Sample records for factores ii vii

  1. Factor VII assay

    MedlinePlus

    Stable factor; Proconvertin; Autoprothrombin I ... be caused by an abnormally low level of factor VII. ... Decreased factor VII activity may be related to: Deficiency of factor VII Disorder in which the proteins that control ...

  2. Preparation of factor VII concentrate using CNBr-activated Sepharose 4B immunoaffinity chromatography

    PubMed Central

    Mousavi Hosseini, Kamran; Nasiri, Saleh

    2015-01-01

    Background: Factor VII concentrates are used in patients with congenital or acquired factor VII deficiency or treatment of hemophilia patients with inhibitors. In this research, immunoaffinity chromatography was used to purify factor VII from prothrombin complex (Prothrombin- Proconvertin-Stuart Factor-Antihemophilic Factor B or PPSB) which contains coagulation factors II, VII, IX and X. The aim of this study was to improve purity, safety and tolerability as a highly purified factor VII concentrate. Methods: PPSB was prepared using DEAE-Sephadex and was used as the starting material for purification of coagulation factor VII. Prothrombin complex was treated by solvent/detergent at 24°C for 6 h with constant stirring. The mixture of PPSB in the PBS buffer was filtered and then chromatographed using CNBr-activated Sepharose 4B coupled with specific antibody. Factors II, IX, VII, X and VIIa were assayed on the fractions. Fractions of 48-50 were pooled and lyophilized as a factor VII concentrate. Agarose gel electrophoresis was performed and Tween 80 was measured in the factor VII concentrate. Results: Specific activity of factor VII concentrate increased from 0.16 to 55.6 with a purificationfold of 347.5 and the amount of activated factor VII (FVIIa) was found higher than PPSB (4.4-fold). Results of electrophoresis on agarose gel indicated higher purity of Factor VII compared to PPSB; these finding revealed that factor VII migrated as alpha-2 proteins. In order to improve viral safety, solvent-detergent treatment was applied prior to further purification and nearly complete elimination of tween 80 (2 μg/ml). Conclusion: It was concluded that immuonoaffinity chromatography using CNBr-activated Sepharose 4B can be a suitable choice for large-scale production of factor VII concentrate with higher purity, safety and activated factor VII. PMID:26034723

  3. Preparation of factor VII concentrate using CNBr-activated Sepharose 4B immunoaffinity chromatography.

    PubMed

    Mousavi Hosseini, Kamran; Nasiri, Saleh

    2015-01-01

    Factor VII concentrates are used in patients with congenital or acquired factor VII deficiency or treatment of hemophilia patients with inhibitors. In this research, immunoaffinity chromatography was used to purify factor VII from prothrombin complex (Prothrombin- Proconvertin-Stuart Factor-Antihemophilic Factor B or PPSB) which contains coagulation factors II, VII, IX and X. The aim of this study was to improve purity, safety and tolerability as a highly purified factor VII concentrate. PPSB was prepared using DEAE-Sephadex and was used as the starting material for purification of coagulation factor VII. Prothrombin complex was treated by solvent/detergent at 24°C for 6 h with constant stirring. The mixture of PPSB in the PBS buffer was filtered and then chromatographed using CNBr-activated Sepharose 4B coupled with specific antibody. Factors II, IX, VII, X and VIIa were assayed on the fractions. Fractions of 48-50 were pooled and lyophilized as a factor VII concentrate. Agarose gel electrophoresis was performed and Tween 80 was measured in the factor VII concentrate. Specific activity of factor VII concentrate increased from 0.16 to 55.6 with a purificationfold of 347.5 and the amount of activated factor VII (FVIIa) was found higher than PPSB (4.4-fold). RESULTS of electrophoresis on agarose gel indicated higher purity of Factor VII compared to PPSB; these finding revealed that factor VII migrated as alpha-2 proteins. In order to improve viral safety, solvent-detergent treatment was applied prior to further purification and nearly complete elimination of tween 80 (2 μg/ml). It was concluded that immuonoaffinity chromatography using CNBr-activated Sepharose 4B can be a suitable choice for large-scale production of factor VII concentrate with higher purity, safety and activated factor VII.

  4. Genetics Home Reference: factor VII deficiency

    MedlinePlus

    ... Facebook Twitter Home Health Conditions Factor VII deficiency Factor VII deficiency Printable PDF Open All Close All Enable Javascript to view the expand/collapse boxes. Description Factor VII deficiency is a rare bleeding disorder that varies ...

