowledge of virtualization and managing cloud environments is expected.

  12. AFRL Materials and Manufacturing Directorate

    Science.gov (United States)

    Flight Wright-Patterson Medical Clinic Contact Us Search Wright-Patterson Air Force Base: AFRL Logo AFRL follow in footsteps of legendary WWII flight nurse New satellite communication technology positioned for commanders with new decision making tools Public Health Education Division: Educating to Protect AFRL ENSPIRE

  13. Leadership training in Endocrinology fellowship A survey of program directors and recent graduates

    Science.gov (United States)

    2017-06-16

    Program Directors and Recent Graduates presented at/ published to SAMHS and Universities Research Forum (SURF) 2017, San Antonio, TX 16 June 2017 m...Research Division may pay for your basic journal publishing charges (to include costs for tables and black and white photos). We cannot pay for...efforts. LINDA STEEL-GOODWIN, Col, USAF, BSC Director , Clinical Investigations & Research Support Warrior Medics - Mission Ready - Patient Focused

  14. Factor VIII (F8) inversions in severe hemophilia A: Male germ cell origin and diagnosis with RT-PCR

    Energy Technology Data Exchange (ETDEWEB)

    Antonarakis, S.E. [Geneva Medical School (Switzerland)]|[Johns Hopkins School of Medicine, Baltimore, MD (United States); Rossiter, J.P. [Johns Hopkins School of Medicine, Baltimore, MD (United States); Young, M. [Geneva Medical School (Switzerland)] [and others

    1994-09-01

    The Factor VIII (F8) gene, which is defective in hemophilia A, is located in the most telomeric megabase of Xq. Inversions due to intrachromosomal homologous recombination between mispaired copies of gene A located within intron 22 of the gene and about 500 kb telomeric to it account for nearly half of the cases of severe hemophilia A. We hypothesized that pairing of Xq with its homolog inhibits the inversion process, and that therefore the event originates predominantly in male germ cells. In all 21 informative cases in which the inversion originated in a maternal grandparent, DNA polymorphism analysis using markers within or very closely linked to F8, determined that it occurred in the male germline. In addition, all but one of 56 mothers of sporadic cases due to inversions were carriers. The data indicate that the F8 gene inversions leading to severe hemophilia A occur almost exclusively in male germ cells. The mean age of maternal grandfathers at the birth of their carrier daughters was 29.9 years (13 cases), i.e. not different from the mean paternal age in the general population, supporting the hypothesis that the inversions occur in meiosis. The inversions can be diagnosed by Southern blot analysis. For more rapid diagnosis we have used RT-PCR of RNA ectopically expressed in blood. Oligonucleotides were used to PCR amplify, after the initial RT reaction of RNA samples using random hexamers, either the normal transcript (F8 exons 21 to 24;312 bp product) or the novel abnormal transcript that is generated after the inversion. Both type 1 and 2 inversions can be recognized in affecteds and carriers by the presence of the diagnostic PcR product of 248 bp. Correct diagnoses were made in samples from 6 patients and 2 carriers with type 1 inversions, 2 patients and 2 carriers with type 2 inversions and 5 normal controls.

  15. Critical appraisal of the role of recombinant activated factor VII in the treatment of hemophilia patients with inhibitors

    Directory of Open Access Journals (Sweden)

    Ampaiwan Chuansumrit

    2010-03-01

    Full Text Available Ampaiwan Chuansumrit1, Pantep Angchaisuksiri2, Nongnuch Sirachainan11Departments of Pediatrics and 2Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University,  Bangkok, ThailandAbstract: Hemophilia patients with inhibitors faced the constraint of inadequate treatment for several years before the era of recombinant factor VIIa (rFVII. Initially, rFVIIa was used in the compassionate-use programs. After a worldwide license was issued, more than 1.5 million doses were administered. Bleeding of joints and muscles was controlled effectively by means of an early home treatment program, with either a standard dose of 90 μg/kg every 2 to 3 hours for a few doses or a single dose of 270 μg/kg. For more serious bleeding episodes or minor surgery, an initial dose of 90 μg/kg was given every 2 hours for 24 to 48 hours followed by increased intervals of 3 to 6 hours according to the severity of bleeding and efficacy of bleeding control. In cases of major surgery such as orthopedic procedures, the same regimen can be applied except for a higher initial dose of 120 to 180 μg/kg. However, increasing the dose should be considered if there are unexpected bleeding complications since the half-life and clearance of rFVIIa differ between individuals. In addition, prophylaxis is administered to a small number of patients. Finally, the reported thromboembolic events found in hemophilia patients with inhibitors receiving rFVIIa are extremely low, much less than 1%.Keywords: bleeding disorder, hemophilia, inhibitor, NovoSeven, recombinant factor VIIa

  16. Oral delivery of bioencapsulated coagulation factor IX prevents inhibitor formation and fatal anaphylaxis in hemophilia B mice.

    Science.gov (United States)

    Verma, Dheeraj; Moghimi, Babak; LoDuca, Paul A; Singh, Harminder D; Hoffman, Brad E; Herzog, Roland W; Daniell, Henry

    2010-04-13

    To address complications of pathogenic antibody or life-threatening anaphylactic reactions in protein replacement therapy for patients with hemophilia or other inherited protein deficiencies, we have developed a prophylactic protocol using a murine hemophilia B model. Oral delivery of coagulation factor IX fused with cholera toxin beta-subunit (with or without a furin cleavage site; CTB-FFIX or CTB-FIX), expressed in chloroplasts (up to 3.8% soluble protein or 0.4 mg/g leaf tissue), bioencapsulated in plant cells, effectively blocked formation of inhibitory antibodies (undetectable or up to 100-fold less than controls). Moreover, this treatment eliminated fatal anaphylactic reactions that occurred after four to six exposures to intravenous F.IX. Whereas only 20-25% of control animals survived after six to eight F.IX doses, 90-93% of F.IX-fed mice survived 12 injections without signs of allergy or anaphylaxis. Immunostaining confirmed delivery of F.IX to Peyer's patches in the ileum. Within 2-5 h, feeding of CTB-FFIX additionally resulted in systemic delivery of F.IX antigen. This high-responder strain of hemophilia B mice represents a new animal model to study anaphylactic reactions. The protocol was effective over a range of oral antigen doses (equivalent to 5-80 microg recombinant F.IX/kg), and controlled inhibitor formation and anaphylaxis long-term, up to 7 months (approximately 40% life span of this mouse strain). Oral antigen administration caused a deviant immune response that suppressed formation of IgE and inhibitory antibodies. This cost-effective and efficient approach of antigen delivery to the gut should be applicable to several genetic diseases that are prone to pathogenic antibody responses during treatment.

  17. Targeting factor VIII expression to platelets for hemophilia A gene therapy does not induce an apparent thrombotic risk in mice.

    Science.gov (United States)

    Baumgartner, C K; Mattson, J G; Weiler, H; Shi, Q; Montgomery, R R

    2017-01-01

    Essentials Platelet-Factor (F) VIII gene therapy is a promising treatment in hemophilia A. This study aims to evaluate if platelet-FVIII expression would increase the risk for thrombosis. Targeting FVIII expression to platelets does not induce or elevate thrombosis risk. Platelets expressing FVIII are neither hyper-activated nor hyper-responsive. Background Targeting factor (F) VIII expression to platelets is a promising gene therapy approach for hemophilia A, and is successful even in the presence of inhibitors. It is well known that platelets play important roles not only in hemostasis, but also in thrombosis and inflammation. Objective To evaluate whether platelet-FVIII expression might increase thrombotic risk and thereby compromise the safety of this approach. Methods In this study, platelet-FVIII-expressing transgenic mice were examined either in steady-state conditions or under prothrombotic conditions induced by inflammation or the FV Leiden mutation. Native whole blood thrombin generation assay, rotational thromboelastometry analysis and ferric chloride-induced vessel injury were used to evaluate the hemostatic properties. Various parameters associated with thrombosis risk, including D-dimer, thrombin-antithrombin complexes, fibrinogen, tissue fibrin deposition, platelet activation status and activatability, and platelet-leukocyte aggregates, were assessed. Results We generated a new line of transgenic mice that expressed 30-fold higher levels of platelet-expressed FVIII than are therapeutically required to restore hemostasis in hemophilic mice. Under both steady-state conditions and prothrombotic conditions induced by lipopolysaccharide-mediated inflammation or the FV Leiden mutation, supratherapeutic levels of platelet-expressed FVIII did not appear to be thrombogenic. Furthermore, FVIII-expressing platelets were neither hyperactivated nor hyperactivatable upon agonist activation. Conclusion We conclude that, in mice, more than 30-fold higher levels of

  18. A genome-wide association study of resistance to HIV infection in highly exposed uninfected individuals with hemophilia A

    Science.gov (United States)

    Lane, Jérôme; McLaren, Paul J.; Dorrell, Lucy; Shianna, Kevin V.; Stemke, Amanda; Pelak, Kimberly; Moore, Stephen; Oldenburg, Johannes; Alvarez-Roman, Maria Teresa; Angelillo-Scherrer, Anne; Boehlen, Francoise; Bolton-Maggs, Paula H.B.; Brand, Brigit; Brown, Deborah; Chiang, Elaine; Cid-Haro, Ana Rosa; Clotet, Bonaventura; Collins, Peter; Colombo, Sara; Dalmau, Judith; Fogarty, Patrick; Giangrande, Paul; Gringeri, Alessandro; Iyer, Rathi; Katsarou, Olga; Kempton, Christine; Kuriakose, Philip; Lin, Judith; Makris, Mike; Manco-Johnson, Marilyn; Tsakiris, Dimitrios A.; Martinez-Picado, Javier; Mauser-Bunschoten, Evelien; Neff, Anne; Oka, Shinichi; Oyesiku, Lara; Parra, Rafael; Peter-Salonen, Kristiina; Powell, Jerry; Recht, Michael; Shapiro, Amy; Stine, Kimo; Talks, Katherine; Telenti, Amalio; Wilde, Jonathan; Yee, Thynn Thynn; Wolinsky, Steven M.; Martinson, Jeremy; Hussain, Shehnaz K.; Bream, Jay H.; Jacobson, Lisa P.; Carrington, Mary; Goedert, James J.; Haynes, Barton F.; McMichael, Andrew J.; Goldstein, David B.; Fellay, Jacques

    2013-01-01

    Human genetic variation contributes to differences in susceptibility to HIV-1 infection. To search for novel host resistance factors, we performed a genome-wide association study (GWAS) in hemophilia patients highly exposed to potentially contaminated factor VIII infusions. Individuals with hemophilia A and a documented history of factor VIII infusions before the introduction of viral inactivation procedures (1979–1984) were recruited from 36 hemophilia treatment centers (HTCs), and their genome-wide genetic variants were compared with those from matched HIV-infected individuals. Homozygous carriers of known CCR5 resistance mutations were excluded. Single nucleotide polymorphisms (SNPs) and inferred copy number variants (CNVs) were tested using logistic regression. In addition, we performed a pathway enrichment analysis, a heritability analysis, and a search for epistatic interactions with CCR5 Δ32 heterozygosity. A total of 560 HIV-uninfected cases were recruited: 36 (6.4%) were homozygous for CCR5 Δ32 or m303. After quality control and SNP imputation, we tested 1 081 435 SNPs and 3686 CNVs for association with HIV-1 serostatus in 431 cases and 765 HIV-infected controls. No SNP or CNV reached genome-wide significance. The additional analyses did not reveal any strong genetic effect. Highly exposed, yet uninfected hemophiliacs form an ideal study group to investigate host resistance factors. Using a genome-wide approach, we did not detect any significant associations between SNPs and HIV-1 susceptibility, indicating that common genetic variants of major effect are unlikely to explain the observed resistance phenotype in this population. PMID:23372042

  19. The value of usability testing for Internet-based adolescent self-management interventions: “Managing Hemophilia Online”

    Science.gov (United States)

    2013-01-01

    Background As adolescents with hemophilia approach adulthood, they are expected to assume responsibility for their disease management. A bilingual (English and French) Internet-based self-management program, “Teens Taking Charge: Managing Hemophilia Online,” was developed to support adolescents with hemophilia in this transition. This study explored the usability of the website and resulted in refinement of the prototype. Methods A purposive sample (n=18; age 13–18; mean age 15.5 years) was recruited from two tertiary care centers to assess the usability of the program in English and French. Qualitative observations using a “think aloud” usability testing method and semi-structured interviews were conducted in four iterative cycles, with changes to the prototype made as necessary following each cycle. This study was approved by research ethics boards at each site. Results Teens responded positively to the content and appearance of the website and felt that it was easy to navigate and understand. The multimedia components (videos, animations, quizzes) were felt to enrich the experience. Changes to the presentation of content and the website user-interface were made after the first, second and third cycles of testing in English. Cycle four did not result in any further changes. Conclusions Overall, teens found the website to be easy to use. Usability testing identified end-user concerns that informed improvements to the program. Usability testing is a crucial step in the development of Internet-based self-management programs to ensure information is delivered in a manner that is accessible and understood by users. PMID:24094082

  20. Characterization of the anti-factor VIII immunoglobulin profile in patients with hemophilia A by use of a fluorescence-based immunoassay

    Science.gov (United States)

    Boylan, Brian; Rice, Anne S.; Dunn, Amy L.; Tarantino, Michael D.; Brettler, Doreen B.; Barrett, John C.; Miller, Connie H.

    2015-01-01

    Summary Background The development of neutralizing antibodies, referred to as inhibitors, against factor VIII (FVIII) is a major complication associated with FVIII infusion therapy for the treatment of hemophilia A (HA). Previous studies have shown that a subset of HA patients and a low percentage of healthy individuals harbor non-neutralizing anti-FVIII antibodies that do not elicit the clinical manifestations associated with inhibitor development. Objective Assess HA patients' anti-FVIII antibody profiles as potential predictors of clinical outcomes. Methods A fluorescence immunoassay (FLI) was used to detect anti-FVIII antibodies in 491 samples from 371 HA patients. Results Assessments of antibody profiles showed that the presence of anti-FVIII IgG1, IgG2, or IgG4 correlated qualitatively and quantitatively with the presence of a FVIII inhibitor as reported by the Nijmegen-Bethesda assay (NBA). Forty-eight patients with a negative inhibitor history contributed serial samples to the study, including seven patients who had negative NBA titers initially and later converted to NBA-positive. The FLI detected anti-FVIII IgG1 in five of those seven patients prior to their conversion to NBA-positive. Five of 15 serial-sample patients who had a negative inhibitor history and a positive anti-FVIII IgG1 later developed an inhibitor, compared to 2 of 33 patients with a negative inhibitor history without anti-FVIII IgG1. Conclusions These data provide a rationale for future studies designed both to monitor the dynamics of anti-FVIII antibody profiles in HA patients as a potential predictor of future inhibitor development and to assess the value of the anti-FVIII FLI as a supplement to traditional inhibitor testing. PMID:25354263

  1. Direct Puncture Embolization of Scalp Arteriovenous Malformation in a Patient with Severe Hemophilia A: A Case Report

    International Nuclear Information System (INIS)

    Lee, Kyung Mi; Kim, Eui Jong; Park, Bong Jin; Kim, Keon Ha

    2011-01-01

    We present a case of scalp arteriovenous malformation (AVM) in a patient with severe hemophilia A. The 22-year-old man presented with a pulsatile right parietal scalp mass. Digital subtraction angiography revealed an AVM in the right parietal scalp, supplied by superficial temporal and occipital arteries that drained into multiple venous structures. We successfully performed direct puncture embolization followed by surgical resection of the scalp AVM in conjunction with supplemental infusion of coagulation factor VIII before, during and after the embolization and the operation.

  2. Direct Puncture Embolization of Scalp Arteriovenous Malformation in a Patient with Severe Hemophilia A: A Case Report

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Kyung Mi; Kim, Eui Jong [Dept. of Radiology, Kyung Hee University Hospital, Kyung Hee University Graduate School of Medicine, Seoul (Korea, Republic of); Park, Bong Jin [Dept. of Neurosurgery, Kyung Hee University Hospital, Kyung Hee University Graduate School of Medicine, Seoul (Korea, Republic of); Kim, Keon Ha [Dept. of Radiology, Samsug Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of)

    2011-09-15

    We present a case of scalp arteriovenous malformation (AVM) in a patient with severe hemophilia A. The 22-year-old man presented with a pulsatile right parietal scalp mass. Digital subtraction angiography revealed an AVM in the right parietal scalp, supplied by superficial temporal and occipital arteries that drained into multiple venous structures. We successfully performed direct puncture embolization followed by surgical resection of the scalp AVM in conjunction with supplemental infusion of coagulation factor VIII before, during and after the embolization and the operation.

  3. 2011 Computation Directorate Annual Report

    Energy Technology Data Exchange (ETDEWEB)

    Crawford, D L

    2012-04-11

    From its founding in 1952 until today, Lawrence Livermore National Laboratory (LLNL) has made significant strategic investments to develop high performance computing (HPC) and its application to national security and basic science. Now, 60 years later, the Computation Directorate and its myriad resources and capabilities have become a key enabler for LLNL programs and an integral part of the effort to support our nation's nuclear deterrent and, more broadly, national security. In addition, the technological innovation HPC makes possible is seen as vital to the nation's economic vitality. LLNL, along with other national laboratories, is working to make supercomputing capabilities and expertise available to industry to boost the nation's global competitiveness. LLNL is on the brink of an exciting milestone with the 2012 deployment of Sequoia, the National Nuclear Security Administration's (NNSA's) 20-petaFLOP/s resource that will apply uncertainty quantification to weapons science. Sequoia will bring LLNL's total computing power to more than 23 petaFLOP/s-all brought to bear on basic science and national security needs. The computing systems at LLNL provide game-changing capabilities. Sequoia and other next-generation platforms will enable predictive simulation in the coming decade and leverage industry trends, such as massively parallel and multicore processors, to run petascale applications. Efficient petascale computing necessitates refining accuracy in materials property data, improving models for known physical processes, identifying and then modeling for missing physics, quantifying uncertainty, and enhancing the performance of complex models and algorithms in macroscale simulation codes. Nearly 15 years ago, NNSA's Accelerated Strategic Computing Initiative (ASCI), now called the Advanced Simulation and Computing (ASC) Program, was the critical element needed to shift from test-based confidence to science-based confidence

  4. Clinical audit of inherited bleeding disorders in a developing country

    Directory of Open Access Journals (Sweden)

    Sajid Raihan

    2010-01-01

    Full Text Available Objective: We did a clinical audit to determine the status of coagulation disorders in a hemophilia care center in Pakistan. Setting: Fatimid foundation blood bank and hematological diseases center, Lahore. Study Design: This is a retrospective descriptive study. Materials and Methods: All patients registered at Lahore center were included. Data was collected using a questionnaire including age, gender, diagnosis, hepatitis and human immune deficiency virus (HIV status, number of episodes of bleeding, most common site of bleeding, severity of disorder and number of transfusions required to treat the episode. Results: During the study period, a total of 923 registered patients were reviewed at Lahore center and of these, 408 patients (44.2% were on regular follow-up. Inherited bleeding disorders identified in these patients included hemophilia A, hemophilia B, vWD, factor VII deficiency, factor V deficiency, factor X deficiency, dysfibrinogenemia, afibrinogenemia, factor XIII deficiency; and platelet function defects. Median age was 17 years with a range of three to 57 years. Median age at diagnosis was one year. There were 329 (80.6% males and 79 (19.3% females. The products used in these patients included factor VIII concentrate, fresh frozen plasma, cryoprecipitate, cryosupernatant and platelets. Testing for transmission of viral infections was also done in these patients and one patient (0.2% was found hepatitis B positive, six patients (1.4% were hepatitis C positive and two patients (0.49% were HIV positive. Conclusion: Hemophilia A, hemophilia B and vWD are the commonly encountered inherited bleeding disorders in our patients followed by other recessively transmitted disorders with a median age of 17 years and male to female ratio of 4: 1. Most of the patients utilized services available at Fatimid foundation with good clinical results. In Pakistan, non-governmental organizations (NGOs are trying their best for providing optimal treatment

  5. School directors and management in education

    Directory of Open Access Journals (Sweden)

    Srdić Vesna M.

    2015-01-01

    Full Text Available The main features of school management and organization comprise planning, decision making, management, leadership and communication. Research suggests that successful school management requires not only advanced managerial but also leadership skills, with highly developed social skills as the main competence. In a complex social system, good leadership becomes a fundamental component of a successful organization or institution. Although leadership has for a long time been of interest for theoreticians and practitioners alike, there are still numerous questions waiting to be answered in the area of management and leadership in education. According to the Law on the Basis of Educational System, the person who can be named a school director must posses appropriate education, competences, license and experience in education. Legal requirements allow the provision of effective training, but the fact that personal disposition can be both an advantage and an obstacle for acquiring necessary items of knowledge and skills, points to the necessity of including selection into the standard procedure for the election of a director. Democratization and decentralization of the educational system presupposes a series of structural, systemic and functional changes which reflect on school management and the role played by the director. This paper considers responsibilities and competences of directors, both in legislation and in school practice and addresses the question whether a school director is a manager or a leader, and what are the possibilities for the provision of professional resources for school management.