  5. Synergistic effect of factor VII gene polymorphisms causing mild factor VII deficiency in a case of severe factor X deficiency.

    PubMed

    Deshpande, Rutuja; Ghosh, Kanjaksha; Shetty, Shrimati

    2017-01-01

    Congenital combined deficiency of coagulation factors VII and X are mainly attributed to large deletions involving both the genes in chromosome 13 or occasionally due to the coincidental occurrence of independently occurring mutations. We report the molecular basis of congenital combined deficiency of factors VII and X in a 6-year-old female child. Direct DNA sequencing of both factor VII (F7) and factor X (F10) genes showed a novel homozygous missense mutation p.Cys90Tyr (c.307G>A) in exon 4 of F10. No mutations were detected in F7; however, the patient was homozygous for three polymorphic alleles known to be associated with reduced factor VII levels. The present case illustrates the synergistic effect of multiple polymorphisms resulting in phenotypic factor VII deficiency in the absence of a pathogenic mutation.

  6. Increased volume of distribution for recombinant activated factor VII and longer plasma-derived factor VII half-life may explain their long lasting prophylactic effect.

    PubMed

    Mathijssen, Natascha C J; Masereeuw, Rosalinde; Holme, Pal Andre; van Kraaij, Marian G J; Laros-van Gorkom, Britta A P; Peyvandi, Flora; van Heerde, Waander L

    2013-08-01

    Prophylaxis with plasma-derived or recombinant activated factor VII is beneficial in severe factor VII deficiency. To understand why prophylactic treatment with both products is efficacious, we conducted a pharmacokinetic study. Ten factor VII deficient patients were treated with either recombinant activated (20 μg/kg) or plasma-derived (25 IU/kg) factor VII in a cross-over design. Pharmacokinetic parameters were analyzed through activated factor VII activity, factor VII clotting activity, and factor VII antigen levels on depicted time points. Factor VII activity half-lifes, determined by non-compartmental and one-compartmental analysis (results in brackets), were shorter for recombinant activated (1.4h; 0.7h) than for plasma-derived factor VII (6.8h; 3.2h); both recombinant activated (5.1h; 2.1h and plasma-derived factor VII (5.8h; 3.2h) resulted in longer half-lives of factor VII antigen. Activated factor VII half-lives (based on activated factor VII activity levels) were significantly higher compared to factor VII clotting activity (1.6h; 0.9h). Volumes of distribution were significantly higher for activated factor VII (236 ml/kg; 175 ml/kg, measured by activated factor VII) as compared to plasma-derived factor VII (206 ml/kg; 64 ml/kg, measured by factor FVII activity), suggesting a plasma- and extracellular fluid distribution for recombinant activated factor VII. Recombinant activated factor VII showed significantly shorter half-lifes than plasma-derived factor VII. Volumes of distribution were significantly higher for treatment with recombinant activated factor VII. The longer half-life for plasma-derived factor VII, compared to recombinant activated factor VII, and the increased volume of distribution for recombinant activated factor VII, compared to plasma-derived factor VII may further elucidate the beneficial effect of prophylactic treatment of both products. Copyright © 2013 Elsevier Ltd. All rights reserved.

  7. Investigating the air oxidation of V(II) ions in a vanadium redox flow battery

    NASA Astrophysics Data System (ADS)

    Ngamsai, Kittima; Arpornwichanop, Amornchai

    2015-11-01

    The air oxidation of vanadium (V(II)) ions in a negative electrolyte reservoir is a major side reaction in a vanadium redox flow battery (VRB), which leads to electrolyte imbalance and self-discharge of the system during long-term operation. In this study, an 80% charged negative electrolyte solution is employed to investigate the mechanism and influential factors of the reaction in a negative-electrolyte reservoir. The results show that the air oxidation of V(II) ions occurs at the air-electrolyte solution interface area and leads to a concentration gradient of vanadium ions in the electrolyte solution and to the diffusion of V(II) and V(III) ions. The effect of the ratio of the electrolyte volume to the air-electrolyte solution interface area and the concentrations of vanadium and sulfuric acid in an electrolyte solution is investigated. A higher ratio of electrolyte volume to the air-electrolyte solution interface area results in a slower oxidation reaction rate. The high concentrations of vanadium and sulfuric acid solution also retard the air oxidation of V(II) ions. This information can be utilized to design an appropriate electrolyte reservoir for the VRB system and to prepare suitable ingredients for the electrolyte solution.

  8. Newly diagnosed congenital factor VII deficiency and utilization of recombinant activated factor VII (NovoSeven(®)).

    PubMed

    Bartosh, Nicole S; Tomlin, Tara; Cable, Christian; Halka, Kathleen

    2013-01-01

    This case report presents a newly diagnosed congenital factor VII deficiency treated with recombinant activated factor VII (rFVIIa). Congenital factor VII deficiency is a rare autosomal-recessive bleeding disorder that occurs in fewer than 1/500,000 persons. Its presentation can vary from epistaxis to hemarthroses and severe central nervous system bleeding, and correlates poorly with factor VII levels. Our patient had not had a significant hemostatic challenge prior to his presentation and therefore never had any symptomatology suggestive of this disease. He was treated with rFVIIa, and was able to undergo repair of his fractures without bleeding. A 19-year-old African-American male presented to the emergency room after an altercation that resulted in significant trauma. He sustained bilateral mandibular angle fractures and orbital floor fractures, requiring urgent surgical correction. On initial evaluation, he was noted to have a prolonged prothrombin time of 40.1 seconds, with an International Normalized Ratio of 4.0, a normal activated partial thromboplastin time of 29.9 seconds, and a platelet count of 241. After receiving vitamin K and fresh frozen plasma, he was taken to the operating room for a temporary rigid maxillomandibular fixation. A 1:1 mixing study with normal plasma corrected the prothrombin time (decreasing from 40.7 to 14.7 seconds) and a factor VII assay revealed 5% of the normal factor VII level. The patient was diagnosed with congenital factor VII deficiency. Due to his coagulopathy and the extensive surgical correction needed, rFVIIa was administered and surgery was accomplished without hemorrhagic sequelae. This case report and review describes a rare congenital disease, the history of rFVIIa use, and its mechanism. rFVIIA use in our patient provided a treatment option that allowed the necessary surgical correction, but further prospective studies on dose optimization would ensure adequate dosing with minimal risk of severe side effects.

  9. [Coagulation factor VII levels in uremic patients and theirs influence factors].

    PubMed

    Fang, Jun; Xia, Ling-Hui; Wei, Wen-Ning; Song, Shan-Jun

    2004-12-01

    This study was aimed to investigate coagulation factor VII level in uremic patients with chronic renal failure and to explore theirs influence factors. The plasma levels of coagulation factor VII were detected in 30 uremic patients with chronic renal failure before and after hemodialysis for 1 month, the factor VII activity (FVII:C) was determined by one-stage coagulation method, while activated factor VII (FVIIa) was measured by one-stage coagulation method using recombinant soluble tissue factor, and factor VII antigen was detected by ELISA. The results showed that: (1) The FVIIa, FVII:C and FVIIAg levels in chronic uremic patients before hemodialysis were 4.00 +/- 0.86 microg/L, (148.5 +/- 40.4)% and (99.8 +/- 21.1)% respectively, which were significantly increased, as compared with healthy controls [2.77 +/- 1.02 microg/L, (113.1 +/- 33.0)% and (73.7 +/- 18.3)% respectively, P < 0.05]. (2) After hemodialysis the FVIIa, FVII:C and FVIIAg levels in uremic patients significantly enhanced to 5.56 +/- 1.45 microg/L, (200.8 +/- 68.7)% and (124.1 +/- 19.3)% respectively (P < 0.05). (3) The abnormal increase of coagulation factor VII was positively correlated with levels of blood uria nitrogen and serum creatinine before hemodialysis but not after hemodialysis. It is concluded that the enhanced levels of coagulation factor VII in chronic uremic patients suggested abnormal activated state, herperactivity and elevated production of factor VII which correlated with renal functional injury. The abnormality of factor VII in uremia may be aggravated by hemodialysis. Coagulation factor (FVII) may be a risk factor for cardiovascular events in uremic patients who especially had been accepted long-term hemodialysis.

  10. Role of hepsin in factor VII activation in zebrafish.

    PubMed

    Khandekar, Gauri; Jagadeeswaran, Pudur

    2014-01-01

    Factor VII, the initiator of the extrinsic coagulation cascade, circulates in human plasma mainly in its zymogen form, factor VII and in small amounts in its activated form, factor VIIa. However, the mechanism of initial generation of factor VIIa is not known despite intensive research using currently available model systems. Earlier findings suggested serine proteases factor VII activating protease and hepsin play a role in activating factor VII, however, it has remained controversial. In this paper we estimated the levels of factor VIIa and factor VII for the first time in zebrafish adult population and also reevaluated the role of the above two serine proteases in activating factor VII in vivo using zebrafish as a model system. Knockdown of factor VII activating protease and hepsin was performed followed by assaying for their effect on factor VIIa concentration and extrinsic coagulation as measured by the kinetic prothrombin time. Factor VII activating protease knockdown showed no change in kinetic prothrombin time and no effect on factor VIIa levels while hepsin knockdown increased the kinetic prothrombin time and significantly reduced the factor VIIa plasma levels. Our results thus indicate that hepsin plays a physiologically important role in factor VII activation and hemostasis in zebrafish. © 2013.