  6. METHODOLOGY OF THE DRUGS MARKET VOLUME MODELING ON THE EXAMPLE OF HEMOPHILIA A

    Directory of Open Access Journals (Sweden)

    N. B. Molchanova

    2015-01-01

    Full Text Available Hemophilia A is a serious genetic disease, which may lead to disability of a patient even in early ages without a required therapy. The only one therapeutic approach is a replacement therapy with drugs of bloodcoagulation factor VIII (FVIII. The modeling of coagulation drugs market volume will allow evaluation of the level of patients’ provision with a necessary therapy. Modeling of a “perfect” market of drugs and its comparison with the real one was the purpose of the study. During the modeling of market volume we have used the data about the number of hamophilia A patients on the basis of the federal registry, Russian and international morbidity indices, and the data of a real practice about average consumption of drugs of bloodcoagulation factors and data about the drugs prescription according to the standards and protocols of assistance rendering. According to the standards of care delivery, average annual volume of FVIII drugs consumption amounted to 406 325 244 IU for children and 964 578 678 IU for adults, i.e. an average volume of a “perfect” market is equal to 1 370 903 922 IU for all patients. The market volume is 1.8 times bigger than a real volume of FVIII drugs which, according to the data of IMS marketing agency, amounted to 765 000 000 IU in 2013. The modeling conducted has shown that despite a relatively high patients’ coverage there is a potential for almost double growth.

  7. Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A

    Science.gov (United States)

    Mahlangu, Johnny; Powell, Jerry S.; Ragni, Margaret V.; Chowdary, Pratima; Josephson, Neil C.; Pabinger, Ingrid; Hanabusa, Hideji; Gupta, Naresh; Kulkarni, Roshni; Fogarty, Patrick; Perry, David; Shapiro, Amy; Pasi, K. John; Apte, Shashikant; Nestorov, Ivan; Jiang, Haiyan; Li, Shuanglian; Neelakantan, Srividya; Cristiano, Lynda M.; Goyal, Jaya; Sommer, Jurg M.; Dumont, Jennifer A.; Dodd, Nigel; Nugent, Karen; Vigliani, Gloria; Luk, Alvin; Brennan, Aoife

    2014-01-01

    This phase 3 pivotal study evaluated the safety, efficacy, and pharmacokinetics of a recombinant FVIII Fc fusion protein (rFVIIIFc) for prophylaxis, treatment of acute bleeding, and perioperative hemostatic control in 165 previously treated males aged ≥12 years with severe hemophilia A. The study had 3 treatment arms: arm 1, individualized prophylaxis (25-65 IU/kg every 3-5 days, n = 118); arm 2, weekly prophylaxis (65 IU/kg, n = 24); and arm 3, episodic treatment (10-50 IU/kg, n = 23). A subgroup compared recombinant FVIII (rFVIII) and rFVIIIFc pharmacokinetics. End points included annualized bleeding rate (ABR), inhibitor development, and adverse events. The terminal half-life of rFVIIIFc (19.0 hours) was extended 1.5-fold vs rFVIII (12.4 hours; P < .001). Median ABRs observed in arms 1, 2, and 3 were 1.6, 3.6, and 33.6, respectively. In arm 1, the median weekly dose was 77.9 IU/kg; approximately 30% of subjects achieved a 5-day dosing interval (last 3 months on study). Across arms, 87.3% of bleeding episodes resolved with 1 injection. Adverse events were consistent with those expected in this population; no subjects developed inhibitors. rFVIIIFc was well-tolerated, had a prolonged half-life compared with rFVIII, and resulted in low ABRs when dosed prophylactically 1 to 2 times per week. This trial was registered at www.clinicaltrials.gov as #NCT01181128. PMID:24227821

  8. F8 haplotype and inhibitor risk: results from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort

    Science.gov (United States)

    Schwarz, John; Astermark, Jan; Menius, Erika D.; Carrington, Mary; Donfield, Sharyne M.; Gomperts, Edward D.; Nelson, George W.; Oldenburg, Johannes; Pavlova, Anna; Shapiro, Amy D.; Winkler, Cheryl A.; Berntorp, Erik

    2012-01-01

    Background Ancestral background, specifically African descent, confers higher risk for development of inhibitory antibodies to factor VIII (FVIII) in hemophilia A. It has been suggested that differences in the distribution of factor VIII gene (F8) haplotypes, and mismatch between endogenous F8 haplotypes and those comprising products used for treatment could contribute to risk. Design and Methods Data from the HIGS Combined Cohort were used to determine the association between F8 haplotype 3 (H3) vs. haplotypes 1 and 2 (H1+H2) and inhibitor risk among individuals of genetically-determined African descent. Other variables known to affect inhibitor risk including type of F8 mutation and HLA were included in the analysis. A second research question regarding risk related to mismatch in endogenous F8 haplotype and recombinant FVIII products used for treatment was addressed. Results H3 was associated with higher inhibitor risk among those genetically-identified (N=49) as of African ancestry, but the association did not remain significant after adjustment for F8 mutation type and the HLA variables. Among subjects of all racial ancestries enrolled in HIGS who reported early use of recombinant products (N=223), mismatch in endogenous haplotype and the FVIII proteins constituting the products used did not confer greater risk for inhibitor development. Conclusion H3 was not an independent predictor of inhibitor risk. Further, our findings did not support a higher risk of inhibitors in the presence of a haplotype mismatch between the FVIII molecule infused and that of the individual. PMID:22958194

  9. Acquired hemophilia in the patient suffering from rheumatoid arthritis: case report.

    Science.gov (United States)

    Drobiecki, Arkadiusz; Pasiarski, Marcin; Hus, Iwona; Sokołowska, Bożena; Wątek, Marzena

    2013-12-01

    Acquired hemophilia is a severe bleeding diathesis caused by autoantibodies against a coagulation factor VIII (FVIII inhibitor). Massive bleeding diathesis, often life threatening are observed in almost 90% of patients. In 50-60% of cases, inhibitor emerges spontaneously. However, there are some conditions like pregnancy, puerperium, autoimmune disorders or cancers that seem to induce acquired hemophilia. We report a case of a 49-year-old woman suffering from rheumatoid arthritis (RA) for several years, who was diagnosed with acquired hemophilia in September 2011. The patient had been treated by steroids and leflunomide during the last few months. At the time of diagnosis, diffuse bruising of the forearms and the trunk was observed. The patient was treated with recombinant activated factor VII, and the first-line immunosuppressive therapy was introduced (cyclophosphamide and prednisone). We observed the elimination of symptoms and the disappearance of diathesis. Significant reduction of the titer of inhibitor was achieved, but only partial remission was obtained. It lasted until the beginning of December 2011, when the titer of the inhibitor increased again and massive bleeding to the left lower limb occurred. It was necessary to administer recombinant factor VIIa together with the second-line immunosuppressive therapy based on the Budapest protocol. The rapid reduction of the diathesis and improvement of the patient's general condition was achieved as previously. However, still there was no complete remission. After 2 weeks of treatment, the titer of inhibitor diminished, and factor VIII activity increased slightly. Because of RA, the patient was treated with methylprednisolone in maintenance doses during the next few weeks. Unfortunately, after over a month, the increase of inhibitor titer and the decrease of FVIII level were observed again. Some bruises appeared. It was necessary to increase doses of corticosteroids to therapeutic levels and add cyclophosphamide

  10. Intensity of factor VIII treatment and the development of inhibitors in non-severe hemophilia A patients: results of the INSIGHT case-control study.

    Science.gov (United States)

    van Velzen, A S; Eckhardt, C L; Peters, M; Leebeek, F W G; Escuriola-Ettingshausen, C; Hermans, C; Keenan, R; Astermark, J; Male, C; Peerlinck, K; le Cessie, S; van der Bom, J G; Fijnvandraat, K

    2017-07-01

    Essentials Research suggests that intensive treatment episodes may increase the risk to develop inhibitors. We performed an international nested case-control study with 298 non-severe hemophilia A patients. Surgery and a high dose of factor VIII concentrate were associated with increased inhibitor risk. Physicians need to review arguments for factor VIII dose and elective surgery extra critically. Background Inhibitor development is a major complication of treatment with factor VIII concentrates in hemophilia. Findings from studies among severe hemophilia A patients suggest that intensive treatment episodes increase the risk of developing inhibitors. Objectives We set out to assess whether intensive treatment is also associated with an increased risk of inhibitor development among non-severe hemophilia A patients. Patients/Methods We performed a nested case-control study. A total of 75 inhibitor patients (cases) and 223 control patients were selected from 2709 non-severe hemophilia A patients (FVIII:C, 2-40%) of the INSIGHT cohort study. Cases and controls were matched for date of birth and cumulative number of exposure days (EDs) to FVIII concentrates. Conditional logistic regression was used to calculate both unadjusted and adjusted odds ratios (aOR); the latter were adjusted for a priori specified confounders. Results Peak treatment of 5 or 10 consecutive EDs did not increase inhibitor risk (aOR, 1.0; 95% confidence interval (CI), 0.4-2.5; and aOR, 1.8; CI, 0.6-5.5, respectively). Both surgical intervention (aOR, 4.2; CI, 1.7-10.3) and a high mean dose (> 45 IU kg -1 /ED) of FVIII concentrate (aOR, 7.5; CI, 1.6-35.6) were associated with an increased inhibitor risk. Conclusions Our findings suggest that high-dose FVIII treatment and surgery increase the risk of inhibitor development in non-severe hemophilia A. Together with the notion that non-severe hemophilia A patients are at a lifelong risk of inhibitor development, we suggest that in the future physicians

  11. Low cost industrial production of coagulation factor IX bioencapsulated in lettuce cells for oral tolerance induction in hemophilia B.

    Science.gov (United States)

    Su, Jin; Zhu, Liqing; Sherman, Alexandra; Wang, Xiaomei; Lin, Shina; Kamesh, Aditya; Norikane, Joey H; Streatfield, Stephen J; Herzog, Roland W; Daniell, Henry

    2015-11-01

    Antibodies (inhibitors) developed by hemophilia B patients against coagulation factor IX (FIX) are challenging to eliminate because of anaphylaxis or nephrotic syndrome after continued infusion. To address this urgent unmet medical need, FIX fused with a transmucosal carrier (CTB) was produced in a commercial lettuce (Simpson Elite) cultivar using species specific chloroplast vectors regulated by endogenous psbA sequences. CTB-FIX (∼1 mg/g) in lyophilized cells was stable with proper folding, disulfide bonds and pentamer assembly when stored ∼2 years at ambient temperature. Feeding lettuce cells to hemophilia B mice delivered CTB-FIX efficiently to the gut immune system, induced LAP(+) regulatory T cells and suppressed inhibitor/IgE formation and anaphylaxis against FIX. Lyophilized cells enabled 10-fold dose escalation studies and successful induction of oral tolerance was observed in all tested doses. Induction of tolerance in such a broad dose range should enable oral delivery to patients of different age groups and diverse genetic background. Using Fraunhofer cGMP hydroponic system, ∼870 kg fresh or 43.5 kg dry weight can be harvested per 1000 ft(2) per annum yielding 24,000-36,000 doses for 20-kg pediatric patients, enabling first commercial development of an oral drug, addressing prohibitively expensive purification, cold storage/transportation and short shelf life of current protein drugs. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  12. Risk Factors for High-Titer Inhibitor Development in Children with Hemophilia A: Results of a Cohort Study

    Directory of Open Access Journals (Sweden)

    Susan Halimeh

    2013-01-01

    Full Text Available Among the discussed risk factors for high-titre inhibitor (HRI development in patients with hemophilia A (HA are high dose FVIII replacement therapy and use of recombinant FVIII concentrates (rFVIII. The aim of this study was to evaluate the aforementioned risk factors for HRI development in children with hemophilia A ≤2%. About 288 ascertained PUPs (Israel and Germany were followed after initial HA diagnosis over 200 exposure days. Inhibitor-free survival, hazard ratios (HR, and 95% confidence intervals (CIs were calculated. Adjustment was performed for factor VIII concentrates, median single dose over the first three months of treatment, first FVIII administration before the age of three months, presence of risk HA gene mutations, “intensive treatment moments” and “year of birth” (proxy for different treatment periods. HRI occurred in 71/288 children (24.7%. In multivariate analysis adjusted for “year of birth”, underlying risk gene mutations (HR/CI: 2.37/1.40–3.99, FVIII dose, measured per one IU increase per kgbw (HR/CI: 1.05/1.04–1.07, and first FVIII administration before the age of three months showed a significant impact on HR development. The risk of HRI development was similar for recombinant or plasmatic FVIII products. Children at risk should be treated with carefully calculated lower dose regimens, adapted to individual bleeding situations.

  13. Prolonged activity of a recombinant factor VIII-Fc fusion protein in hemophilia A mice and dogs

    Science.gov (United States)

    Dumont, Jennifer A.; Liu, Tongyao; Low, Susan C.; Zhang, Xin; Kamphaus, George; Sakorafas, Paul; Fraley, Cara; Drager, Douglas; Reidy, Thomas; McCue, Justin; Franck, Helen W. G.; Merricks, Elizabeth P.; Nichols, Timothy C.; Bitonti, Alan J.; Pierce, Glenn F.

    2012-01-01

    Despite proven benefits, prophylactic treatment for hemophilia A is hampered by the short half-life of factor VIII. A recombinant factor VIII-Fc fusion protein (rFVIIIFc) was constructed to determine the potential for reduced frequency of dosing. rFVIIIFc has an ∼ 2-fold longer half-life than rFVIII in hemophilia A (HemA) mice and dogs. The extension of rFVIIIFc half-life requires interaction of Fc with the neonatal Fc receptor (FcRn). In FcRn knockout mice, the extension of rFVIIIFc half-life is abrogated, and is restored in human FcRn transgenic mice. The Fc fusion has no impact on FVIII-specific activity. rFVIIIFc has comparable acute efficacy as rFVIII in treating tail clip injury in HemA mice, and fully corrects whole blood clotting time (WBCT) in HemA dogs immediately after dosing. Furthermore, consistent with prolonged half-life, rFVIIIFc shows 2-fold longer prophylactic efficacy in protecting HemA mice from tail vein transection bleeding induced 24-48 hours after dosing. In HemA dogs, rFVIIIFc also sustains partial correction of WBCT 1.5- to 2-fold longer than rFVIII. rFVIIIFc was well tolerated in both species. Thus, the rescue of FVIII by Fc fusion to provide prolonged protection presents a novel pathway for FVIII catabolism, and warrants further investigation. PMID:22246033

  14. Somatic mosaicism and female-to-female transmission in a kindred with hemophilia B (factor IX deficiency)

    International Nuclear Information System (INIS)

    Taylor, S.A.M.; Deugau, K.V.; Lillicrap, D.P.

    1991-01-01

    Studies have shown that hemophilia B (Christmas disease; factor IX deficiency) results from many different mutations in the factor IX gene, of which >95% are single nulceotide substitutions. This study has identified a previously unreported form of hemophilia B in a patient who was a somatic mosaic for a guanine-to-cytosine transversion at nucleotide 31,170 in the factor IX gene. This point mutation changes the codon for residue 350 in the catalytic domain of factor IX from a cysteine to a serine. The authors used differential termination of primer extension to confirm and measure the degree of mosaicism. The study shows that a varying proportion of cells from hepatic, renal, smooth muscle, and hematopoietic populations possessed normal as well as mutant factor IX sequences. These results indicate that the mutation in this patient occurred either as an uncorrected half-chromatid mutation in the female gamete or as a replication or postreplication error in the initial mitotic divisions of the zygote preceding implantation. In addition, this kindred also contains two females in successive generations who have moderately severe factor IX deficiency. The molecular pathogenesis of this latter phenomenon has been studied and seems to relate to the unaccompanied expression of the mutant factor IX gene consequent upon a second, as yet undefined, genetic event that has prevented inactivation of sequences including the mutant factor IX gene on the X chromosome inherited from the affected male

  15. Low cost industrial production of coagulation factor IX bioencapsulated in lettuce cells for oral tolerance induction in hemophilia B

    Science.gov (United States)

    Su, Jin; Zhu, Liqing; Sherman, Alexandra; Wang, Xiaomei; Lin, Shina; Kamesh, Aditya; Norikane, Joey H.; Streatfield, Stephen J.; Herzog, Roland W.; Daniell, Henry

    2015-01-01

    Antibodies (inhibitors) developed by hemophilia B patients against coagulation factor IX (FIX) are challenging to eliminate because of anaphylaxis or nephrotic syndrome after continued infusion. To address this urgent unmet medical need, FIX fused with a transmucosal carrier (CTB) was produced in a commercial lettuce (Simpson Elite) cultivar using species specific chloroplast vectors regulated by endogenous psbA sequences. CTB-FIX (~1mg/g) in lyophilized cells was stable with proper folding, disulfide bonds and pentamer assembly when stored ~2 years at ambient temperature. Feeding lettuce cells to hemophilia B mice delivered CTB-FIX efficiently to the gut immune system, induced LAP+ regulatory T cells and suppressed inhibitor/IgE formation and anaphylaxis against FIX. Lyophilized cells enabled 10-fold dose escalation studies and successful induction of oral tolerance was observed in all tested doses. Induction of tolerance in such a broad dose range should enable oral delivery to patients of different age groups and diverse genetic background. Using Fraunhofer cGMP hydroponic system, ~870 kg fresh or 43.5 kg dry weight can be harvested per 1000 ft2 per annum yielding 24,000–36,000 doses for 20-kg pediatric patients, enabling first commercial development of an oral drug, addressing prohibitively expensive purification, cold storage/transportation and short shelf life of current protein drugs. PMID:26302233

  16. 16 CFR 1000.27 - Directorate for Health Sciences.

    Science.gov (United States)

    2010-01-01

    ... 16 Commercial Practices 2 2010-01-01 2010-01-01 false Directorate for Health Sciences. 1000.27... AND FUNCTIONS § 1000.27 Directorate for Health Sciences. The Directorate for Health Sciences is managed by the Associate Executive Director for Health Sciences and is responsible for reviewing and...

  17. 16 CFR 1000.29 - Directorate for Engineering Sciences.

    Science.gov (United States)

    2010-01-01

    ... 16 Commercial Practices 2 2010-01-01 2010-01-01 false Directorate for Engineering Sciences. 1000... ORGANIZATION AND FUNCTIONS § 1000.29 Directorate for Engineering Sciences. The Directorate for Engineering Sciences, which is managed by the Associate Executive Director for Engineering Sciences, is responsible for...

  18. 30 CFR 282.10 - Jurisdiction and responsibilities of Director.

    Science.gov (United States)

    2010-07-01

    ... part and are under the jurisdiction of the Director: Exploration, testing, and mining operations... 30 Mineral Resources 2 2010-07-01 2010-07-01 false Jurisdiction and responsibilities of Director... Jurisdiction and Responsibilities of Director § 282.10 Jurisdiction and responsibilities of Director. Subject...

  19. 16 CFR 1000.26 - Directorate for Epidemiology.

    Science.gov (United States)

    2010-01-01

    ... 16 Commercial Practices 2 2010-01-01 2010-01-01 false Directorate for Epidemiology. 1000.26... AND FUNCTIONS § 1000.26 Directorate for Epidemiology. The Directorate for Epidemiology, managed by the Associate Executive Director for Epidemiology, is responsible for the collection and analysis of data on...

  20. 42 CFR 493.1406 - Standard; Laboratory director qualifications on or before February 28, 1992.

    Science.gov (United States)

    2010-10-01

    ... Medical Microbiology, the American Board of Clinical Chemistry, the American Board of Bioanalysis, or... exists; and (b) The laboratory director must: (1) Be a physician certified in anatomical or clinical... biological science as a major subject and (i) Is certified by the American Board of Medical Microbiology, the...

  1. Leadership styles of hospital pharmacy directors.

    Science.gov (United States)

    Parrett, E E; Hurd, P D; Northcraft, G; McGhan, W F; Bootman, J L

    1985-05-01

    The leadership styles of hospital pharmacy directors and the association between leadership style, participative management, and innovative pharmaceutical services were studied using a mail questionnaire. The questionnaire was sent to 570 randomly selected hospital pharmacy directors. Included were a validated instrument that measures task-oriented versus relationship-oriented leadership behavior and other questions about participation of staff members, innovative services, and respondents' personal characteristics. The response rate was 69%. The majority of respondents perceived their leadership as highly relationship-oriented as well as highly task-oriented. Respondents with the "high relationship-high task" leadership style had the highest scores for subordinate participation. There were no significant differences in scores for innovative services by leadership style. A positive correlation between scores for subordinate participation and scores for innovative services was demonstrated. Most hospital pharmacy directors used a management style in which relationships and staff participation were important.

  2. Assessment of healthcare measures, healthcare resource use, and cost of care among severe hemophilia A patients in Mumbai region of India.

    Science.gov (United States)

    Jadhav, U; Mukherjee, K

    2017-10-23

    In India, the low public health priority given to rare disorders such as hemophilia hinders their management and optimal care, leading to relatively poor health outcomes. This study aims to profile the multidimensional health status of patients with severe hemophilia A, and its association with the use of healthcare resources and the cost of care in Mumbai region of India. A cross-sectional, single-center study was conducted during January-May 2011, among 160 patients diagnosed with severe hemophilia A in Mumbai region of India. Their health status was documented using the Hemophilia Utilization Group Study's validated instrument of Functional Health Status Measure (FHS) and a single item of Self-care Measure. Of 160 patients, 55% (n = 88) scored on the lower side on the FHS, with an average score of 6.65 ± 2.85. The use of healthcare resources and cost of treatment were considerable for patients with a lower mean rank score on the FHS and a higher mean rank score on the self-care measure. The consumption of clotting factor concentrates (CFCs), number of visits to a health facility and incidence of inpatient episodes were significantly associated with a relatively low score on the FHS. Similarly, a higher cost of treatment, in terms of the cost of CFCs, direct cost, emergency room cost, and indirect cost, were significantly associated with a lower score on the FHS. The health status of patients with severe hemophilia A is compromised and has a significant impact on the use of healthcare resources and the cost of treatment.

  3. The important role of von Willebrand factor in platelet-derived FVIII gene therapy for murine hemophilia A in the presence of inhibitory antibodies.

    Science.gov (United States)

    Shi, Q; Schroeder, J A; Kuether, E L; Montgomery, R R

    2015-07-01

    Our previous studies have demonstrated that targeting FVIII expression to platelets results in FVIII storage together with von Willebrand factor (VWF) in platelet α-granules and that platelet-derived FVIII (2bF8) corrects the murine hemophilia A phenotype even in the presence of high-titer anti-FVIII inhibitory antibodies (inhibitors). To explore how VWF has an impact on platelet gene therapy for hemophilia A with inhibitors. 2bF8 transgenic mice in the FVIII(-/-) background (2bF8(tg+/-) F8(-/-) ) with varying VWF phenotypes were used in this study. Animals were analyzed by VWF ELISA, FVIII activity assay, Bethesda assay and tail clip survival test. Only 18% of 2bF8(tg+/-) F8(-/-) VWF(-/-) animals, in which VWF was deficient, survived the tail clip challenge with inhibitor titers of 3-8000 BU mL(-1) . In contrast, 82% of 2bF8(tg+/-) F8(-/-) VWF(+/+) mice, which had normal VWF levels, survived tail clipping with inhibitor titers of 10-50,000 BU mL(-1) . All 2bF8(tg+/-) F8(-/-) VWF(-/-) mice without inhibitors survived tail clipping and no VWF(-/-) F8(-/-) mice survived this challenge. Because VWF is synthesized by endothelial cells and megakaryocytes and is distributed in both plasma and platelets in peripheral blood, we further investigated the effect of each compartment of VWF on platelet-FVIII gene therapy for hemophilia A with inhibitors. In the presence of inhibitors, 42% of animals survived tail clipping in the group with plasma-VWF and 50% survived in the platelet-VWF group. VWF is essential for platelet gene therapy for hemophilia A with inhibitors. Both platelet-VWF and plasma-VWF are required for optimal platelet-derived FVIII gene therapy for hemophilia A in the presence of inhibitors. © 2015 International Society on Thrombosis and Haemostasis.

  4. Efficacy of standard prophylaxis versus on-demand treatment with bayer's sucrose-formulated recombinant FVIII (rFVIII-FS) in Chinese children with severe hemophilia A.

    Science.gov (United States)

    Zhao, Yongqiang; Xiao, Juan; Yang, Renchi; Wu, Runhui; Hu, Yu; Beckmann, Horst; Wu, Junde; Hou, Qingsong; Sun, Jing

    2017-04-01

    In China, care of patients with severe hemophilia primarily involves insufficient dosing of on-demand treatment and secondary low-dose prophylaxis (10 IU/kg 2× /wk). We sought to evaluate 3× /wk, standard-dose prophylaxis with sucrose-formulated recombinant factor VIII (rFVIII-FS; Bayer) compared with on-demand treatment in Chinese children with severe hemophilia A. Children and adolescents aged 2-16 years with severe hemophilia A, no inhibitors, and no prophylaxis for >6 consecutive months before study entry were eligible for this 24-week, interventional, sequential-treatment study. Patients received rFVIII-FS on demand for 12 weeks followed by a 12-week prophylaxis period (25 IU/kg 3× /wk). The primary efficacy endpoint was comparison of the annualized bleeding rate (ABR) of all bleeds in the prophylaxis versus on-demand phase. Additional variables included ABR of joint bleeds, school attendance/activity, daily activity, and hemophilia Joint Health Score (HJHS). Thirty patients (median age, 12 years) were treated and analyzed. Compared with on-demand treatment, prophylaxis reduced median (quartile [Q1; Q3]) ABR of all bleeds (57.5 [44.5; 73.9] vs 0 [0; 4.0]) and joint bleeds (34.5 [26.1; 56.5] vs 0 [0; 4.0]). Median (range) total HJHS improved after both the prophylaxis and on-demand phases (8.0 [0-48.0] and 11.0 [0-55.0], respectively) compared with baseline (16.0 [0-56.0]). School attendance/activity and daily activity improved with prophylaxis versus on demand. No inhibitors or treatment-related adverse events were reported. In this first prospective, standard-dose, secondary prophylaxis study in China, rFVIII-FS prophylaxis reduced bleeding and improved health outcomes versus on-demand treatment in children with severe hemophilia A.

  5. Rolf-Dieter Heuer, next Director General

    CERN Multimedia

    CERN Council appointed Professor Rolf-Dieter Heuer to succeed Dr Robert Aymar as CERN’s Director General. Professor Heuer will serve a five-year term, taking office on 1 January 2009. Rolf-Dieter Heuer is currently Research Director for particle and astroparticle physics at Germany’s DESY laboratory in Hamburg. He was a staff member at CERN from 1984 to 1998, working for the OPAL collaboration at LEP, and from 1994 to 1998 he was the collaboration’s spokesman. See the Press Release.

  6. A DUAL NETWORK MODEL OF INTERLOCKING DIRECTORATES

    Directory of Open Access Journals (Sweden)

    Humphry Hung

    2003-01-01

    Full Text Available The article proposes an integrative framework for the study of interlocking directorates by using an approach that encompasses the concepts of multiple networks and resource endowment. This serves to integrate the traditional views of interorganizational linkages and intra-class cohesion. Through appropriate strategic analysis of relevant resource endowment of internal environment and external networks of organizations and corporate elites, this article argues that the selection of directors, if used effectively, can be adopted as a strategic device to enhance the corporation's overall performance.

  7. 5 CFR 2638.506 - Director's recommendation.

    Science.gov (United States)

    2010-01-01

    ... of the respondent employee's agency that appropriate disciplinary action be taken. If the respondent..., thereafter, will provide appropriate notice of the disciplinary action taken. (c) Notice of noncompliance. If the Director determines that the head of an agency has not taken appropriate disciplinary action...

  8. 50 CFR 18.91 - Director's decision.

    Science.gov (United States)

    2010-10-01

    ... 50 Wildlife and Fisheries 6 2010-10-01 2010-10-01 false Director's decision. 18.91 Section 18.91...) TAKING, POSSESSION, TRANSPORTATION, SALE, PURCHASE, BARTER, EXPORTATION, AND IMPORTATION OF WILDLIFE AND... decision. (a) Upon receipt of the recommended decision and transcript and after the thirty-day period for...

  9. Board of directors and risk management

    NARCIS (Netherlands)

    van der Elst, C.F.; Birkmose, H.; Neville, M.; Sorensen, K.

    2013-01-01

    The board of directors is responsible for an appropriate business risk management environment. The paper studies in a comparative way how legislators and courts fill this duty. We question whether the legislative and regulatory framework will improve the equilibrium between entrepreneurship and risk

  10. Where Is the Next Rose Director?

    OpenAIRE

    John Blundell

    2013-01-01

    Rose Friedman (née Director), the Chicago-trained economist, was a very important contributor to Milton Friedman’s scholarly output, popular writings, and television series. His remarkable role in society was to a significant extent a joint role from which she cannot be separated.

  11. IAEA Director General to Visit Iran

    International Nuclear Information System (INIS)

    2013-01-01

    Full text: IAEA Director General Yukiya Amano will travel to Tehran on 10 November 2013 to meet senior Iranian leaders on Monday, 11 November 2013, with the aim of strengthening dialogue and cooperation. Separately, as previously announced, IAEA and Iranian experts will meet in Tehran on Monday to discuss technical issues. IAEA)

  12. Foreword by the director of Bohunice NPPs

    International Nuclear Information System (INIS)

    1998-01-01

    In this foreword the director briefly describes activities of the NPP Bohunice in 1997. Main activities were: electric and heat production , the V-1 NPP Gradual Reconstruction Programme, nuclear safety programmes, environment protection, international co-operation as well as national and international public information

  13. Annual review and directors' report and accounts

    International Nuclear Information System (INIS)

    1992-07-01

    This annual report of Midlands Electricity PLC (MEB) presents a financial review of the Group and the directors' and auditors reports. Historical and current cost profit and loss accounts, balance sheets and cash flow statements are tabulated. The Group's financial history and regulatory accounts are also presented. (UK)

  14. Directors' report and accounts 1990-1991

    International Nuclear Information System (INIS)

    1992-01-01

    The Director's Report and accounts for Scottish Hydro-Electric PLC are presented for the period 1990-91. Details are given of the accounting policies, profit and loss account, balance sheet, source and application of funds and abridged current cost information. (UK)

  15. Summer Principals'/Directors' Orientation Training Module.

    Science.gov (United States)

    Mata, Robert L.; Garcia, Richard L.

    Intended to provide current or potential project principals/directors with the basic knowledge, skills, abilities, and sensitivities needed to manage a summer migrant school project in the local educational setting, this module provides instruction in the project management areas of planning, preparation, control, and termination. The module…

  16. Board diligence, director business and corporate governance

    Directory of Open Access Journals (Sweden)

    Saibal Ghosh

    2007-11-01

    Full Text Available The paper examines the association between financial performance and boards of non-financial firms. Using data on over 200 listed manufacturing firms in India for 2005, the findings indicate that, after controlling for various firm-specific factors, board diligence as well as director busyness exerts a positive influence on corporate performance.

  17. A Director's Guide to High School Horns.

    Science.gov (United States)

    Conway, Collen

    1998-01-01

    Conveys that the horn (French horn) is the most difficult instrument for band and orchestra directors to teach because playing the horn requires students to have very strong aural skills. Identifies the horn specific techniques students should know, such as hand positions, alternate fingerings, and transposition. Provides different methods for…

  18. 75 FR 56667 - Facilitating Shareholder Director Nominations

    Science.gov (United States)

    2010-09-16

    ...', nominees for director. We believe that these rules will benefit shareholders by improving corporate suffrage, the disclosure provided in connection with corporate proxy solicitations, and communication... Communications E. Costs 1. Costs Related to Potential Adverse Effects on Company and Board Performance 2. Costs...

  19. 45 CFR 1700.5 - Executive Director.

    Science.gov (United States)

    2010-10-01

    ... 45 Public Welfare 4 2010-10-01 2010-10-01 false Executive Director. 1700.5 Section 1700.5 Public Welfare Regulations Relating to Public Welfare (Continued) NATIONAL COMMISSION ON LIBRARIES AND..., recommendation and implementation of overall plans and policies to achieve the Commission's goals. (d) To...

  20. VMware vCloud Director essentials

    CERN Document Server

    Pal, Lipika

    2014-01-01

    If you are a technical professional with system administration knowledge, then this book is for you. The book also covers areas of importance if you are a virtualization engineer, consultant, architect, senior system engineer, or senior system analyst. You should possess core vSphere platform knowledge necessary to serve as a base to learn vCloud Director and its associated components.

  1. Critical Care Pharmacist Market Perceptions: Comparison of Critical Care Program Directors and Directors of Pharmacy.

    Science.gov (United States)

    Hager, David R; Persaud, Rosemary A; Naseman, Ryan W; Choudhary, Kavish; Carter, Kristen E; Hansen, Amanda

    2017-05-01

    Background: While hospital beds continue to decline as patients previously treated as inpatients are stabilized in ambulatory settings, the number of critical care beds available in the United States continues to rise. Growth in pharmacy student graduation, postgraduate year 2 critical care (PGY2 CC) residency programs, and positions has also increased. There is a perception that the critical care trained pharmacist market is saturated, yet this has not been evaluated since the rise in pharmacy graduates and residency programs. Purpose: To describe the current perception of critical care residency program directors (CC RPDs) and directors of pharmacy (DOPs) on the critical care pharmacist job market and to evaluate critical care postresidency placement and anticipated changes in PGY2 CC programs. Methods: Two electronic surveys were distributed from October 2015 to November 2015 through Vizient/University HealthSystem Consortium, American Society of Health-System Pharmacists (ASHP), Society of Critical Care Medicine, and American College of Clinical Pharmacy listservs to target 2 groups of respondents: CC RPDs and DOPs. Questions were based on the ASHP Pharmacy Forecast and the Pharmacy Workforce Center's Aggregate Demand Index and were intended to identify perceptions of the critical care market of the 2 groups. Results: Of 116 CC RPDs, there were 66 respondents (56.9% response rate). Respondents have observed an increase in applicants; however, they do not anticipate increasing the number of positions in the next 5 years. The overall perception is that there is a balance in supply and demand in the critical care trained pharmacist market. A total of 82 DOPs responded to the survey. Turnover of critical care pharmacists within respondent organizations is expected to be low. Although a majority of DOPs plan to expand residency training positions, only 9% expect to increase positions in critical care PGY2 training. Overall, DOP respondents indicated a balance of

  2. Population pharmacokinetics of recombinant coagulation factor VIII-SingleChain in patients with severe hemophilia A.

    Science.gov (United States)

    Zhang, Y; Roberts, J; Tortorici, M; Veldman, A; St Ledger, K; Feussner, A; Sidhu, J

    2017-06-01

    Essentials rVIII-SingleChain is a unique recombinant factor VIII (FVIII) molecule. A population pharmacokinetic model was based on FVIII activity of severe hemophilia A patients. The model was used to simulate factor VIII activity-time profiles for various dosing scenarios. The model supports prolonged dosing of rVIII-SingleChain with intervals of up to twice per week. Background Single-chain recombinant coagulation factor VIII (rVIII-SingleChain) is a unique recombinant coagulation factor VIII molecule. Objectives To: (i) characterize the population pharmacokinetics (PK) of rVIII-SingleChain in patients with severe hemophilia A; (ii) identify correlates of variability in rVIII-SingleChain PK; and (iii) simulate various dosing scenarios of rVIII-SingleChain. Patients/Methods A population PK model was developed, based on FVIII activity levels of 130 patients with severe hemophilia A (n = 91 for ≥ 12-65 years; n = 39 for  85% and > 93% of patients were predicted to maintain FVIII activity level above 1 IU dL -1 , at all times with three-times-weekly dosing (given on days 0, 2, and 4.5) at the lowest (20 IU kg -1 ) and highest (50 IU kg -1 ) doses, respectively. For twice weekly dosing (days 0 and 3.5) of 50 IU kg -1 rVIII-SingleChain, 62-80% of patients across all ages were predicted to maintain a FVIII activity level above 1 IU dL -1 at day 7. Conclusions The population PK model adequately characterized rVIII-SingleChain PK, and the model can be utilized to simulate FVIII activity-time profiles for various dosing scenarios. © 2017 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.

  3. Novel factor VIII variants with a modified furin cleavage site improve the efficacy of gene therapy for hemophilia A.

    Science.gov (United States)

    Nguyen, G N; George, L A; Siner, J I; Davidson, R J; Zander, C B; Zheng, X L; Arruda, V R; Camire, R M; Sabatino, D E

    2017-01-01

    Essentials Factor (F) VIII is an inefficiently expressed protein. Furin deletion FVIII variants were purified and characterized using in vitro and in vivo assays. These minimally modified novel FVIII variants have enhanced function. These variants provide a strategy for increasing FVIII expression in hemophilia A gene therapy. Background The major challenge for developing gene-based therapies for hemophilia A is that human factor VIII (hFVIII) has intrinsic properties that result in inefficient biosynthesis. During intracellular processing, hFVIII is predominantly cleaved at a paired basic amino acid cleaving enzyme (PACE) or furin cleavage site to yield a heterodimer that is the major form of secreted protein. Previous studies with B-domain-deleted (BDD) canine FVIII and hFVIII-R1645H, both differing from hFVIII by a single amino acid at this site, suggested that these proteins are secreted mainly in a single polypeptide chain (SC) form and exhibit enhanced function. Objective We hypothesized that deletion(s) of the furin site modulates FVIII biology and may enhance its function. Methods A series of recombinant hFVIII-furin deletion variants were introduced into hFVIII-BDD [Δ1645, 1645-46(Δ2), 1645-47(Δ3), 1645-48(Δ4), or Δ1648] and characterized. Results In vitro, recombinant purified Δ3 and Δ4 were primarily SC and, interestingly, had 2-fold higher procoagulant activity compared with FVIII-BDD. In vivo, the variants also have improved hemostatic function. After adeno-associated viral (AAV) vector delivery, the expression of these variants is 2-4-fold higher than hFVIII-BDD. Protein challenges of each variant in mice tolerant to hFVIII-BDD showed no anti-FVIII immune response. Conclusions These data suggest that the furin deletion hFVIII variants are superior to hFVIII-BDD without increased immunogenicity. In the setting of gene-based therapeutics, these novel variants provide a unique strategy to increase FVIII expression, thus lowering the vector dose, a

  4. Identifying influential directors in the United States corporate governance network

    Science.gov (United States)

    Huang, Xuqing; Vodenska, Irena; Wang, Fengzhong; Havlin, Shlomo; Stanley, H. Eugene

    2011-10-01

    The influence of directors has been one of the most engaging topics recently, but surprisingly little research has been done to quantitatively evaluate the influence and power of directors. We analyze the structure of the US corporate governance network for the 11-year period 1996-2006 based on director data from the Investor Responsibility Research Center director database, and we develop a centrality measure named the influence factor to estimate the influence of directors quantitatively. The US corporate governance network is a network of directors with nodes representing directors and links between two directors representing their service on common company boards. We assume that information flows in the network through information-sharing processes among linked directors. The influence factor assigned to a director is based on the level of information that a director obtains from the entire network. We find that, contrary to commonly accepted belief that directors of large companies, measured by market capitalization, are the most powerful, in some instances, the directors who are influential do not necessarily serve on boards of large companies. By applying our influence factor method to identify the influential people contained in the lists created by popular magazines such as Fortune, Networking World, and Treasury and Risk Management, we find that the influence factor method is consistently either the best or one of the two best methods in identifying powerful people compared to other general centrality measures that are used to denote the significance of a node in complex network theory.

  5. Identifying influential directors in the United States corporate governance network.

    Science.gov (United States)

    Huang, Xuqing; Vodenska, Irena; Wang, Fengzhong; Havlin, Shlomo; Stanley, H Eugene

    2011-10-01

    The influence of directors has been one of the most engaging topics recently, but surprisingly little research has been done to quantitatively evaluate the influence and power of directors. We analyze the structure of the US corporate governance network for the 11-year period 1996-2006 based on director data from the Investor Responsibility Research Center director database, and we develop a centrality measure named the influence factor to estimate the influence of directors quantitatively. The US corporate governance network is a network of directors with nodes representing directors and links between two directors representing their service on common company boards. We assume that information flows in the network through information-sharing processes among linked directors. The influence factor assigned to a director is based on the level of information that a director obtains from the entire network. We find that, contrary to commonly accepted belief that directors of large companies, measured by market capitalization, are the most powerful, in some instances, the directors who are influential do not necessarily serve on boards of large companies. By applying our influence factor method to identify the influential people contained in the lists created by popular magazines such as Fortune, Networking World, and Treasury and Risk Management, we find that the influence factor method is consistently either the best or one of the two best methods in identifying powerful people compared to other general centrality measures that are used to denote the significance of a node in complex network theory.

  6. Cross-reacting Material-positive Hemophilia A Diagnosed in a Patient with a Spontaneous Thigh Hemorrhage.

    Science.gov (United States)

    Saito, Tatsuya; Mukae, Jyunichi; Nakamura, Yosuke; Inaba, Hiroshi; Nogami, Keiji; Koyama, Takatoshi; Fukutake, Katsuyuki; Yamamoto, Koh

    2017-01-01

    A 53-year-old man, who had been diagnosed with mild hemophilia A (HA) at 35 years of age, was hospitalized with a thigh hematoma. His bleeding continued despite the administration of recombinant factor VIII (FVIII). The results of an FVIII/von Willebrand factor binding assay were normal. The patient's FVIII coagulant activity (FVIII:C) was low, but his FVIII antigen levels were within the normal limits, suggesting FVIII protein dysfunction. The FVIII:C measurements obtained by one-stage clotting and chromogenic assays were different. An FVIII gene analysis revealed a missense mutation p.Ser308Leu, which is rare in Japan. This case highlights that gene analyses and chromogenic assays are necessary to interpret the discrepancies between FVIII:C and the bleeding phenotype of patients with mild HA.