  11. Newly diagnosed congenital factor VII deficiency and utilization of recombinant activated factor VII (NovoSeven®)

    PubMed Central

    Bartosh, Nicole S; Tomlin, Tara; Cable, Christian; Halka, Kathleen

    2013-01-01

    This case report presents a newly diagnosed congenital factor VII deficiency treated with recombinant activated factor VII (rFVIIa). Congenital factor VII deficiency is a rare autosomal-recessive bleeding disorder that occurs in fewer than 1/500,000 persons. Its presentation can vary from epistaxis to hemarthroses and severe central nervous system bleeding, and correlates poorly with factor VII levels. Our patient had not had a significant hemostatic challenge prior to his presentation and therefore never had any symptomatology suggestive of this disease. He was treated with rFVIIa, and was able to undergo repair of his fractures without bleeding. Case report A 19-year-old African-American male presented to the emergency room after an altercation that resulted in significant trauma. He sustained bilateral mandibular angle fractures and orbital floor fractures, requiring urgent surgical correction. On initial evaluation, he was noted to have a prolonged prothrombin time of 40.1 seconds, with an International Normalized Ratio of 4.0, a normal activated partial thromboplastin time of 29.9 seconds, and a platelet count of 241. After receiving vitamin K and fresh frozen plasma, he was taken to the operating room for a temporary rigid maxillomandibular fixation. A 1:1 mixing study with normal plasma corrected the prothrombin time (decreasing from 40.7 to 14.7 seconds) and a factor VII assay revealed 5% of the normal factor VII level. The patient was diagnosed with congenital factor VII deficiency. Due to his coagulopathy and the extensive surgical correction needed, rFVIIa was administered and surgery was accomplished without hemorrhagic sequelae. Conclusion This case report and review describes a rare congenital disease, the history of rFVIIa use, and its mechanism. rFVIIA use in our patient provided a treatment option that allowed the necessary surgical correction, but further prospective studies on dose optimization would ensure adequate dosing with minimal risk of

  12. Use of recombinant factor VII for tooth extractions in a patient with severe congenital factor VII deficiency: a case report.

    PubMed

    Weinstock, Robert J; Onyejiuwa, Andrew; Shnayder, Garry; Clarkson, Earl I

    2015-04-01

    Patients with factor VII deficiency have an increased risk of prolonged perioperative hemorrhage. In this article, the authors present a case of severe factor VII deficiency in a patient who required tooth extraction. A 44-year-old woman with severe congenital factor VII deficiency sought care for a symptomatic, carious, and nonrestorable maxillary right second molar that required extraction. The authors obtained hematologic consultation, and the patient underwent the extraction under general anesthesia in the inpatient setting. Perioperative management included performing relevant laboratory studies, preoperative recombinant factor VII infusion, and postoperative intravenous aminocaproic acid administration. No hemorrhagic complications occurred throughout the perioperative course. The degree of factor VII deficiency correlates poorly with bleeding risk. Perioperative management is variable, requiring preoperative consultation with a hematologist. Copyright © 2015 American Dental Association. Published by Elsevier Inc. All rights reserved.

  13. Recombinant factor VIIa treatment for asymptomatic factor VII deficient patients going through major surgery.

    PubMed

    Livnat, Tami; Shenkman, Boris; Spectre, Galia; Tamarin, Ilia; Dardik, Rima; Israeli, Amnon; Rivkind, Avraham; Shabtai, Moshe; Marinowitz, Uri; Salomon, Ophira

    2012-07-01

    Factor VII deficiency is the most common among the rare autosomal recessive coagulation disorders worldwide. In factor VII deficient patients, the severity and clinical manifestations cannot be reliably determined by factor VII levels. Severe bleeding tends to occur in individuals with factor VII activity levels of 2% or less of normal. Patients with 2-10% factor VII vary between asymptomatic to severe life threatening haemorrhages behaviour. Recombinant factor VIIa (rFVIIa) is the most common replacement therapy for congenital factor VII deficiency. However, unlike haemophilia patients for whom treatment protocols are straight forward, in asymptomatic factor VII deficiency patients it is still debatable. In this study, we demonstrate that a single and very low dose of recombinant factor VIIa enabled asymptomatic patients with factor VII deficiency to go through major surgery safely. This suggestion was also supported by thrombin generation, as well as by thromboelastometry.