  7. Modeling of Body Weight Metrics for Effective and Cost-Efficient Conventional Factor VIII Dosing in Hemophilia A Prophylaxis

    Directory of Open Access Journals (Sweden)

    Alanna McEneny-King

    2017-10-01

    Full Text Available The total body weight-based dosing strategy currently used in the prophylactic treatment of hemophilia A may not be appropriate for all populations. The assumptions that guide weight-based dosing are not valid in overweight and obese populations, resulting in overdosing and ineffective resource utilization. We explored different weight metrics including lean body weight, ideal body weight, and adjusted body weight to determine an alternative dosing strategy that is both safe and resource-efficient in normal and overweight/obese adult patients. Using a validated population pharmacokinetic model, we simulated a variety of dosing regimens using different doses, weight metrics, and frequencies; we also investigated the implications of assuming various levels of endogenous factor production. Ideal body weight performed the best across all of the regimens explored, maintaining safety while moderating resource consumption for overweight and obese patients.

  8. Factor IX expression in skeletal muscle of a severe hemophilia B patient 10 years after AAV-mediated gene transfer.

    Science.gov (United States)

    Buchlis, George; Podsakoff, Gregory M; Radu, Antonetta; Hawk, Sarah M; Flake, Alan W; Mingozzi, Federico; High, Katherine A

    2012-03-29

    In previous work we transferred a human factor IX-encoding adeno-associated viral vector (AAV) into skeletal muscle of men with severe hemophilia B. Biopsy of injected muscle up to 1 year after vector injection showed evidence of gene transfer by Southern blot and of protein expression by IHC and immunofluorescent staining. Although the procedure appeared safe, circulating F.IX levels remained subtherapeutic (< 1%). Recently, we obtained muscle tissue from a subject injected 10 years earlier who died of causes unrelated to gene transfer. Using Western blot, IHC, and immunofluorescent staining, we show persistent factor IX expression in injected muscle tissue. F.IX transcripts were detected in injected skeletal muscle using RT-PCR, and isolated whole genomic DNA tested positive for the presence of the transferred AAV vector sequence. This is the longest reported transgene expression to date from a parenterally administered AAV vector, with broad implications for the future of muscle-directed gene transfer.

  9. OTA director to be Clinton's science advisor

    Science.gov (United States)

    Leath, Audrey

    President Clinton has nominated John H. “Jack” Gibbons to be Assistant to the President for Science and Technology, and director of the White House Office of Science and Technology Policy (OSTP). For over a decade, Gibbons has served as director of the Office of Technology Assessment (OTA), a bipartisan research arm of Congress.In nominating Gibbons, Clinton said, “I am delighted to appoint a brilliant scientist and gifted administrator… It is profoundly important that the president have a science advisor who understands science, who understands technology, who understands the practical application of these disciplines to the myriad of problems we face today. And I can tell you that from [Vice-president] Al Gore on down to every other member of Congress I have discussed John Gibbons with, I have hardly ever received more glowing and more consistent recommendations for anyone.”

  10. What competencies should directors possess? Malaysia perspective

    Directory of Open Access Journals (Sweden)

    Wan Fauziah Wan Yusoff

    2011-07-01

    Full Text Available Directors’ competencies are seeing to be of importance to corporate governance. As this issue has not yet being studied extensively in Malaysia, this study determines the key competencies of Malaysian company’s directors using qualitative approach involving two stages of Delphi Technique. In the first stage all information pertaining to directors’ competences in the literature had been reviewed. In the second stage, the key competencies identified in stage one were the criteria for developing a semi structured questionnaire. Participants were asked to rank the competencies in term of their importance for directors’ performance. Based on personel interviews with 41 participants eight types of competencies were found to be essential for Malaysian companies’ directors. Financial competencies received the highest responses, followed by corporate planning, business forecasting, legal, risk management, marketing, human resource and international business. This paper provides important evidence to support the conclusions drawn from the study about the importance of relevant directors’ competencies for board and corporate effectiveness.

  11. IAEA Director General welcomes NPT consensus

    International Nuclear Information System (INIS)

    2000-01-01

    The document informs that the Director General of the IAEA welcomed the adoption with consensus by the Review Conference of the Parties to the Treaty on the Non-Proliferation of Nuclear Weapons of the final document on the review and operation of the Treaty, and that he was pleased by the vote of confidence shown in the IAEA and its role in the implementation of the Treaty

  12. OSG Director reports on grid progress

    CERN Multimedia

    Pordes, Ruth

    2006-01-01

    "In this Q&A from the Open Science Grid (OSG), executive director Ruth Prodes provides a brief history of the OSG, an overview of current projects and partners, and a glimpse at future plans, including how the recent $30 million award from the ODE's office of Science and the NSF will be employed. She also shares her thoughts of SC, saying the personal contacts are the best part."(4,5 pages)

  13. Diversity of what? Multifaceted Boards and Directors

    OpenAIRE

    A. Hillman; S. Nielsen; A. Zattoni

    2012-01-01

    Board diversity has long intrigued practitioners and scholars. Constituents encourage companies to vary of director characteristics, but companies often resist. Academics debate whether diversity is beneficial for board decision-making and the empirical evidence is mixed, partly because “diversity” is treated as a singular construct despite representing many different forms (e.g. demographic, human capital and social capital). We propose a theoretical model of board diversit...

  14. UNC Cancer Center Director to Lead NCI.

    Science.gov (United States)

    2017-08-01

    President Donald Trump has selected Norman "Ned" Sharpless, MD, director of the University of North Carolina Lineberger Comprehensive Cancer Center, to lead the NCI. The news was met with widespread approval among cancer researchers, who view Sharpless as a strong communicator who can ably represent the needs of the cancer community in the face of proposed funding cuts. ©2017 American Association for Cancer Research.

  15. Severe hemophilia A in a female by cryptic translocation: Order and orientation of factor VIII within Xq28

    Energy Technology Data Exchange (ETDEWEB)

    Migeon, B.R.; McGinniss, M.J.; Antonarakis, S.E.; Axelman, J.; Stasiowski, B.A.; Youssoufian, H.; Kearns, W.G.; Chung, A.; Pearson, P.L.; Kazazian, H.H. Jr. (Johns Hopkins Univ., Baltimore, MD (United States)); Muneer, R.S. (Univ. of Oklahoma, Norman (United States))

    1993-04-01

    The authors report studies of a female with severe hemophilia A resulting from a complex de novo translocation of chromosomes X and 17 (46,X,t(X; 17)). Somatic cell hybrids containing the normal X, the der(X), or the der(17) were analyzed for coagulation factor VIII (F8C) sequences using Southern blots and polymerase chain reaction. The normal X, always late replicating, contains a normal F8C gene, whereas the der(X) has no F8C sequences. The der(17) chromosome containing Xq24-Xq28 carries a functional G6PD locus and a deleted F8C allele that lacks exons 1--15. Also, it lacks the DXYS64-X locus, situated between the F8C locus and the Xq telomere. These results indicate that a cryptic breakpoint within Xq28 deleted the 5[prime] end of F8C, but left the more proximal G6PD locus intact on the der(17)chromosome. As the deleted segment includes the 5[prime] half of F8C as well as the subtelomeric DXYS64 locus, F8C must be oriented on the chromosome with its 5[prime] region closest to the telomere. Therefore, the order of these loci is Xcen-G6PD-3[prime]F8C-5[prime]F8C-DXYS64-Xqtel. The analysis of somatic cell hybrids has elucidated the true nature of the F8C mutation in the pro-band, revealing a more complex rearrangement (three chromosomes involved) than that expected from cytogenetic analysis, chromosome painting, and Southern blots. A 900-kb segment within Xq28 has been translocated to another autosome. Hemophilia A in this heterozygous female is due to the decapitation of the F8C gene on the der(17) and inactivation of the intact allele on the normal X. 27 refs., 5 figs., 1 tab.

  16. Acquired hemophilia as the cause of life-threatening hemorrhage in a 94-year-old man: a case report

    Directory of Open Access Journals (Sweden)

    Blanchard Elizabeth

    2010-07-01

    Full Text Available Abstract Introduction Acquired factor VIII deficiency is a rare entity that can lead to severe and life-threatening bleeding. We describe a case of severe bleeding from the tongue secondary to acquired hemophilia and discuss treatment options, including aminocaproic acid and recombinant factor VIII, which have not been widely reported in the literature for the management of such patients. Case presentation A 94-year-old Caucasian man presented to our institution with diffuse bruising and extensive bleeding from the tongue secondary to mechanical trauma. He had no prior history of bleeding and his medical history was unremarkable except for dementia and hypertension. Coagulation studies revealed a prolonged activated partial thromboplastin time and a mixing study was consistent with the presence of an inhibitor. Quantitative assays revealed a reduced level of factor VIII activity (1% and the presence of a factor VIII inhibitor, measured at seven Bethesda units, in the serum. Oral prednisone therapy (60mg/day was given. He also received intravenous aminocaproic acid and human concentrate of factor VIII (Humate-P and topical anti-thrombolytic agents (100 units of topical thrombin cream. His hospital course was prolonged because of persistent bleeding and the development of profuse melena. He required eight units of packed red blood cells for transfusion. Hospitalization was also complicated by bradycardia of unclear etiology, which started after infusion of aminocaproic acid. His activated partial thromboplastin time gradually normalized. He was discharged to a rehabilitation facility three weeks later with improving symptoms, stable hematocrit and resolving bruises. Conclusions Clinicians should suspect a diagnosis of acquired hemophilia in older patients with unexplained persistent and profound bleeding from uncommon soft tissues, including the tongue. Use of factor VIII (Humate-P and aminocaproic acid can be useful in this coagulopathy but

  17. Validation of the Brazilian version of the VERITAS-Pro scale to assess adherence to prophylactic regimens in hemophilia

    Directory of Open Access Journals (Sweden)

    Adriana Aparecida Ferreira

    2018-01-01

    Full Text Available Introduction: Prophylaxis is the treatment of choice for patients with severe hemophilia. Low adherence may limit the effectiveness of the prophylactic regimen, thereby compromising outcomes. Objective: The objective of this study was to validate the Brazilian version of the VERITAS-Pro prophylaxis adherence scale, originally an American questionnaire that can be answered by the individual responsible for prophylaxis as well as by an observer. Methods: The scale has 24 questions divided into six subscales: Routine, Dosage, Plan, Remember, Skip and Communicate. Participants were recruited at a blood center in southeastern Brazil for validation and reliability analyses. Validation measures included the results obtained using analog visual scales of adherence, interval between medication dispensed by the treatment center pharmacy and the percentage of recommended doses administered and infusions registered in the patients’ logs. Results: The study included 32 individuals responsible for prophylaxis and five observers. The internal consistency was very good for the VERITAS-Pro total score, excellent for the Remember, Skip and Communicate subscales, good for the Dosage subscale, and acceptable for the Routine and Plan subscales. Twelve participants answered the questionnaire on more than one occasion to evaluate reproducibility. The intraclass correlation coefficient was excellent. Regarding convergent validity, the VERITAS-Pro scores were moderately correlated with the global adherence scale and with infusion log records, but showed a weak correlation with pharmacy dispensation records. Conclusion: The Brazilian version of VERITAS-Pro is a valid and reliable instrument, enabling the understanding of specific factors related to non-adherence and allowing targeted interventions for proper treatment. Keywords: Hemophilia, Medication adherence, Questionnaire, Validation study

  18. Direct detection of hemophilia B F9 gene mutation using multiplex PCR and conformation sensitive gel electrophoresis

    Directory of Open Access Journals (Sweden)

    Ki Young Yoo

    2010-03-01

    Full Text Available Purpose : The F9 gene is known to be the causative gene for hemophilia B, but unfortunately the detection rate for restriction fragment length polymorphism-based linkage analysis is only 55.6%. Direct DNA sequencing can detect 98% of mutations, but this alternative procedure is very costly. Here, we conducted multiplex polymerase chain reactions (PCRs and conformation sensitive gel electrophoresis (CSGE to perform a screened DNA sequencing for the F9 gene, and we compared the results with direct sequencing in terms of accuracy, cost, simplicity, and time consumption. Methods : A total of 27 unrelated hemophilia B patients were enrolled. Direct DNA sequencing was performed for 27 patients by a separate institute, and multiplex PCR-CSGE screened sequencing was done in our laboratory. Results of the direct DNA sequencing were used as a reference, to which the results of the multiplex PCR-CSGE screened sequencing were compared. For the patients whose mutation was not detected by the 2 methods, multiplex ligation-dependent probe amplification (MLPA was conducted. Results : With direct sequencing, the mutations could be identified from 26 patients (96.3%, whereas for multiplex PCR- CSGE screened sequencing, the mutations could be detected in 23 (85.2%. One patient’s mutation was identified by MLPA. A total of 21 different mutations were found among the 27 patients. Conclusion : Multiplex PCR-CSGE screened DNA sequencing detected 88.9% of mutations and reduced costs by 55.7% compared with direct DNA sequencing. However, it was more labor-intensive and time-consuming.

  19. Hospital management's linchpin: the medical director.

    Science.gov (United States)

    Cohn, R E

    1988-01-01

    The practice of medicine has become increasingly complex in this era of diagnosis-related groups (DRGs) and other direct government involvement in health care; complex and seemingly inappropriate legal decisions; liability chaos; and increasing competition from peers, entrepreneurs, and other health care organizations. In this new environment, an old player, the medical director (vice president of medical affairs) has been given new visibility and increased responsibilities to help physicians live with and overcome these environmental factors. In showing how the medical director can be of assistance in putting these factors into perspective, it is helpful to take a look at some aspects of the history of medicine, analyze the education process for physicians, point out where the profession began to be driven off course, and identify some of the overall problems of the profession and of the health care field. It is my intent here to project the position of medical director as a vital, frequently missing, link in the attempt to maximize communications, understanding, and achievement in health care organizations.

  20. Emotional intelligence model for directors of research centers in mexico

    Directory of Open Access Journals (Sweden)

    Mara Maricela Trujillo Flores

    2008-01-01

    H5 Social skills exhibited by directors, that are also part of interpersonal intelligence, allow a director to exert a greater influence on the working group, facilitating communication, conflict management, leadership, collaboration, cooperation and development of team skills.

  1. Nursing home director of nursing leadership style and director of nursing-sensitive survey deficiencies.

    Science.gov (United States)

    McKinney, Selina H; Corazzini, Kirsten; Anderson, Ruth A; Sloane, Richard; Castle, Nicholas G

    2016-01-01

    Nursing homes are becoming increasingly complex clinical environments because of rising resident acuity and expansion of postacute services within a context of historically poor quality performance. Discrete quality markers have been linked to director of nursing (DON) leadership behaviors. However, the impact of DON leadership across all measured areas of DON jurisdiction has not been tested using comprehensive domains of quality deficiencies. The aim of this study was to examine the effects of DON leadership style including behaviors that facilitate the exchange of information between diverse people on care quality domains through the lens of complexity science. Three thousand six hundred nine DONs completed leadership and intent-to-quit surveys. Quality markers that were deemed DON sensitive included all facility survey deficiencies in the domains of resident behaviors/facility practices, quality of life, nursing services, and quality of care. Logistic regression procedures estimated associations between variables. The odds of deficiencies for all DON sensitive survey domains were lower in facilities where DONs practiced complexity leadership including more staff input and shared decisional authority. DON quit intentions were aligned with higher odds of facility deficiencies across all domains. Results supported the hypotheses that DONs using complexity leadership approaches by interacting more freely with staff, discussing resident issues, and sharing decision making produced better care outcomes from every DON sensitive metric assessed by Centers for Medicare and Medicaid Services. The mechanism linking poor quality with high DON quit intentions is an area for future research. Encouraging DON use of complexity leadership approaches has the potential to improve a broad swath of quality outcomes.

  2. Administrative behavior of directors in hospitals: the Israeli case.

    Science.gov (United States)

    Stern, Z; Schmid, H; Nirel, N

    1994-01-01

    This article presents research findings on the behavior of directors in hospitals in Israel. According to the findings, hospital directors devote most of their time to internal organization processes and less time to the management of the external organizational environment. The findings also reveal that the orientation of these directors is toward centralization of authority and concentration of the decision-making process.

  3. 12 CFR 918.2 - Annual directors' compensation policy.

    Science.gov (United States)

    2010-01-01

    ... § 918.3. At a minimum, such policy shall address the activities or functions for which attendance is... 12 Banks and Banking 7 2010-01-01 2010-01-01 false Annual directors' compensation policy. 918.2... HOME LOAN BANKS BANK DIRECTOR COMPENSATION AND EXPENSES § 918.2 Annual directors' compensation policy...

  4. 7 CFR 2.95 - Director, Office of Ethics.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 1 2010-01-01 2010-01-01 false Director, Office of Ethics. 2.95 Section 2.95... Administration § 2.95 Director, Office of Ethics. The Director, Office of Ethics, shall be the USDA Alternate Agency Ethics Official, pursuant to 5 CFR 2638.202, and shall exercise the authority reserved to the...

  5. Weerts to lead Physical Sciences and Engineering directorate | Argonne

    Science.gov (United States)

    Physical Sciences and Engineering directorate By Lynn Tefft Hoff * August 10, 2015 Tweet EmailPrint Hendrik Engineering (PSE) directorate at the U.S. Department of Energy's Argonne National Laboratory. Weerts has , chemistry, materials science and nanotechnology. Weerts joined Argonne in 2005 as director of Argonne's High

  6. Health Risks Faced by Public School Band Directors

    Science.gov (United States)

    Woolery, Danielle N.; Woolery, Jesse A.

    2013-01-01

    Public school band directors face many work-related hazards in their grueling, yet rewarding job. As a school year progresses, directors are expected to work long hours, while trying to balance professional and personal responsibilities. A band director whose career spans multiple decades can potentially face a number of serious medical problems.…

  7. 30 CFR 732.11 - Review by the Director.

    Science.gov (United States)

    2010-07-01

    ... proposed State program, the Director shall publish in the Federal Register and in a newspaper of general... determined by the Director and published in the Federal Register notice required by paragraph (a). (2) When... 30 Mineral Resources 3 2010-07-01 2010-07-01 false Review by the Director. 732.11 Section 732.11...

  8. 75 FR 28262 - Office of the Director, National Institutes of Health; Notice of Meeting

    Science.gov (United States)

    2010-05-20

    ... discussion are: (1) NIH Director's Report; (2) Work Group for Human Embryonic Stem Cell Review; (3) Work... available. (Catalogue of Federal Domestic Assistance Program Nos. 93.14, Intramural Research Training Award; 93.22, Clinical Research Loan Repayment Program for Individuals from Disadvantaged Backgrounds; 93...

  9. Polymorphisms in the F8 gene and MHC-II variants as risk factors for the development of inhibitory anti-factor VIII antibodies during the treatment of hemophilia a: a computational assessment.

    Directory of Open Access Journals (Sweden)

    Gouri Shankar Pandey

    Full Text Available The development of neutralizing anti-drug-antibodies to the Factor VIII protein-therapeutic is currently the most significant impediment to the effective management of hemophilia A. Common non-synonymous single nucleotide polymorphisms (ns-SNPs in the F8 gene occur as six haplotypes in the human population (denoted H1 to H6 of which H3 and H4 have been associated with an increased risk of developing anti-drug antibodies. There is evidence that CD4+ T-cell response is essential for the development of anti-drug antibodies and such a response requires the presentation of the peptides by the MHC-class-II (MHC-II molecules of the patient. We measured the binding and half-life of peptide-MHC-II complexes using synthetic peptides from regions of the Factor VIII protein where ns-SNPs occur and showed that these wild type peptides form stable complexes with six common MHC-II alleles, representing 46.5% of the North American population. Next, we compared the affinities computed by NetMHCIIpan, a neural network-based algorithm for MHC-II peptide binding prediction, to the experimentally measured values and concluded that these are in good agreement (area under the ROC-curve of 0.778 to 0.972 for the six MHC-II variants. Using a computational binding predictor, we were able to expand our analysis to (a include all wild type peptides spanning each polymorphic position; and (b consider more MHC-II variants, thus allowing for a better estimation of the risk for clinical manifestation of anti-drug antibodies in the entire population (or a specific sub-population. Analysis of these computational data confirmed that peptides which have the wild type sequence at positions where the polymorphisms associated with haplotypes H3, H4 and H5 occur bind MHC-II proteins significantly more than a negative control. Taken together, the experimental and computational results suggest that wild type peptides from polymorphic regions of FVIII constitute potential T-cell epitopes

  10. Minimizing the Risk of Perioperative Bleeding in a Child with Hemophilia A during Dental Rehabilitation under General Anesthesia: A Case Report

    OpenAIRE

    Yehia El Batawi, Hisham

    2013-01-01

    ABSTRACT Hemophilia, among other bleeding disorders, raises concerns for dental service providers who routinely use sharp hand and rotary instruments, address highly vascular soft tissue and provide dental extractions. In pediatric dentistry, dealing with fearful or irritable children increases the possibility of trauma and subsequent bleeding risks in hemophilic pediatric dental patients. In the current report, we discuss how anesthetic, pediatric and dental management may contribute to the ...

  11. Effects of therapeutic exercise and hydrotherapy on pain severity and knee range of motion in patients with hemophilia: a randomized controlled trial.

    Science.gov (United States)

    Mazloum, Vahid; Rahnama, Nader; Khayambashi, Khalil

    2014-01-01

    Pain and limited range of motion (ROM) are the crucial subsequent results of joint hemorrhages in individuals with bleeding disorders and hemophilia. Exercise interventions are particularly recommended in treatment of such patients. The purpose of this study was to detect the influences of conventional exercise therapy and hydrotherapy on the knee joint complications in patients with hemophilia. A total of 40 patients engaging hemophilia A were randomized into one of three groups: Therapeutic exercise (N = 13), hydrotherapy (N = 14) or control (N = 13). While the first two groups followed their specific programs for 4 weeks, routine life-style was maintained by subjects in the control group in this period. To evaluate the pain level and knee ROM the visual analog scale and standard goniometer were utilized, respectively. The outcome was measured at baseline and after completing the prescribed protocols. Data analysis was performed using one-way analysis of variance and Scheffe statistical tests (P hydrotherapy in comparison to exercise therapy, the difference in ROM improvement was not statistically significant (P > 0.05). Using hydrotherapy in addition to usual rehabilitation training can result in beneficial effect in terms of pain and knee joint ROM. However, it appears that hydrotherapy is more effective in reducing pain.

  12. Directors' report and accounts 1992/1993

    International Nuclear Information System (INIS)

    1993-01-01

    This item is the Directors' Report and Accounts for the financial year 1992/1993 for Scottish Hydro-Electric plc, a United Kingdom utility which generates, distributes and sells electricity to its customers in that country. While generation is based in Scotland, the company is seeking to penetrate the energy market in England and Wales, and increase earnings in Scotland through improved performance. Increased customer and shareholder satisfaction is identified as a continuing goal. Turnover, profits and dividends to shareholders have all increased during the year. (UK)

  13. First report of real-time monitoring of coagulation function potential and IgG subtype of anti-FVIII autoantibodies in a child with acquired hemophilia A associated with streptococcal infection and amoxicillin.

    Science.gov (United States)

    Takeyama, Masahiro; Nogami, Keiji; Kajimoto, Takahiro; Ogiwara, Kenichi; Matsumoto, Tomoko; Shima, Midori

    2018-01-01

    We describe an 8-year-old boy with acquired hemophilia A (AHA) associated with streptococcal infection and amoxicillin. Laboratory data revealed low factor VIII activity (FVIII:C, 1.5 IU/dl), and FVIII inhibitor (15.9 BU/ml). Comprehensive coagulation function assays, including rotation thromboelastometry (ROTEM ® ), revealed a markedly prolonged clotting time. Thrombin and plasmin generation (TG/PG) appeared to be moderately impaired. The inhibitor epitope of his anti-FVIII autoantibody recognized light and heavy chains. He was treated with Novoseven ® and prednisolone, resulting in rapid improvement. ROTEM showed the return of coagulation time to normal level on day 20, and TG gradually improved. PG was moderately reduced in the clinical early phase, but improved at day 20. The patient's IgG subtype was IgG 4 at onset. IgG 1 was transiently positive on day 20, but negative on day 46. FVIII inhibitor gradually decreased and was completely absent after day 46, along with the elevated FVIII:C. IgG4 was again elevated on day 83, followed by a rapid decrease, indicative of the presence of non-neutralizing antibody, which remains currently undetected. We for the first time report changes in comprehensive coagulation function and IgG subtype of anti-FVIII antibody in a rare pediatric case of AHA.

  14. Reproductive Psychiatry Residency Training: A Survey of Psychiatric Residency Program Directors.

    Science.gov (United States)

    Osborne, Lauren M; MacLean, Joanna V; Barzilay, Erin Murphy; Meltzer-Brody, Samantha; Miller, Laura; Yang, Sarah Nagle

    2018-04-01

    The reproductive life cycle has unique influences on the phenotypic expression of mental illness in women. Didactic and clinical training focused on these sex-specific influences should be a vital component of the education of future psychiatrists. The authors sought to determine the current state of and attitudes toward reproductive psychiatry in resident education. The authors administered a web-based survey to psychiatry residency training directors. They assessed the availability of both mandated and optional didactic and clinical training experiences in reproductive psychiatry. Fifty residency program directors answered the survey, for a response rate of 28%. More than half of residency program directors (59%) reported requiring some training in reproductive psychiatry. Both the breadth and depth of topics covered varied greatly among programs. Lack of time (48%) and lack of qualified faculty (26%) were the most frequently cited barriers to more training. Only 40% of residency directors surveyed agreed that all residents should be competent in reproductive psychiatry. These findings suggest that specific training in reproductive psychiatry is inconsistent in US residency programs, and that training that does exist varies considerably in clinical time and content. Given that women comprise more than 50% of all psychiatric patients and most women will menstruate, give birth, and undergo menopause, future psychiatrists would benefit from more systematic instruction in this area. The authors propose the development of a national, standardized reproductive psychiatry curriculum to address this gap and aid in producing psychiatrists competent to treat women at all stages of life.

  15. Massive adrenal vein aneurysm mimicking an adrenal tumor in a patient with hemophilia A: a case report and review of the literature

    Directory of Open Access Journals (Sweden)

    Richard Sleightholm

    2016-12-01

    Full Text Available Abstract Background Visceral venous aneurysms are exceedingly rare, and until now, there have been no reports of this phenomenon in the adrenal vasculature. This report details the first adrenal venous aneurysm reported in the literature. The aneurysm presented as an 18-cm mass that was initially suspected to be a hematoma or tumor on the basis of the complex medical history of the patient, which included hemophilia A and testicular cancer. After surgical excision, pathologic examination confirmed this mass to be a 15.9-cm adrenal vein aneurysm, the largest aneurysm of any type or location recorded in the medical literature. Case presentation A 58-year-old caucasian male with hemophilia A presented to the emergency room of another institution with abdominal pain, blood in the stool, and a history of diverticulosis and symptomatic hemorrhoids. A large, left-sided adrenal mass was detected by computed tomography, and because of the patient’s hemophilia A and imaging consistent with a hemorrhagic mass, a hematoma was initially suspected. The patient was transferred to our institution, monitored for further bleeding with a stable hospital course, and discharged from the hospital under close monitoring. After 7–8 weeks with no change in the size of the mass, concerns grew regarding increasing symptoms of both satiety and mass effects from the large anomaly, as well as about the patient’s complicated medical history, which also included cancer. Surgical excision was recommended because of the concerns about increasing symptoms and the possibility of a malignancy. Correction and maintenance of factor VIII levels were incorporated pre-, intra-, and postoperatively, and en bloc surgical resection was performed to minimize bleeding and provide oncologic extirpation of the mass. A bowling ball-sized mass was removed, and careful pathologic examination revealed the mass to be a venous adrenal aneurysm. After a brief hospital stay, the patient made a

  16. Massive adrenal vein aneurysm mimicking an adrenal tumor in a patient with hemophilia A: a case report and review of the literature.

    Science.gov (United States)

    Sleightholm, Richard; Wahlmeier, Steven; Carson, Jeffrey S; Drincic, Andjela; Lazenby, Audrey; Foster, Jason M

    2016-12-01

    Visceral venous aneurysms are exceedingly rare, and until now, there have been no reports of this phenomenon in the adrenal vasculature. This report details the first adrenal venous aneurysm reported in the literature. The aneurysm presented as an 18-cm mass that was initially suspected to be a hematoma or tumor on the basis of the complex medical history of the patient, which included hemophilia A and testicular cancer. After surgical excision, pathologic examination confirmed this mass to be a 15.9-cm adrenal vein aneurysm, the largest aneurysm of any type or location recorded in the medical literature. A 58-year-old caucasian male with hemophilia A presented to the emergency room of another institution with abdominal pain, blood in the stool, and a history of diverticulosis and symptomatic hemorrhoids. A large, left-sided adrenal mass was detected by computed tomography, and because of the patient's hemophilia A and imaging consistent with a hemorrhagic mass, a hematoma was initially suspected. The patient was transferred to our institution, monitored for further bleeding with a stable hospital course, and discharged from the hospital under close monitoring. After 7-8 weeks with no change in the size of the mass, concerns grew regarding increasing symptoms of both satiety and mass effects from the large anomaly, as well as about the patient's complicated medical history, which also included cancer. Surgical excision was recommended because of the concerns about increasing symptoms and the possibility of a malignancy. Correction and maintenance of factor VIII levels were incorporated pre-, intra-, and postoperatively, and en bloc surgical resection was performed to minimize bleeding and provide oncologic extirpation of the mass. A bowling ball-sized mass was removed, and careful pathologic examination revealed the mass to be a venous adrenal aneurysm. After a brief hospital stay, the patient made a full recovery. Extensive review of the literature revealed 11

  17. A new director for Arts@CERN

    CERN Multimedia

    CERN Bulletin

    2015-01-01

    On 2 March 2015, Mónica Bello will take the reins of the Arts@CERN programme. A few days before taking over the new job, the curator and art critic talked to the CERN Bulletin about her interest in arts and science, her motivations for the job, and her plans for the future of the programme.   Mónica Bello. “The exciting nature of CERN almost demands an artistic programme like Arts@CERN,” says Mónica, former artistic director of VIDA (one of the most important competitions in digital and new media arts worldwide), who has recently been appointed as the new director of the Arts@CERN programme. “The programme is unique as it provides the artist not only with resources, but also with interesting scientific topics and a natural way for the artists to become involved. Thanks to this programme, artists can come to CERN, bring their individuality, and really benefit from the sharing experience with scientists.” Mónica,...

  18. An interview with the Director-General

    CERN Multimedia

    James Gillies

    2012-01-01

    At its March meeting, the Council took the step of extending Rolf Heuer’s mandate until the end of 2015. What can we expect from the extra two years?   Extensions to Director-General’s mandates are few and far between, with the last being for Herwig Schopper, who served an eight-year term in the 1980s. For Rolf Heuer, the proposal was raised by the Belgian delegation, so we asked delegate Walter Van Doninck why the Council felt that circumstances warranted an extension now. “We felt that the LHC's first long shutdown needed management continuity, given the important nature of the work to be carried out,” he explained. “That’s why we proposed extending the mandate of the current Director-General.” James Gillies spoke to Professor Heuer to find out what he plans to achieve with the extra time. James Gillies: First of all, how do you feel about your time in office so far? Rolf Heuer: I feel I’m about midwa...

  19. Clinical Cancer Genetics and Prevention

    Science.gov (United States)

    Olufunmilayo F. Olopade MD, FACP, Professor of Medicine and Human Genetics and Director of the Cancer Risk Clinic Department of Medicine, BSD Section of Hematology/Oncology University of Chicago, presented "Clinical Cancer Genetics and Prevention".

  20. Case management directors: how to manage in a transition-focused world: part 2.

    Science.gov (United States)

    Bankston White, Cheri; Birmingham, Jackie

    2015-01-01

    directors who are drawn from clinical case management or other leadership positions and thrust into this role are prepared to navigate within the organization, much less across the whole spectrum of payer, provider, and monitoring organizations. Yet the external focus of the director's role continues to grow in importance as the health care industry evolves and more focus is placed on population management and relationships with payers and community providers.

  1. The upward spiral of drug costs: a time series analysis of drugs used in the treatment of hemophilia.

    Science.gov (United States)

    Rogoff, Edward G; Guirguis, Hany S; Lipton, Richard A; Seremetis, Stephanie V; DiMichele, Donna M; Agnew, George M; Karpatkin, Margaret; Barish, Robert J; Jones, Robert L; Bianco, Celso; Knothe, Barbara D; Lee, Myung-Soo

    2002-10-01

    Hemophilia is an expensive disease because its treatment is heavily dependent on costly clotting factor drugs. Over the last nine years,a consortium of three Comprehensive Hemophilia Treatment Centers and other hospitals, which purchased clotting factors for their patients, has seen treatment costs escalate on average 17% annually. Currently, new, even more expensive drugs are entering the market. This study analyzes 3,244 purchases that were made over a nine-year period totaling nearly 500 million units of clotting factor, representing every product on the market. Purchases were made both apart from and under the Federal Public Health Service (PHS)discount pricing rules. The main cause of the increases was the move to newer, more expensive products. The average price of existing products increased less than 2%per year, but new products were priced, on average, 47% higher than existing products. Overall consumption increased by an average of 5% per year, likely reflecting prophylactic treatment modalities that require greater amounts of clotting factor. Government pricing programs, such as the PHS program, were ineffective or counterproductive at reducing costs. There is a notable absence of competition in this market, with a few dominant companies having a functional monopoly in the largest segments of the market. Prices of older products are not lowered, even when new products are brought to market. A few products that serve small patient groups have had their prices increased substantially. This escalation is likely to continue as new, more expensive clotting factor drugs are developed. Since these new products are not proven to be any safer or more effective than the current products, this situation creates a risk of intervention by government and insurers to address both treatment costs and exhaustion of patients' insurance caps. Drug companies are not serving the patients by pricing new, but often very similar, products so aggressively. The trends seen in

  2. 4th July 2011 - Russian Deputy Director-General Director of Directorate for Scientific and Technical Complex ROSATOM V. Pershukov in the ATLAS underground experimental area with Adviser T. Kurtyka, ATLAS Technical Coordinator M. Nessi and ATLAS Russian users.

    CERN Multimedia

    Maximilien Brice

    2011-01-01

    4th July 2011 - Russian Deputy Director-General Director of Directorate for Scientific and Technical Complex ROSATOM V. Pershukov in the ATLAS underground experimental area with Adviser T. Kurtyka, ATLAS Technical Coordinator M. Nessi and ATLAS Russian users.

  3. 2015 Science Mission Directorate Technology Highlights

    Science.gov (United States)

    Seablom, Michael S.

    2016-01-01

    The role of the Science Mission Directorate (SMD) is to enable NASA to achieve its science goals in the context of the Nation's science agenda. SMD's strategic decisions regarding future missions and scientific pursuits are guided by Agency goals, input from the science community including the recommendations set forth in the National Research Council (NRC) decadal surveys and a commitment to preserve a balanced program across the major science disciplines. Toward this end, each of the four SMD science divisions -- Heliophysics, Earth Science, Planetary Science, and Astrophysics -- develops fundamental science questions upon which to base future research and mission programs. Often the breakthrough science required to answer these questions requires significant technological innovation, e.g., instruments or platforms with capabilities beyond the current state of the art. SMD's targeted technology investments fill technology gaps, enabling NASA to build the challenging and complex missions that accomplish groundbreaking science.

  4. Nanotechnology Concepts at MSFC: Engineering Directorate

    Science.gov (United States)

    Bhat, Biliyar; Kaul, Raj; Shah, Sandeep; Smithers, Gweneth; Watson, Michael D.

    2000-01-01

    Nanotechnology is the art and science of building materials and devices at the ultimate level of finesse: atom by atom. Our nation's space program has needs for miniaturization of components, minimization of weight and maximization of performance, and nanotechnology will help us get there. MSFC - Engineering Directorate (ED) is committed to developing nanotechnology that will enable MSFC missions in space transportation, space science and space optics manufacturing. MSFC-ED has a dedicated group of technologists who are currently developing high pay-off nanotechnology concepts. This poster presentation will outline some of the concepts being developed at this time including, nanophase structural materials, carbon nanotube reinforced metal and polymer matrix composites, nanotube temperature sensors and aerogels. The poster will outline these concepts and discuss associated technical challenges in turning these concepts into real components and systems.

  5. Results of the Association of Directors of Radiation Oncology Programs (ADROP) Survey of Radiation Oncology Residency Program Directors

    International Nuclear Information System (INIS)

    Harris, Eleanor; Abdel-Wahab, May; Spangler, Ann E.; Lawton, Colleen A.; Amdur, Robert J.

    2009-01-01

    Purpose: To survey the radiation oncology residency program directors on the topics of departmental and institutional support systems, residency program structure, Accreditation Council for Graduate Medical Education (ACGME) requirements, and challenges as program director. Methods: A survey was developed and distributed by the leadership of the Association of Directors of Radiation Oncology Programs to all radiation oncology program directors. Summary statistics, medians, and ranges were collated from responses. Results: Radiation oncology program directors had implemented all current required aspects of the ACGME Outcome Project into their training curriculum. Didactic curricula were similar across programs nationally, but research requirements and resources varied widely. Program directors responded that implementation of the ACGME Outcome Project and the external review process were among their greatest challenges. Protected time was the top priority for program directors. Conclusions: The Association of Directors of Radiation Oncology Programs recommends that all radiation oncology program directors have protected time and an administrative stipend to support their important administrative and educational role. Departments and institutions should provide adequate and equitable resources to the program directors and residents to meet increasingly demanding training program requirements.

  6. 23rd October 2010 - UNESCO Director-General I. Bokova signing the Guest Book with CERN Director for Research and Scientific Computing S. Bertolucci and CERN Director-General R. Heuer.

    CERN Multimedia

    Maximilien Brice

    2010-01-01

    CERN-HI-1010244 37: in the SM18 hall: Ms Jasmina Sopova, Communication Officer J. Sopova; Director, Division of Basic & Engineering Sciences M. Nalecz, Assistant Director-General for the Natural Sciences G. Kalonji; Former CERN Director-General H. Schopper, CERN Head of Education R. Landua; UNESCO Director-General I. Bokova; CERN Adviser M. Bona; CERN Director for Research and Scientific Computing S. Bertolucci and UNESCO Office in Geneva Director Luis M. Tiburcio.

  7. Postdramatic Theatre of Director Christoph Marthaler

    Directory of Open Access Journals (Sweden)

    Arina R. Shevchenko

    2017-11-01

    Full Text Available The present paper deals with the main tendencies of modern European theatre represented in the creativity of a famous Swiss director Christoph Marthaler. Drama and theatre of the end of the 20th – the beginning of the 21st century were exposed to radical transformation. This change has been reflected in the theory of postdramatic theatre. A contemporary theatre is becoming more visual. Nowadays natural theatrical synthesis of various arts – visual, plastic, verbal, musical becomes an intersection of all kinds of artistic and medial practices as it has never been before. The new drama and theatre decline mimesis as the main principle of attitude to reality, they do not depict and do not reflect life, but strive to create a magic and/or ritual space of performative living and a special type of communication with audience. These peculiarities of modern theatre get a vivid evocation in the works of Christoph Marthaler. Having entered into theatre from music, the director creates his own unique language of art. The article proves that Marthaler’s works are an individual model of postdramatic theatre. The author concludes that its main distinctive feature is to blur the border between musical and dramatic performance. Marthaler does not stage the play – the images appear from musical phrases, fleeting impressions, observations and dramatic improvisations. The analysis enables to claim that the theatre in a real process of performance replaces the mimetic acting today. The applied principles of drama analysis can be used in studying of the other contemporary postdramatic theatre’s models.

  8. INTERFIRM COOPERATION AND INFORMATION SHARING THROUGH INTERLOCKING DIRECTORATES

    Directory of Open Access Journals (Sweden)

    Mohammed Belal UDDIN

    2012-01-01

    Full Text Available When firms engage in cooperative efforts, interfirm relations get particular interest to be studied. A direct interlock occurs when an executive or director of one firm sits on the board of another firm, and an indirect interlock occurs when two firms have directors or executives who sit on the board of a third firm. The three commonly used theoretical models such as social network theory, learning theory, and theory of strategic choice are more relevant for the formation and management of interlocking directorates. Uncertainty, resource scarcity, mutual trust, dependency, etc. influence the formation of interlocking directorates. Consequently, interlocking directorates allow sharing of information and overall cooperation between partners through learning, collaboration, networking, and effective relationship, etc. Proper management of interlocking directorates requires communication and collaboration among partners that enhance exchange of knowledge and cooperation.

  9. Misleading outside directors in public companies – The Israeli case

    Directory of Open Access Journals (Sweden)

    David A. Frenkel

    2006-01-01

    Full Text Available The external directors, who serve by law on the board of directors, are responsible for ensuring that, in addition to protecting the interests of stakeholders, the company will take the public interest into consideration. In this research we critically assess this system of corporate governance, and examine whether the external directors can actually succeed in looking out for the public’s interest. The research is based on in-depth interviews with external directors of leading public companies in Israel, representing different sectors. The issue at stake is both conceptual and practical: Conceptually there is an issue of how the notion of "the public interest" is understood and whether the legal construct of "outside directors" is capable of manifesting the public interest. Practically the issue at stake has to do with organisational sociology and how the relations within the Board are set and who are the outside directors.

  10. Council appoints CERN’s next Director General

    CERN Multimedia

    Maximilien Brice

    2007-01-01

    On 14 December 2007, CERN Council appointed Professor Rolf-Dieter Heuer to succeed Dr Robert Aymar as CERN Director General. Professor Heuer will serve a five-year term, taking office on 1 January 2009. From Left to right: Dr Robert Aymar, current CERN Director General, Professor Torsten Åkesson, President of CERN Council, and Professor Rolf-Dieter Heuer, CERN's next Director General.

  11. Female Institutional Directors on Boards and Firm Value

    OpenAIRE

    Pucheta Martínez, María Consuelo; Bel Oms, Inmaculada; Olcina Sempere, Gustau

    2016-01-01

    The aim of this research is to examine what impact female institutional directors on boards have on corporate performance. Previous research shows that institutional female directors cannot be considered as a homogeneous group since they represent investors who may or may not maintain business relations with the companies on whose corporate boards they sit. Thus, it is not only the effect of female institutional directors as a whole on firm value that has been analysed, but also the impact of...

  12. Management and Use of Director, Operational Test and Evaluation Funds

    National Research Council Canada - National Science Library

    2000-01-01

    .... The reorganization disestablished the functions of the Director, Test, Systems Engineering, and Evaluation, within the Office of Under Secretary of Defense for Acquisition, Technology, and Logistics...

  13. 12 CFR 905.10 - Board of Directors.

    Science.gov (United States)

    2010-01-01

    ... the five directors may belong to the same political party. (2) Responsibilities. The Board of..., functioning and organization of the Finance Board; (iii) Ensuring effective coordination and communication...

  14. The Development of FVIII Inhibitors in Relation to IL10 Gene Polymorphism in Hemophilia A Egyptian Pediatric Patients.

    Science.gov (United States)

    Sadek, Hoda; Youssry, Ilham; Ibrahim, Nihal Salah Eldeen; Abou-Elalla, Amany Ahmed; Atef, Gehad; Mousa, Somaia Mohammed

    2017-06-01

    Development of inhibitors against Factor VIII (FVIII) in hemophilia A patients is a serious complication of therapy. Many cytokines, including interleukin-10 (IL10), may affect inhibitor development; however, literature data are not sufficient to prove this association. The aim of this study was to investigate the relation between FVIII inhibitor formation and IL10-1082A/G polymorphism among Egyptian hemophiliacs. Patients were screened for FVIII inhibitors using the Bethesda method. IL10-1082A/G polymorphism was detected by polymerase chain reaction-restriction fragment length polymorphism. Six patients (12%) developed inhibitors. No statistically significant difference was found between inhibitor positive and negative patients regarding IL10-1082A/G genotypes, disease severity, or treatment-related variables (type of FVIII received, treatment regimen, age at first exposure to FVIII, and frequency of replacement therapy). FVIII inhibitor formation in this group of Egyptian hemophiliacs was not correlated to IL10-1082A/G polymorphism, disease severity, or any of the treatment variables.

  15. The new albumin-free recombinant factor VIII concentrates for treatment of hemophilia: do they represent an actual incremental improvement?

    Science.gov (United States)

    Josephson, Cassandra D; Abshire, Thomas

    2004-07-01

    The goal of eliminating the low levels of infectious disease risk from hemophilia treatment has resulted in the development of multiple generations of recombinant factor VIII (rFVIII) products. The ideal product should be devoid of human and animal proteins, which may transmit infectious agents. These products should also maintain molecular integrity, hemostatic efficacy, similar immunogenicity, and acceptable side effect profiles as compared to plasma-derived factor VIII. Currently available first-, second-, and third-generation rFVIII products include Recombinate; Kogenate FS/Helixate FS and ReFacto; and Advate, respectively. During the evolution of rFVIII products, either full-length or B-domain-deleted factor VIII were transfected into immortalized cell lines. The B-domain-deleted product, ReFacto, has resulted in an additional method to monitor factor VIII levels. The third-generation products offer the theoretical advantage of being produced without human and/or animal proteins. Upon initial introduction into the marketplace, the newer products have a higher cost. However, when analyzing historical trends, the prices of these products are almost equivalent to first-generation products within 3 years of licensure. Thus, the initial cost of the product may be a minimal issue in the medical decision process when selecting rFVIII replacement therapy.

  16. Single nucleotide primer extension to detect genetic diseases: Experimental application to hemophilia B (factor IX) and cystic fibrosis genes

    International Nuclear Information System (INIS)

    Kuppuswamy, M.N.; Hoffmann, J.W.; Spitzer, S.G.; Groce, S.L.; Bajaj, S.P.; Kasper, C.K.

    1991-01-01

    In this report, the authors describe an approach to detect the presence of abnormal alleles in those genetic diseases in which frequency of occurrence of the same mutation is high (e.g., hemophilia B). Initially, from each subject, the DNA fragment containing the putative mutation site is amplified by the polymerase chain reaction. For each fragment two reaction mixtures are then prepared. Each contains the amplified fragment, a primer (18-mer or longer) whose sequence is identical to the coding sequence of the normal gene immediately flanking the 5' end of the mutation site, and either an α- 32 P-labeled nucleotide corresponding to the normal coding sequence at the mutation site or an α- 32 P-labeled nucleotide corresponding to the mutant sequence. An essential feature of the present methodology is that the base immediately 3' to the template-bound primer is one of those altered in the mutant, since in this way an extension of the primer by a single base will give an extended molecule characteristic of either the mutant or the wild type. The method is rapid and should be useful in carrier detection and prenatal diagnosis of every genetic disease with a known sequence variation

  17. Limited protective effect of the CCR5Delta32/CCR5Delta32 genotype on human immunodeficiency virus infection incidence in a cohort of patients with hemophilia and selection for genotypic X4 virus

    DEFF Research Database (Denmark)

    Iversen, Astrid K N; Christiansen, Claus Bohn; Attermann, Jørn

    2003-01-01

    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 approximately 2% of the Scand......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 approximately 2...

  18. Los directores aprendiendo de sus maestros

    Directory of Open Access Journals (Sweden)

    Manuel Ortega Muñoz

    2016-07-01

    Full Text Available El presente artículo de investigación está enmarcado dentro de la línea de indagación Aprendizaje para la Gestión y versa sobre los principales aprendizajes que han adquirido los directivos de educación básica del estado de Durango, México, para el mejor ejercicio de su función. Desde un estudio de narrativa, se recopilaron historias de 16 directores de educación primaria estatal pertenecientes a la zona escolar 24 del sector educativo no. 1 de la Secretaría de Educación Pública. El análisis de los datos se llevó a cabo mediante la herramienta de análisis de información cualitativa Atlas ti versión 7.5. Los hallazgos de la investigación muestran que los principales aprendizajes que los directivos de educación básica del estado de Durango, México han adquirido de sus maestros para el mejor ejercicio de su función son dos: a el trabajo en equipo, del cual se desprenden componentes como una eficaz y eficiente organización del trabajo, el trabajar siempre en colaboración y tener la mejor de las actitudes para trabajar; y b el liderazgo compartido, aspecto en que se perciben elementos como el óptimo manejo y resolución de conflictos, el liderazgo y la toma de decisiones en conjunto por parte del colectivo escolar. Abstract This research paper, framed within the line of inquiry Learning Management, deals with the main lessons that have acquired the management of basic education in the state of Durango, Mexico, for the best performance of their duties, from a study of narrative histories of 16 directors of state primary education outside the school zone 24 the education sector 1 of the Ministry of Education. The data analysis was performed using the computer statistical package you Atlas ti version 7.5. The research findings show that there are two main lessons that have acquired the management of basic education in the state of Durango, Mexico from their teachers for the better performance of their function: a teamwork

  19. Women’s Health Training in Gastroenterology Fellowship: A National Survey of Fellows and Program Directors

    Science.gov (United States)

    Roberson, Erica; Richie, Kelly; Lindstrom, Mary J.; Esposti, Silvia Degli; Wald, Arnold

    2013-01-01

    Background and Aims The Gastroenterology Core Curriculum requires training in women’s digestive disorders; however, requirements do not necessarily produce knowledge and competence. Our study goals were: (1) to compare perceptions of education, fellow-reported levels of competence, and attitudes towards training in women’s gastrointestinal (GI) health issues during fellowship between gastroenterology fellows and program directors, and (2) to determine the barriers for meeting training requirements. Methods A national survey assessing four domains of training was conducted. All GI program directors in the United States (n = 153) and a random sample of gastroenterology fellows (n = 769) were mailed surveys. Mixed effects linear modeling was used to estimate all mean scores and to assess differences between the groups. Cronbach’s alpha was used to assess the consistency of the measures which make up the means. Results Responses were received from 61% of program directors and 31% of fellows. Mean scores in perceived didactic education, clinical experiences, and competence in women’s GI health were low and significantly differed between the groups (P < 0.0001). Fellows’ attitudes towards women’s GI health issues were more positive compared to program directors’ (P = 0.004). Barriers to training were: continuity clinic at a Veteran’s Administration hospital, low number of pregnant patients treated, low number of referrals from obstetrics and gynecology, and lack of faculty interest in women’s health. Conclusions (1) Fellows more so than program directors perceive training in women’s GI health issues to be low. (2) Program directors more so than fellows rate fellows to be competent in women’s GI health. (3) Multiple barriers to women’s health training exist. PMID:21267780

  20. Family and Provider/Teacher Relationship Quality: Director Measure

    Science.gov (United States)

    Administration for Children & Families, 2015

    2015-01-01

    The director measure is intended for use with program directors in center-based, family child care, and Head Start/Early Head Start settings for children from birth through five years old. This measure asks respondents general questions about the early childhood education environment, the children enrolled in the program, and how the program…

  1. Do Director Networks Help Manager Plan and Forecast Better?

    NARCIS (Netherlands)

    Schabus, M.

    I examine whether directors' superior access to information and resources through their board network improves the quality of firms' planning and forecasting. Managers may benefit from well-connected directors as, even though managers have firm specific knowledge, they may have only limited insight

  2. Veterinary Technician Program Director Leadership Style and Program Success

    Science.gov (United States)

    Renda-Francis, Lori A.

    2012-01-01

    Program directors of American Veterinary Medical Association (AVMA) accredited veterinary technician programs may have little or no training in leadership. The need for program directors of AVMA-accredited veterinary technician programs to understand how leadership traits may have an impact on student success is often overlooked. The purpose of…

  3. 7 CFR 2.36 - Director, Office of Communications.

    Science.gov (United States)

    2010-01-01

    ... are made by the Secretary of Agriculture to Director, Office of Communications: (1) Related to public...) Organize and direct the activities of a public affairs office to include press relations of the secretary... 7 Agriculture 1 2010-01-01 2010-01-01 false Director, Office of Communications. 2.36 Section 2.36...

  4. 50 CFR 11.13 - Decision by the Director.

    Science.gov (United States)

    2010-10-01

    ... 50 Wildlife and Fisheries 1 2010-10-01 2010-10-01 false Decision by the Director. 11.13 Section 11..., POSSESSION, TRANSPORTATION, SALE, PURCHASE, BARTER, EXPORTATION, AND IMPORTATION OF WILDLIFE AND PLANTS CIVIL PROCEDURES Assessment Procedure § 11.13 Decision by the Director. Upon expiration of the period required or...

  5. Food Recall Attitudes and Behaviors of School Nutrition Directors

    Science.gov (United States)

    Grisamore, Amber; Roberts, Kevin R.

    2014-01-01

    Purpose/Objectives: The purpose of this study was to explore school nutrition directors' attitudes and behaviors about food recalls. Specific objectives included: 1) Determine current food recall attitudes and the relationship between demographics and these attitudes; 2) Determine current practices of school nutrition directors related to…

  6. 78 FR 69927 - SJI Board of Directors Meeting, Notice

    Science.gov (United States)

    2013-11-21

    ... STATE JUSTICE INSTITUTE SJI Board of Directors Meeting, Notice AGENCY: State Justice Institute. ACTION: Notice of meeting. SUMMARY: The SJI Board of Directors will be meeting on Monday, December 9, 2013 at 1:00 p.m. The meeting will be held at the 9th Judicial Circuit of Florida in Orlando, Florida...

  7. The Managerial Roles of Academic Library Directors: The Mintzberg Model.

    Science.gov (United States)

    Moskowitz, Michael Ann

    1986-01-01

    A study based on a model developed by Henry Mintzberg examined the internal and external managerial roles of 126 New England college and university library directors. Survey results indicate that the 97 responding directors were primarily involved with internal managerial roles and work contacts. (CDD)

  8. Continuous director-field transformation of nematic tactoids

    NARCIS (Netherlands)

    Prinsen, P.; Schoot, van der P.P.A.M.

    2004-01-01

    We theoretically investigate the director field inside spindle-shaped nematic droplets, known as tactoids. Tactoids typically form in dispersions of rod-like colloidal particles. By optimising the bulk elastic and surface energies, we find that the director field crosses over smoothly from a

  9. Examining the concept of de facto director in corporate governance

    Directory of Open Access Journals (Sweden)

    Anthony O. Nwafor

    2016-07-01

    Full Text Available There are different categories of persons involved in the execution of the company’s affairs, but not all have the capacity to bind the company as the embodiment of the company itself. Those who exercise acts of management and control over the company’s business are usually referred to as the directors. Where persons who satisfy the statutorily prescribed qualification standard are duly appointed by the shareholders to exercise control and manage the affairs of the company function in that capacity, they are usually identified as de jure directors. But where there is no such appointment, or irregular appointment, the law demands, for the protection of those dealing with the company, that the role performed by the person be examined to ascertain whether such a person is a de facto director. The more difficult part lies in identifying a de facto director where the subject company has a corporate body as its director. The extant judicial authority suggests that the human person in the corporate director must be performing functions which are beyond the natural call of duty in relation to the corporate director to constitute a de facto director of the subject company. The paper argues that the standard is satisfied in any case where the human person is involved in the initiation and execution of the affairs of the subject company, and more so where the conducts of the subject company are patently unlawful.

  10. 76 FR 58303 - Regular Board of Directors Meeting; Sunshine Act

    Science.gov (United States)

    2011-09-20

    ..., Washington, DC 20005. STATUS: Open. CONTACT PERSON FOR MORE INFORMATION: Erica Hall, Assistant Corporate... Directors Minutes III. Approval of the Special Board of Directors Minutes IV. Approval of the Corporate Administration Committee Minutes V. Approval of the Finance, Budget and Program Committee Minutes VI. Approval of...

  11. 19 CFR 146.2 - Port director as Board representative.

    Science.gov (United States)

    2010-04-01

    ...; DEPARTMENT OF THE TREASURY (CONTINUED) FOREIGN TRADE ZONES General Provisions § 146.2 Port director as Board representative. The appropriate port director shall be in charge of the zone as the representative of the Board. [T.D. 86-16, 51 FR 5049, Feb. 11, 1986, as amended by T.D. 99-27, 64 FR 13676, Mar. 22, 1999] ...

  12. Creating the Vision: Directors Don't Do It Alone.

    Science.gov (United States)

    Carlisle, Barbara; Drapeau, Don

    1997-01-01

    Argues that good directors are not as autocratic and individualistic as they are often portrayed. Suggests that theater is much more of an ensemble effort. States that good theater grows out of the performers' desire to reach the audience. Articulates guidelines for the teacher or theater director who wishes to change "I" to…

  13. CEA nuclear energy Directorate - Activity report 2012

    International Nuclear Information System (INIS)

    2013-01-01

    After an overview of the activities of the Directorate at the international level, of its scientific activities, and of the consideration given to quality, and a presentation of the transverse program on advanced materials, this report proposes presentations of activities in different domains: future nuclear industrial systems (reactors of 4. generation, back-end of the future cycle, sustainable management of nuclear materials, fundamental scientific and technological research), optimization of the present industrial nuclear activity (reactors of 2. and 3. generation, front-end and back-end of the fuel cycle), the main tools for nuclear development (numerical simulation, the Jules Horowitz reactor), valorisation, economic support of Haute-Marne and Meuse territories (the Syndiese project), nuclear dismantling and decontamination (dismantling projects, projects and works in Fontenay-aux-Roses, Grenoble and Saclay, waste and material flow management, nuclear service facilities, transports). It also presents the activities of some specific CEA centres like Marcoule (R and D in fuel cycle), Cadarache (future energies) and Saclay (nuclear sciences and simulation of reactors and fuel cycle)

  14. JSC Director's Discretionary Fund 1992 Annual Report

    Science.gov (United States)

    Jenkins, Lyle (Compiler)

    1993-01-01

    Annual report of the Johnson Space Center Director's Discretionary Fund documenting effective use of resources. The $1,694,000 funding for FY92 was distributed among 27 projects. The projects are an overall aid to the NASA mission, as well as providing development opportunities for the science and engineering staff with eventual spinoff to commercial uses. Projects described include space-based medical research such as the use of stable isotopes of deuterium and oxygen to measure crew energy use and techniques for noninvasive motion sickness medication. Recycling essentials for space crew support is conducted in the Regenerative Life Support and the Hybrid Regenerative Water Recovery test beds. Two-phase fluid flow simulated under low-gravity conditions, hypervelocity particle impact on open mesh bumpers, and microcalorimetry to measure the long-term hydrazine/material compatibility were investigated. A patent application was made on a shape-memory-alloy release nut. Computer estimate of crew accommodations for advanced concepts was demonstrated. Training techniques were evaluated using multimedia and virtual environment. Upgrades of an electronic still camera provide high resolution images from orbit are presented.

  15. What skills should new internal medicine interns have in july? A national survey of internal medicine residency program directors.

    Science.gov (United States)

    Angus, Steven; Vu, T Robert; Halvorsen, Andrew J; Aiyer, Meenakshy; McKown, Kevin; Chmielewski, Amy F; McDonald, Furman S

    2014-03-01

    The transition from medical student to intern may cause stress and burnout in new interns and the delivery of suboptimal patient care. Despite a formal set of subinternship curriculum guidelines, program directors have expressed concern regarding the skill set of new interns and the lack of standardization in that skill set among interns from different medical schools. To address these issues, the Accreditation Council for Graduate Medical Education's Next Accreditation System focuses on the development of a competency-based education continuum spanning undergraduate, graduate, and continuing medical education. In 2010, the Clerkship Directors in Internal Medicine subinternship task force, in collaboration with the Association of Program Directors in Internal Medicine survey committee, surveyed internal medicine residency program directors to determine which competencies or skills they expected from new medical school graduates. The authors summarized the results using categories of interest. In both an item rank list and free-text responses, program directors were nearly uniform in ranking the skills they deemed most important for new interns-organization and time management and prioritization skills; effective communication skills; basic clinical skills; and knowing when to ask for assistance. Stakeholders should use the results of this survey as they develop a milestone-based curriculum for the fourth year of medical school and for the internal medicine subinternship. By doing so, they should develop a standardized set of skills that meet program directors' expectations, reduce the stress of transitions across the educational continuum, and improve the quality of patient care.

  16. The long-term benefits of director stock ownership

    Directory of Open Access Journals (Sweden)

    Brian Bolton

    2009-11-01

    Full Text Available In October 2009, the United States Treasury Department and Congress considered new regulations requiring executives and directors to receive much of their compensation in the form of long-term stock. One concern with this is that it may have negative consequences by entrenching managers and directors over the long term. This study compares the potential benefits of long-term director ownership with the potential costs of entrenchment. Using the dollar amount of stock owned by independent directors, the results suggest that the incentive effect dominates any costs related to entrenchment: firms with greater stock ownership outperform other firms, regardless of the degree of managerial entrenchment that may be present. The implication for policy-makers is that providing directors with incentives through stock ownership can be a very effective corporate governance mechanism.

  17. Director Experience and the Performance of IPOs: Evidence from Sweden

    Directory of Open Access Journals (Sweden)

    Anders Isaksson

    2014-03-01

    Full Text Available private to public. In this paper the experience of directors is examined to determine the extent of the role they play in ensuring a successful listing. Unique data from 122 IPOs on the Swedish Stock Exchange have been examined in a search for the effect of director experience on aftermarket performance. Specific aspects of director experience within a board, such as interlocking directorships and average tenure, are connected to the underpricing of Swedish IPOs. Contrary to expectations, no statistically significant relationship was found between long-run aftermarket performance and director experience at the time of an IPO. This suggests that the previous experience of directors, as measured in earlier studies, is less relevant to long-term aftermarket performance in Sweden compared to other countries studied in the literature review. This emphasises the importance of examining different institutional contexts.

  18. Characteristics of CEOs and corporate boards with women inside directors

    Directory of Open Access Journals (Sweden)

    Deborah Dahlen Zelechowski

    2006-07-01

    Full Text Available Women corporate inside (executive directors constitute an elite minority of leaders of large corporations. This study examines the characteristics of CEOs and boards of Fortune 1000 firms that had women who held the dual leadership positions of corporate director and executive officer in 1998 in order to determine whether firms with women insiders had substantially different characteristics than firms without. We find that compared with firms without women inside directors, firms with women inside directors were characterized by CEOs with longer board tenure, more family ties, and fewer director interlocks, and by boards that were larger, with more insiders, and that utilize a management Chair of the board. Corporate governance implications are drawn for the presence of women at the top of the executive hierarchy.

  19. Auditor’s Risk Assessment of Independent Directors in Nigeria

    Directory of Open Access Journals (Sweden)

    Salau Abdulmalik

    2017-01-01

    Full Text Available The objective of this study is to investigate the external auditor’s risk assessment of independent directors in Nigeria. The study utilized data from 94 non-financial listed companies on the Nigerian Stock Exchange for the periods 2008-2013. The study used cross-sectional time-series feasible generalized least square regression, which account for heteroscedasticity and autocorrelation to test the influence independent non-executive director on auditor pricing decision in Nigeria. Our result indicates that the proportion of independent non-executive director has a positive relationship with audit fees, suggesting that this class of directors is priced high by the Nigerian auditors. These findings have both policy and practical implication on corporate governance. For instance, future regulatory reforms could consider collaborative board model instead of the insistence on more independent director presence in the boardroom.

  20. Five-Year Data of Clinical Characteristics and Laboratory Findings of Hospitalized Hemophilic Patients in Dr. Hasan Sadikin General Hospital

    Directory of Open Access Journals (Sweden)

    Dina Marlina

    2016-12-01

    Full Text Available Background: Hemophilia A has the highest incidence, more than 80% of 172.323 cases worldwide in 2012. It is stated that clinical characteristics of hemophilia A is worse than others, so it is required to prove and to know further about the clinical characteristics and severity likelihood in all hemophilic patients in order to prevent re-bleeding and re-injury and also for a better medical response. Methods: A retrospective cross-sectional study was carried out to 43 medical records of hospitalized hemophilic patients from 2009 to 2013 in Dr Hasan Sadikin General Hospital. The inclusion criteria were a complete patient identity (name, age, sex, written chief complaint, complete physical examination (bleeding, edema, hematoma, hemarthrosis, anemic symptoms and laboratory test results (factor level, hemoglobin, hematocrit, platelet and Activated Partial Thromboplastin Time. The data was collected from August‒October 2014, analyzed and presented using frequency distribution. Results: Most of the patients were 5-10 years old, male and had hemophilia A. The most common complaint was external bleeding, followed by edema. From 43 patients, 38 (88% cases were classified as severe factor deficiency, had mild to severe anemia, however the platelet count in most of the cases was in normal value. About 91% cases had prolonged Activated Partial Thromboplastin Time in moderate to severe level. Conclusions: Similar with other studies worldwide, most of the hospitalized hemophilic patients have hemophilia A. Most of the patents has moderate to severe bleeding with laboratory test result between moderate to severe level as well.

  1. Germ-line origins of mutation in families with hemophilia B: The sex ratio varies with the type of mutation

    Energy Technology Data Exchange (ETDEWEB)

    Ketterling, R.P.; Vielhaber, E.; Bottema, C.D.K.; Schaid, D.J.; Sommer, S.S. (Mayo Clinic/Foundation, Rochester, MN (United States)); Cohen, M.P. (Vanderbilt Univ., Nashville, TN (United States)); Sexauer, C.L. (Children' s Hospital, Oklahoma City, OK (United States))

    1993-01-01

    Previous epidemiological and biochemical studies have generated conflicting estimates of the sex ratio of mutation. Direct genomic sequencing in combination with haplotype analysis extends previous analyses by allowing the precise mutation to be determined in a given family. From analysis of the factor IX gene of 260 consecutive families with hemophilia B, the authors report the germ-line origin of mutation in 25 families. When combined with 14 origins of mutation reported by others and with 4 origins previously reported by them, a total of 25 occur in the female germ line, and 18 occur in the male germ line. The excess of germ-line origins in females does not imply an overall excess mutation rate per base pair in the female germ line. Bayesian analysis of the data indicates that the sex ratio varies with the type of mutation. The aggregate of single-base substitutions shows a male predominance of germ-line mutations (P < .002). The maximum-likelihood estimate of the male predominance is 3.5-fold. Of the single-base substitutions, deletions display a sex ratio of unity. Analysis of the parental age at transmission of a new mutation suggests that germ-line mutations are associated with a small increase in parental age in females but little, if any, increase in males. Although direct genomic sequencing offers a general method for defining the origin of mutation in specific families, accurate estimates of the sex ratios of different mutational classes require large sample sizes and careful correction for multiple biases of ascertainment. The biases in the present data result in an underestimate of the enhancement of mutation in males. 62 refs., 1 fig., 5 tabs.

  2. Somatic mosaicism in families with hemophilia B: 11% of germline mutations originate within a few cell divisions post-fertilization

    Energy Technology Data Exchange (ETDEWEB)

    Knoell, A.; Ketterling, R.P.; Vielhaber, E. [Mayo Clinic/Foundation, Rochester, MN (United States)] [and others

    1994-09-01

    Previous molecular estimates of mosaicism in the dystrophin and other genes generally have focused on the transmission of the mutated allele to two or more children by an individual without the mutation in leukocyte DNA. We have analyzed 414 families with hemophilia B by direct genomic sequencing and haplotype analysis, and have deduced the origin of mutation in 56 families. There was no origin individual who transmitted a mutant allele to more than one child. However, somatic mosaicism was detected by sequence analysis of four origin individuals (3{female} and 1{male}). The sensitivity of this analysis is typically one part in ten. In one additional female who had close to a 50:50 ratio of mutant to normal alleles, three of four noncarrier daughters inherited the haplotype associated with the mutant allele. This highlights a caveat in molecular analysis: a presumptive carrier in a family with sporadic disease does not necessarily have a 50% probability of transmitting the mutant allele to her offspring. After eliminating those families in which mosaicism could not be detected because of a total gene deletion or absence of DNA from a deduced origin individual, 5 of 43 origin individuals exhibited somatic mosaicism at a level that reflects a mutation within the first few cell divisions after fertilization. In one patient, analysis of cervical scrapings and buccal mucosa confirm the generalized distribution of somatic mutation. Are the first few cell divisions post-fertilization highly mutagenic, or do mutations at later divisions also give rise to somatic mosaicism? To address this question, DNA from origin individuals are being analyzed to detect somatic mosaicism at a sensitivity of 1:1000. Single nucleotide primer extension (SNuPE) has been utilized in eight families to date and no mosaicism has been detected. When the remaining 30 samples are analyzed, it will be possible to compare the frequency of somatic mosaicism at 0.1-10% with that of {ge}10%.

  3. Limited protective effect of the CCR5Δ32/CCR5Δ32 genotype on human immunodeficiency virus infection incidence in a cohort of patients with hemophilia and selection for genotypic X4 virus

    DEFF Research Database (Denmark)

    Iversen, Astrid K. N.; Christiansen, Claus Bohn; Attermann, Jørn

    2003-01-01

    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 CCR5Δ32/CCR5Δ32 genotype (which occurs in ∼2% of the Scandinavian population...

  4. SOME CONSIDERATIONS REGARDING THE REVOCATION OF THE COMPANY DIRECTOR

    Directory of Open Access Journals (Sweden)

    Cristina Cojocaru

    2013-11-01

    Full Text Available In principle, in Romania, according to current regulations, the director of a company can not address the court against the decision of the general meeting of shareholders through which he/she was revoked from his/her position, regardless of the reasons for the revocation. However, if the director is also the shareholder of that company, he/she may appeal the decision of the general meeting of shareholders, for other reasons than the revocation itself. This is the case even if, by that decision of the general meeting of shareholders it has been decided, inter alia, the revocation of the director. Also, the laws of Romania stipulate that the revoked director has the possibility to claim in court damages if he/she fulfilled correctly the duties as director of the company. At the same time, the article looks at the concept of director, his/her relations with the company and the revocation of the director as general concept.

  5. Plant-based oral tolerance to hemophilia therapy employs a complex immune regulatory response including LAP+CD4+ T cells.

    Science.gov (United States)

    Wang, Xiaomei; Su, Jin; Sherman, Alexandra; Rogers, Geoffrey L; Liao, Gongxian; Hoffman, Brad E; Leong, Kam W; Terhorst, Cox; Daniell, Henry; Herzog, Roland W

    2015-04-09

    Coagulation factor replacement therapy for the X-linked bleeding disorder hemophilia is severely complicated by antibody ("inhibitor") formation. We previously found that oral delivery to hemophilic mice of cholera toxin B subunit-coagulation factor fusion proteins expressed in chloroplasts of transgenic plants suppressed inhibitor formation directed against factors VIII and IX and anaphylaxis against factor IX (FIX). This observation and the relatively high concentration of antigen in the chloroplasts prompted us to evaluate the underlying tolerance mechanisms. The combination of oral delivery of bioencapsulated FIX and intravenous replacement therapy induced a complex, interleukin-10 (IL-10)-dependent, antigen-specific systemic immune suppression of pathogenic antibody formation (immunoglobulin [Ig] 1/inhibitors, IgE) in hemophilia B mice. Tolerance induction was also successful in preimmune mice but required prolonged oral delivery once replacement therapy was resumed. Orally delivered antigen, initially targeted to epithelial cells, was taken up by dendritic cells throughout the small intestine and additionally by F4/80(+) cells in the duodenum. Consistent with the immunomodulatory responses, frequencies of tolerogenic CD103(+) and plasmacytoid dendritic cells were increased. Ultimately, latency-associated peptide expressing CD4(+) regulatory T cells (CD4(+)CD25(-)LAP(+) cells with upregulated IL-10 and transforming growth factor-β (TGF-β) expression) as well as conventional CD4(+)CD25(+) regulatory T cells systemically suppressed anti-FIX responses. © 2015 by The American Society of Hematology.

  6. Suppression of inhibitor formation against FVIII in a murine model of hemophilia A by oral delivery of antigens bioencapsulated in plant cells.

    Science.gov (United States)

    Sherman, Alexandra; Su, Jin; Lin, Shina; Wang, Xiaomei; Herzog, Roland W; Daniell, Henry

    2014-09-04

    Hemophilia A is the X-linked bleeding disorder caused by deficiency of coagulation factor VIII (FVIII). To address serious complications of inhibitory antibody formation in current replacement therapy, we created tobacco transplastomic lines expressing FVIII antigens, heavy chain (HC) and C2, fused with the transmucosal carrier, cholera toxin B subunit. Cholera toxin B-HC and cholera toxin B-C2 fusion proteins expressed up to 80 or 370 µg/g in fresh leaves, assembled into pentameric forms, and bound to GM1 receptors. Protection of FVIII antigen through bioencapsulation in plant cells and oral delivery to the gut immune system was confirmed by immunostaining. Feeding of HC/C2 mixture substantially suppressed T helper cell responses and inhibitor formation against FVIII in mice of 2 different strain backgrounds with hemophilia A. Prolonged oral delivery was required to control inhibitor formation long-term. Substantial reduction of inhibitor titers in preimmune mice demonstrated that the protocol could also reverse inhibitor formation. Gene expression and flow cytometry analyses showed upregulation of immune suppressive cytokines (transforming growth factor β and interleukin 10). Adoptive transfer experiments confirmed an active suppression mechanism and revealed induction of CD4(+)CD25(+) and CD4(+)CD25(-) T cells that potently suppressed anti-FVIII formation. In sum, these data support plant cell-based oral tolerance for suppression of inhibitor formation against FVIII. © 2014 by The American Society of Hematology.

  7. Long-term correction of canine hemophilia B by gene transfer of blood coagulation factor IX mediated by adeno-associated viral vector.

    Science.gov (United States)

    Herzog, R W; Yang, E Y; Couto, L B; Hagstrom, J N; Elwell, D; Fields, P A; Burton, M; Bellinger, D A; Read, M S; Brinkhous, K M; Podsakoff, G M; Nichols, T C; Kurtzman, G J; High, K A

    1999-01-01

    Hemophilia B is a severe X-linked bleeding diathesis caused by the absence of functional blood coagulation factor IX, and is an excellent candidate for treatment of a genetic disease by gene therapy. Using an adeno-associated viral vector, we demonstrate sustained expression (>17 months) of factor IX in a large-animal model at levels that would have a therapeutic effect in humans (up to 70 ng/ml, adequate to achieve phenotypic correction, in an animal injected with 8.5x10(12) vector particles/kg). The five hemophilia B dogs treated showed stable, vector dose-dependent partial correction of the whole blood clotting time and, at higher doses, of the activated partial thromboplastin time. In contrast to other viral gene delivery systems, this minimally invasive procedure, consisting of a series of percutaneous intramuscular injections at a single timepoint, was not associated with local or systemic toxicity. Efficient gene transfer to muscle was shown by immunofluorescence staining and DNA analysis of biopsied tissue. Immune responses against factor IX were either absent or transient. These data provide strong support for the feasibility of the approach for therapy of human subjects.

  8. U.S. Senate confirms new USGS director

    Science.gov (United States)

    Showstack, Randy

    Shortly before adjourning in October, the U.S. Senate confirmed Charles Groat as the new director of the U.S. Geological Survey. Interior Secretary Bruce Babbitt is expected to swear him in shortly as the agency's 13th director. Groat takes over from Thomas Casadevall, who has served as acting director since Gordon Eaton resigned in September 1997.Groat, an AGU member, has more than 25 years of experience in the Earth science fields, including energy and minerals resource assessment, groundwater occurrence and protection, geomorphic processes and landform evolution in desert areas, and coastal studies.

  9. Hemophilia care in the state of Rio de Janeiro, Brazil El tratamiento de la hemofilia en el estado de Rio de Janeiro, Brasil

    Directory of Open Access Journals (Sweden)

    Eva M. A. Fontes

    2003-03-01

    Full Text Available In the developing countries of the world, few people with hemophilia receive adequate care. Nevertheless, Brazil has made significant advances in the treatment of hemophilia over the last decade. The provision of factor concentrates imported by the Government of Brazil is gradually increasing, and patients receive the concentrates for free. A national register was established as well as a coordinated program for comprehensive care. Of the 6 297 persons with hemophilia in Brazil who were registered as of January 2001, 689 of them (11.1% were registered in the state of Rio de Janeiro. Of those 689, 664 of them were being monitored at the state's coordinating blood transfusion center, which is located in the city of Rio de Janeiro. Among those 664, factor VIII inhibitors were identified in 81 of them (12.2%. Among 653 of the Rio de Janeiro patients who were tested for transfusion-transmitted diseases, the overall prevalence found was 41.5%, with the specific rates being 13.3% for human immunodeficiency virus (HIV, 2.9% for hepatitis B virus (HBV, and 39.4% for hepatitis C virus (HCV. The state of Rio de Janeiro has adopted a comprehensive hemophilia management approach that includes medical, psychological, and social care. As a result, the quality of life of hemophilia patients has improved noticeably. For example, the rate of hospitalization among patients fell by 30% between 1998 and 2001, and there has also been a decline in the school and work activities that they have missed.En los países en desarrollo, pocas personas con hemofilia reciben un tratamiento adecuado. No obstante, el Brasil ha logrado grandes avances en este sentido en el último decenio. La provisión de concentrados de factores de la coagulación importados por el gobierno de Brasil va aumentando gradualmente y los pacientes reciben el concentrado gratis. Un registro nacional se estableció junto con un programa coordinado de atención global. De las 6 297 personas con

  10. IAEA Director General to visit Libya

    International Nuclear Information System (INIS)

    2003-01-01

    reverse course is a positive development and a step in the right direction. I hope that through verification, dialogue and active engagement, all questions related to Libya's nuclear programme can be resolved and the required corrective actions taken.' The Director General added, 'This latest revelation confirms the need, in parallel with the peace process in the Middle East, for a security dialogue that aims to establish as part and parcel of the peace settlement a sustainable security structure that inter alia turns the Middle East into a zone free from nuclear and other weapons of mass destruction.' (IAEA)

  11. Views of surgery program directors on the current ACGME and proposed IOM duty-hour standards.

    Science.gov (United States)

    Willis, Ross E; Coverdill, James E; Mellinger, John D; Collins, J Craig; Potts, John R; Dent, Daniel L

    2009-01-01

    The purpose of this study was to survey the experiences of surgery program directors with the current Accreditation Council for Graduate Medical Education (ACGME) duty-hour standards and views of the Institute of Medicine (IOM) proposed duty-hour recommendations. A total of 118 program directors (47.6% of all surgery programs in the US) responded to the survey. Results showed that the current duty-hour standards have hindered clinical education opportunities by reducing or eliminating rotations on many services, didactic teaching conferences, and clinical bedside teaching opportunities. Additionally, patient safety has been compromised by frequent hand offs of care. Most IOM recommendations were perceived as extremely difficult or impossible to implement, with the exception of the moonlighting recommendation. The results indicated that adopting the IOM recommendations is not feasible given current workforce limitations, and most program directors supported maintaining the current duty-hour standards until such time as there is evidence-based outcomes research to direct change. The conclusion was that the current ACGME duty-hour standards have reduced teaching opportunities and narrowed the scope of training.

  12. Accelerating medical education: a survey of deans and program directors

    Directory of Open Access Journals (Sweden)

    Joan Cangiarella

    2016-06-01

    Full Text Available Background: A handful of medical schools in the U.S. are awarding medical degrees after three years. While the number of three-year pathway programs is slowly increasing there is little data on the opinions of medical education leaders on the need for shortening training. Purpose: To survey deans and program directors (PDs to understand the current status of 3-year medical degree programs and to elicit perceptions of the need for shortening medical school and the benefits and liabilities of 3-year pathway programs (3YPP. Methods: Online surveys were emailed to the academic deans of all U.S. medical schools and to a convenience sample of residency and fellowship PDs. Frequency distributions are reported for key survey items and content analysis was used to describe open-ended responses. Results: Of the respondents, 7% have a 3YPP, 4% were developing one, and 35% were considering development. In 2014, 47% of educational deans and 32% of PDs agreed that there may be a need to shorten medical school. From a list of benefits, both deans and PDs agreed that the greatest benefit to a 3YPP was debt reduction (68%. PDs and deans felt reduced readiness for independence, reduced exposure to complementary curricula regarding safety and quality improvement, premature commitment to a specialty, and burnout were all potential liabilities. From a list of concerns, PDs were concerned about depth of clinical exposure, direct patient care experience, ability to assume increased responsibility, level of maturity, and certainty regarding career choice. Conclusions: Over one-third of medical schools are considering the development of a 3YPP. While there may be benefits for a select group of students, concerns regarding maturity, depth of clinical exposure, and competency must be addressed for these programs to be well received.

  13. Antibiotic prophylaxis for children with sickle cell disease: a survey of pediatric dentistry residency program directors and pediatric hematologists.

    Science.gov (United States)

    Tate, Anupama Rao; Norris, Chelita Kaye; Minniti, Caterina P

    2006-01-01

    The purposes of this study were to: (1) investigate the current clinical practice regarding the use of antibiotic prophylaxis by pediatric dentistry residency program directors and pediatric hematologists for children with sickle cell disease (SCD) requiring dental treatment; and (2) evaluate the perceived relative risk of bacteremia following specific dental procedures, as defined by pediatric dentistry residency program directors and pediatric hematologists. A written survey depicting various clinical scenarios of SCD children requiring common dental procedures was mailed to directors of pediatric dental advanced education programs and distributed to pediatric hematologists attending the 2003 Annual Sickle Cell Disease Association of America conference in Washington, DC. Surveys were returned by 60% (N=34/57) of the pediatric dentistry residency program directors. The surveys were obtained from 51% of pediatric hematologists at the meeting (N=72/140). At least 50% of all respondents recommended prophylaxis for the following clinical situations: dental extractions, treatment under general anesthesia, and status post splenectomy. The perceived risk of infectious complication was highest for extractions, followed by restorative treatment and tooth polishing. Dental residency program directors were more likely (71%, N=24/34) to recommend additional antibiotic therapy for patients taking penicillin prophylaxis if they required an invasive oral surgical procedure. Conversely, only 38% (N=25/66) of pediatric hematologists recommended additional antibiotic therapy (P=.001). Eighty-six percent of dental residency program directors (N=25/29) chose amoxicillin for prophylaxis whereas only 62% of pediatric hematologists (N=36/58) recommended amoxicillin. (Pchildren undergoing dental treatments. Further research and risk/benefit assessment is needed to create a unified approach.

  14. REP activities of the conference of radiation control program directors

    International Nuclear Information System (INIS)

    Bevill, B.

    1995-01-01

    This talk provides an overview of the activities within the Conference of Radiation Control Program Directors associated with Radiological Emergency Preparedness. Included are summaries of interactions with FEMA, with US DOE, with US FDA, and with US DOT

  15. Board Directors' Selection Process Following a Gender Quota

    DEFF Research Database (Denmark)

    Sigurjonsson, Olaf; Arnardottir, Audur Arna

    -quota selection of new board directors as well as the attitudes of board members towards the quota and perceptions of the effect of quota on processes. We incorporate a dual qualitative and quantitative methodology with in-depth interviews with 20 board directors and chairs, and a survey of 260 directors who...... companies with 50 or more employees. Thereby legislatively going further than any other country, out of the fifteen that have amended and adopted gender quota legislation. This article utilizes resource dependency and status expectations theory lenses to explore how the new legislation affected the post...... conviction. Furthermore, there are different avenues to the board. Although initial attitudes towards quotas are more negative among men than women, these attitudes decrease over time. Finally, consistent with status expectation theory, male directors are more negative than their female counterparts about...

  16. Dr. William C. Harris, Director-General, Science Foundation Ireland

    CERN Multimedia

    Maximilien Brice

    2002-01-01

    Pictured with Robert Eisenstein, former assistant director for mathematical and physical sciences (MPS) at the US National Science Foundation (NSF), who is spending a year at CERN as a member of the ATLAS collaboration.

  17. 12 CFR 611.210 - Director qualifications and training.

    Science.gov (United States)

    2010-01-01

    ... periodically updated and provided to the institution's nominating committee. (2) Each Farm Credit institution... advisor who is a financial expert. The financial advisor must report to the board of directors and be free...

  18. Llewellyn Smith, Director-General designate of CERN, discusses LHC

    CERN Multimedia

    Sweet, William N

    1992-01-01

    Christopher Llewellyn Smith was nominated by the Committee of Council to be Director General of CERN. He aims to pave the way for the Large Hadron Collider and utilize to the full the Large Electron-Positron machine.

  19. CERN stop-over for KEK and Fermilab Directors

    CERN Multimedia

    2001-01-01

    En route for a meeting of the International Committee for Future Accelerators, ICFA, held at Germany's DESY laboratory, the Directors of Japan's KEK laboratory and Fermilab in the United States had a stop-over at CERN last Wednesday 7 February. Dr Hirotaka Sugawara, Director General of Japan's high energy physics laboratory, KEK, visited the Antiproton Decelerator, AD. From left to right, Masaki Hori, member of the ASACUSA collaboration, John Eades, contact person for ASACUSA, Dr Hirotaka Sugawara, Werner Pirkl, the PS Division engineer responsible for the Radio Frequency Quadrupole decelerator in the foreground, and Kurt Hübner, CERN's Director of Accelerators. Dr Michael S. Witherell, Director of the Fermi National Accelerator Laboratory, Fermilab, visited construction sites for the LHC, ATLAS, and CMS. He is seen here with a module of the CMS hadronic calorimeter in building 186.

  20. Juan Antonio Rubio appointed as Director-General of CIEMAT

    CERN Multimedia

    2004-01-01

    Juan Antonio Rubio, Head of CERN's ETT unit (Education and Technology Transfer) has been appointed by the Spanish Ministry of Education and Science as the Director General of the Research Centre for Energy, Environment and Technology, CIEMAT. Dr Rubio's career began at the Spanish Nuclear Energy Commission where he held the posts of Investigator, Head of the High Energy Group and Head of Nuclear Physics and High Energy Division. Later, he was named Director of the Department of Basic Investigation and Scientific Director of the CIEMAT. In 1987 he joined CERN as Scientific Adviser to the Director General and Group Leader of the Scientific Assessment Group. Up to now, Dr Rubio has been the Head of the ETT unit, as well as Coordinator for Latin America and Commissioner for the 50th Anniversary of the Organization. He was born on 4 June 1944 in Madrid, and holds a Doctorate in Physical Sciences from the Universidad Complutense de Madrid.

  1. 22 CFR 67.2 - Board of Directors.

    Science.gov (United States)

    2010-04-01

    ..., Washington, DC 20005-5000. (b) All major policy and funding decisions are made by the Board of Directors. The primary statement of NED's operating philosophy, general principles and priorities is contained in the...

  2. Female Directors and Firm Performance: Evidence from UK Listed Firms

    Directory of Open Access Journals (Sweden)

    Pananda Pasaribu

    2017-08-01

    Full Text Available The impact of female directors on firm performance has lacked consistency in the previously conducted empirical studies, which may be due to the endogeneity problem, or certain characteristics (i.e. governance, industry, competition. This study examines the relationship between female directors and firm performance by addressing those problems. This study analyses all non-financial UK listed firms during the period 2004-2012 and employs several econometric models. The regression results indicate that there is little evidence that female directors have a positive and strong relationship with firm performance. But, further analysis reports that the UK’s small listed firms experience a positive significant effect, because small firms do not suffer from the problem of over-monitoring and they have more flexibility in composing their boards of directors.

  3. Thomas Sinks, Director, Office of the Science Advisor

    Science.gov (United States)

    Biography of the Director of the Office of the Science Advisor which is responsible for is responsible for EPA’s human subject research ethics, scientific integrity, and developing cross-agency science policy guidance.

  4. Institute for Advanced Learning and Research names new executive director

    OpenAIRE

    Virginia Tech News

    2008-01-01

    Virginia Tech's Institute for Advanced Learning and Research has named Liam E. Leightley as executive director, effective Oct. 6, 2008, according to Mike Henderson, chair of the institute's board of trustees.

  5. NREL Manager Elected to IREC Board of Directors

    Science.gov (United States)

    Manager Elected to IREC Board of Directors For more information contact: Sarah Holmes Barba, 303 -275-3023 email: Sarah Barba Golden, Colo., May 14, 2001 - David Warner, manager of the Information and

  6. Creative director as a leader El director como líder creativo

    Directory of Open Access Journals (Sweden)

    Paulo Felipe Quintero

    2011-12-01

    Full Text Available The current organizational dynamic in the world places universities in a relevant role to be performed in the society. Hence, the concept of “creativity” is studied from the hierarchical levels to understand the implications of completing creative processes within an organization. The creativity in the universities require management plans, which demand effort from strategic leaders to materialize and make the mission tangible to all involved actors in the organization; thus, facilitating the achievement of financial quality results, impact on entrepreneurial spirit and optimal labor climate. Subsequently, the creativity could become a strategic topic in the institutional development plans for the directors. This article shows the theoretical construction of the research Creative Abilities of Private Universities Directors in Manizales and the Relation with the Organizational Climate.La dinámica actual de las organizaciones en el mundo, pone a las universidades en unlugar relevante frente al papel que deben desempeñar en la sociedad. En este sentido, seaborda el concepto de “creatividad” tan de moda en el escenario actual, desde los nivelesjerárquicos, con el fin de entender lo que verdaderamente implica llevar a cabo procesoscreativos en una organización. La creatividad en las universidades requiere mucho másque metas en planes de gestión. Exige un esfuerzo de los líderes estratégicos, para quela misión no se quede en el papel y sea tangible para todos los actores involucradosen la empresa, y de esa manera sea el vehículo para lograr resultados de calidad en lofinanciero, impactos en el espíritu empresarial y ambientes de trabajo óptimos, de modoque la creatividad se convierta para los directores en un tema estratégico en los planesde desarrollo institucional para la excelencia en los climas de trabajo. El presente artículoresultó de la construcción teórica del trabajo de investigación

  7. Circumventing furin enhances factor VIII biological activity and ameliorates bleeding phenotypes in hemophilia models

    OpenAIRE

    Siner, Joshua I.; Samelson-Jones, Benjamin J.; Crudele, Julie M.; French, Robert A.; Lee, Benjamin J.; Zhou, Shanzhen; Merricks, Elizabeth; Raymer, Robin; Nichols, Timothy C.; Camire, Rodney M.; Arruda, Valder R.

    2016-01-01

    Processing by the proprotein convertase furin is believed to be critical for the biological activity of multiple proteins involved in hemostasis, including coagulation factor VIII (FVIII). This belief prompted the retention of the furin recognition motif (amino acids 1645–1648) in the design of B-domain–deleted FVIII (FVIII-BDD) products in current clinical use and in the drug development pipeline, as well as in experimental FVIII gene therapy strategies. Here, we report that processing by fu...

  8. Independent Directors and Stakeholders Protection: A Case of Sime Darby

    OpenAIRE

    Prashanth Beleya; Gopalan Raman; Charles Ramendren; Suresh Nodeson

    2012-01-01

    In today’s ever challenging corporate environment, the unfortunate events of decision making by top management has led major companies to suffer huge losses. This results and mistakes made have given a significant impact to the stake holder’s perception and raise a serious questions on the role of board of directors especially the role of independent directors. In today’s fast evolving business pace with stiff economic conditions, unethical and misjudgment in business decisions are driving th...

  9. A practitioner’s research: Director remuneration in Ukraine

    Directory of Open Access Journals (Sweden)

    Alexander N. Kostyuk

    2006-07-01

    Full Text Available Remuneration of members of the supervisory boards in Ukrainian joint-stock companies is the most controversial issue of the corporate board practices. Despite the firm belief of the shareholders that the director remuneration is one of the most important factors influencing the board performance, there are still many companies (21 per cent where directors are not remunerated for their work on the supervisory board. This report examines practices of the director’s remuneration in Ukraine.

  10. Female Directors and Firm Performance: Evidence from UK Listed Firms

    OpenAIRE

    Pasaribu, Pananda

    2017-01-01

    The impact of female directors on firm performance has lacked consistency in the previously conducted empirical studies, which may be due to the endogeneity problem, or certain characteristics (i.e. governance, industry, competition). This study examines the relationship between female directors and firm performance by addressing those problems. This study analyses all non-financial UK listed firms during the period 2004-2012 and employs several econometric models. The regression results indi...

  11. Evaluation of Managerial Needs for Palliative Care Centers: Perspectives of Medical Directors.

    Science.gov (United States)

    Kafadar, Didem; Ince, Nurhan; Akcakaya, Adem; Gumus, Mahmut

    2015-01-01

    Palliative therapies have an important role in increasing the quality of healthcare and in dealing with physical and psychosocial problems due to cancer. We here aimed to evaluate the managerial perspectives and opinions of the hospital managers and clinical directors about specialized palliative care centers. This study was conducted in two large-scale hospitals in which oncology care is given with medical directors (n:70). A questionnaire developed by the researchers asking about demographic characteristics and professional experience, opinions and suggestions of medical directors about providing and integrating palliative care into healthcare was used and responses were analyzed. Potential barriers in providing palliative care (PC) and integrating PC into health systems were perceived as institutional by most of the doctors (97%) and nurses (96%). Social barriers were reported by 54% of doctors and 82% of nurses. Barriers due to interest and knowledge of health professionals about PC were reported by 76% of doctors and 75% of nurses. Among encouragement ideas to provide PC were dealing with staff educational needs (72%), improved working conditions (77%) and establishing a special PC unit (49)%. An independent PC unit was suggested by 27.7% of participants and there was no difference between the hospitals. To overcome the barriers for integration of PC into health systems, providing education for health professionals and patient relatives, raising awareness in society, financial arrangements and providing infrastructure were suggested. The necessity for planning and programming were emphasized. In our study, the opinions and perspectives of hospital managers and clinical directors were similar to current approaches. Managerial needs for treating cancer in efficient cancer centers, increasing the capacity of health professionals to provide care in every stage of cancer, effective education planning and patient care management were emphasized.

  12. El Consejero Dominical y el Gobierno Corporativo / Institutional Directors and Corporate Governance

    OpenAIRE

    Chiva Ortells, Carlos

    2017-01-01

    The aim of this research is to study the role of institutional directors in corporate governance. For this purpose, we have analysed the impact that these directors have on CEO compensation and on corporate social responsibility disclosure. Moreover, institutional directors have been classified into two groups: pressure-resistant institutional directors and pressure-sensitive institutional directors. The results show that institutional directors, as a whole, and pressure-resistant institution...

  13. Energy and Environment Directorate Status Report March 2006

    International Nuclear Information System (INIS)

    Long, J S

    2006-01-01

    The Energy and Environment Directorate (E and ED) is one of 13 directorates at Lawrence Livermore National Laboratory (LLNL), which is operated by the University of California (UC) for the U.S. Department of Energy's National Nuclear Security Administration (NNSA). We operate in the context of a national security laboratory and focus on meeting major national needs, especially from a long-term perspective. In the LLNL context, E and ED is a hybrid ''program'' and ''discipline'' directorate, combining the program development responsibilities in the national energy and environment arenas to the benefit of the entire Laboratory and also serving as the Laboratory's science base of atmospheric, earth, environmental, and energy science. This Status Report is part of the annual evaluation process required by the Department of Energy (DOE) as part of its contract with UC. The annual review typically will focus on about one third of the activities and programs of a directorate, so that the entire organization is evaluated over a three-year window. This year's review is focused on the basic science foundations for the directorate and two major program areas in the directorate, with an update from a third program. The programs for review are: (1) Earth System Science and Engineering; (2) Nuclear Systems Science and Engineering; and (3) NARAC/IMAAC update. Major questions to be addressed during this review include: (1) Are the programmatic directions appropriate? How can they be improved? (2) What actions can E and ED take to ensure success? How well poised for success are the current staff and facilities? What additions are needed? (3) What recommendations can be made to the Director and the University? This Status Report provides background information on the entire directorate including the parts of the directorate that are the focus of this year's review by the Energy and Environment Directorate Review Committee, to be held March 6-9, 2006. The following sections describe

  14. Prevalence and compensation of academic leaders, professors, and trustees on publicly traded US healthcare company boards of directors: cross sectional study.

    Science.gov (United States)

    Anderson, Timothy S; Good, Chester B; Gellad, Walid F

    2015-09-29

    To identify the prevalence, characteristics, and compensation of members of the boards of directors of healthcare industry companies who hold academic appointments as leaders, professors, or trustees. Cross sectional study. US healthcare companies publicly traded on the NASDAQ or New York Stock Exchange in 2013. 3434 directors of pharmaceutical, biotechnology, medical equipment and supply, and healthcare provider companies. Prevalence, annual compensation, and beneficial stock ownership of directors with affiliations as leaders, professors, or trustees of academic medical and research institutions. 446 healthcare companies met the study search criteria, of which 442 (99%) had publicly accessible disclosures on boards of directors. 180 companies (41%) had one or more academically affiliated directors. Directors were affiliated with 85 geographically diverse non-profit academic institutions, including 19 of the top 20 National Institute of Health funded medical schools and all of the 17 US News honor roll hospitals. Overall, these 279 academically affiliated directors included 73 leaders, 121 professors, and 85 trustees. Leaders included 17 chief executive officers and 11 vice presidents or executive officers of health systems and hospitals; 15 university presidents, provosts, and chancellors; and eight medical school deans or presidents. The total annual compensation to academically affiliated directors for their services to companies was $54,995,786 (£35,836,000; €49,185,900) (median individual compensation $193,000) and directors beneficially owned 59,831,477 shares of company stock (median 50,699 shares). A substantial number and diversity of academic leaders, professors, and trustees hold directorships at US healthcare companies, with compensation often approaching or surpassing common academic clinical salaries. Dual obligations to for profit company shareholders and non-profit clinical and educational institutions pose considerable personal, financial, and

  15. Pathology Course Director Perspectives of a Recent LCME Experience

    Directory of Open Access Journals (Sweden)

    Barbara E. C. Knollmann-Ritschel MD

    2017-01-01

    Full Text Available Preparation for a Liaison Committee of Medical Education (LCME accreditation site visit is a daunting task for any medical school, particularly for medical schools that have adopted integrated curricula. The LCME accreditation is the standard that all US and Canadian allopathic medical schools must meet in order for the school to award the degree of medical doctor. The Uniformed Services University of the Health Sciences (USU recently underwent a full-scale LCME accreditation visit that was conducted under the newly revised LCME standards and elements. The site visit occurred just 5 years after our school began implementing a totally revised, organ system-based curriculum. Preparing for a critical, high-stakes site visit shortly after transitioning to a totally revised, integrated module-based preclerkship curriculum presented an array of new challenges that required a major modification to the type of preparation, communication, and collaboration that traditionally occurs between course directors and departmental chairs. These included the need to ensure accurate, timely communication of curricular details to different levels of the academic administration, particularly as it related to the execution of self-directed learning (SDL. Preparation for our site visit, did, however, provide a novel opportunity to highlight the unique educational experiences associated with the study of pathology, as pathology traverses both clinical and basic sciences. Sharing these experiences may be useful to other programs that are either undergoing or who are preparing to undergo an accreditation visit and may also aid in a broader communication of the highlights or initiatives of educational activities.

  16. Quality of life in haemophilia A: Hemophilia Utilization Group Study Va (HUGS-Va).

    Science.gov (United States)

    Poon, J-L; Zhou, Z-Y; Doctor, J N; Wu, J; Ullman, M M; Ross, C; Riske, B; Parish, K L; Lou, M; Koerper, M A; Gwadry-Sridhar, F; Forsberg, A D; Curtis, R G; Johnson, K A

    2012-09-01

    This study describes health-related quality of life (HRQoL) of persons with haemophilia A in the United States (US) and determines associations between self-reported joint pain, motion limitation and clinically evaluated joint range of motion (ROM), and between HRQoL and ROM. As part of a 2-year cohort study, we collected baseline HRQoL using the SF-12 (adults) and PedsQL (children), along with self-ratings of joint pain and motion limitation, in persons with factor VIII deficiency recruited from six Haemophilia Treatment Centres (HTCs) in geographically diverse regions of the US. Clinically measured joint ROM measurements were collected from medical charts of a subset of participants. Adults (N = 156, mean age: 33.5 ± 12.6 years) had mean physical and mental component scores of 43.4 ± 10.7 and 50.9 ± 10.1, respectively. Children (N = 164, mean age: 9.7 ± 4.5 years) had mean total PedsQL, physical functioning, and psychosocial health scores of 85.9 ± 13.8, 89.5 ± 15.2, and 84.1 ± 15.3, respectively. Persons with more severe haemophilia and higher self-reported joint pain and motion limitation had poorer scores, particularly in the physical aspects of HRQoL. In adults, significant correlations (P < 0.01) were found between ROM measures and both self-reported measures. Except among those with severe disease, children and adults with haemophilia have HRQoL scores comparable with those of the healthy US population. The physical aspects of HRQoL in both adults and children with haemophilia A in the US decrease with increasing severity of illness. However, scores for mental aspects of HRQoL do not differ between severity groups. These findings are comparable with those from studies in European and Canadian haemophilia populations. © 2012 Blackwell Publishing Ltd.

  17. The deployed medical director: managing the challenges of a complex trauma system.

    Science.gov (United States)

    Mahoney, P F; Hodgetts, T J; Hicks, I

    2011-09-01

    Contemporary combat casualty care has never been more sophisticated or effective, which is matched by an unprecedented level of clinical complexity. The management of this complexity has demanded the evolution of a more direct clinical leadership model in the field hospital: the Deployed Medical Director (DMD). The DMD has a central co-ordinating role in reducing the friction generated by individuals' unfamiliarity in a rapidly developing clinical environment that has diverged from the NHS; in cementing interoperability within a multinational medical treatment facility working at high intensity; and in maintaining and developing the highest clinical standards within the deployed trauma system. This article describes the evolution of the DMD role and illustrates the challenges through a series of vignettes. Particular emphasis is given to the organisational risk that the role carries through necessary ethical choices, the requirement to integrate multi-national cultural differences and the challenge of dealing with interpersonal frictions amongst senior staff.

  18. A DNA fragment from Xq21 replaces a deleted region containing the entire FVIII gene in a severe hemophilia A patient

    Energy Technology Data Exchange (ETDEWEB)

    Murru, S.; Casula, L.; Moi, P. [Insituto di Clinica e Biologia dell` Eta Evolutiva, Cagliari (Italy)] [and others

    1994-09-15

    In this paper the authors report the molecular characterization of a large deletion that removes the entire Factor VIII gene in a severe hemophilia A patient. Accurate DNA analysis of the breakpoint region revealed that a large DNA fragment replaced the 300-kb one, which was removed by the deletion. Pulsed-field gel electrophoresis analysis revealed that the size of the inserted fragment is about 550 kb. In situ hybridization demonstrated that part of the inserted region normally maps to Xq21 and to the tip of the short arm of the Y chromosome (Yp). In this patient this locus is present both in Xq21 and in Xq28, in addition to the Yp, being thus duplicated in the X chromosome. Sequence analysis of the 3` breakpoint suggested that an illegitimate recombination is probably the cause of this complex rearrangement. 52 refs., 7 figs.

  19. Mutation, detection, prenatal testing, and delineation of the germline origin in a family with sporadic hemophilia B and no living hemophiliacs

    Energy Technology Data Exchange (ETDEWEB)

    Vielhaber, E.; Sommer, S.S. [Mayo Clinic/Foundation, Rochester, MN (United States); Freedenberg, D. [Scott and White Clinic, Temple, TX (United States)

    1994-01-15

    Hemophilia B is an X-linked recessive disorder affecting 1 in 30,000 males. Determination of carrier status for at risk females can be done by utilizing indirect methods such as DNA sequencing. However, in most cases, reliable carrier testing is not possible without first analyzing the DNA from an affected male in the family to determine his haplotype/causative sequence change. In the case presented here, the only affected male in the family has been deceased for 25 years; no DNA was available from him. The sister (III-2) of the affected individual was a suspected carrier based on her factor IX coagulant (36%); she was pregnant with a male fetus, and requested prenatal testing. 6 refs., 2 figs.

  20. An intronic mutation c.6430-3C>G in the F8 gene causes splicing efficiency and premature termination in hemophilia A.

    Science.gov (United States)

    Xia, Zunjing; Lin, Jie; Lu, Lingping; Kim, Chol; Yu, Ping; Qi, Ming

    2018-06-01

    : Hemophilia A is a bleeding disorder caused by coagulation factor VIII protein deficiency or dysfunction, which is classified into severe, moderate, and mild according to factor clotting activity. An overwhelming majority of missense and nonsense mutations occur in exons of F8 gene, whereas mutations in introns can also be pathogenic. This study aimed to investigate the effect of an intronic mutation, c.6430-3C>G (IVS22-3C>G), on pre-mRNA splicing of the F8 gene. We applied DNA and cDNA sequencing in a Chinese boy with hemophilia A to search if any pathogenic mutation in the F8 gene. Functional analysis was performed to investigate the effect of an intronic mutation at the transcriptional level. Human Splicing Finder and PyMol were also used to predict its effect. We found the mutation c.6430-3C>G (IVS22-3C>G) in the F8 gene in the affected boy, with his mother being a carrier. cDNA from the mother and pSPL3 splicing assay showed that the mutation IVS22-3C>G results in a two-nucleotide AG inclusion at the 3' end of intron 22 and leads to a truncated coagulation factor VIII protein, with partial loss of the C1 domain and complete loss of the C2 domain. The in-silico tool predicted that the mutation induces altered pre-mRNA splicing by using a cryptic acceptor site in intron 22. The IVS22-3C>G mutation was confirmed to affect pre-mRNA splicing and produce a truncated protein, which reduces the stability of binding between the F8 protein and von Willebrand factor carrier protein due to the loss of an interaction domain.