  14. A new manufacturing process to remove thrombogenic factors (II, VII, IX, X, and XI) from intravenous immunoglobulin gamma preparations.

    PubMed

    Park, Dong Hwarn; Kang, Gil Bu; Kang, Dae Eun; Hong, Jeung Woon; Lee, Min Gyu; Kim, Ki Yong; Han, Jeung Whan

    2017-01-01

    Coagulation factors (II, VII, IX, X, and particularly XIa) remaining in high concentrations in intravenous immunoglobulin (IVIG) preparations can form thrombi, causing thromboembolic events, and in serious cases, result in death. Therefore, manufacturers of biological products must investigate the ability of their production processes to remove procoagulant activities. Previously, we were able to remove coagulation factors II, VII, IX, and X from our IVIG preparation through ethanol precipitation, but factor XIa, which plays an important role in thrombosis, remained in the intermediate products. Here, we used a chromatographic process using a new resin that binds with high capacity to IgG and removes procoagulant activities. The procoagulant activities were reduced to low levels as determined by the thrombin generation assay: <1.56 mIU/mL, chromogenic FXIa assay: <0.16 mIU/mL, non-activated partial thromboplastin time (NaPTT): >250 s, FXI/FXIa ELISA: <0.31 ng/mL. Even after spiking with FXIa at a concentration 32.5 times higher than the concentration in normal specimens, the procoagulant activities were below the detection limit (<0.31 ng/mL). These results demonstrate the ability of our manufacturing process to remove procoagulant activities to below the detection limit (except by NaPTT), suggesting a reduced risk of thromboembolic events that maybe potentially caused by our IVIG preparation. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  15. First living-related liver transplant to cure factor VII deficiency.

    PubMed

    Mohan, Neelam; Karkra, Sakshi; Jolly, Anu S; Vohra, Vijay; Mohanka, Ravi; Rastogi, Amit; Soin, A S

    2015-09-01

    Congenital factor VII deficiency is an autosomal recessive serious disorder of blood coagulation with wide genotypic and phenotypic variations. The clinical presentation can vary from asymptomatic patients to patients with major bleedings in severe deficiency (factor VII <1%). Investigations show prolonged PT and low factor VII. Treatment modalities include FFP and repeated recombinant factor VII infusions. We hereby report the first successful LRLT for factor VII deficiency in an infant, the first-ever youngest baby reported worldwide. A six-month-old male child presented with easy bruisability, ecchymotic patches, hematuria, and convulsions. CT of the head showed subdural hemorrhage, which was treated conservatively. He had markedly increased PT (120 s) with normal platelets, and aPTT with factor VII level <1%. Despite the treatment by rFVIIa administration weekly, which was very expensive, he still had repeated life-threatening bleeding episodes. LRLT was performed with mother as the donor, whose factor VII level was 57%. A factor VII infusion plan for pre-, intra- and postoperative periods was formulated and TEG followed. Postoperatively, his factor VII started increasing from third day and was 38% on 24th day with PT <14 s. He had uneventful intraoperative and postoperative courses. LT is a safe and definite cure for factor VII deficiency. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  16. Recombinant activated factor VII in cardiac surgery: single-center experience.

    PubMed

    Singh, Sarvesh Pal; Chauhan, Sandeep; Choudhury, Minati; Malik, Vishwas; Choudhary, Shiv Kumar

    2014-02-01

    The widespread off-label use of recombinant activated factor VII for the control of refractory postoperative hemorrhage continues despite a warning from the Food and Drug Administration. Although effective in reducing the need for transfusion of blood and blood products, safety concerns still prevail. To compare the dosing and efficacy of recombinant activated factor VII between pediatric and adult patients, and in the operating room and intensive care unit. The records of 69 patients (33 children and 36 adults) who underwent cardiovascular surgery and received recombinant activated factor VII were reviewed retrospectively. The dose of recombinant activated factor VII, mediastinal drainage, use of blood and blood products, incidence of thrombosis, and 28-day mortality were studied. the efficacy of recombinant activated factor VII was comparable in adults and children, despite the lower dose in adults. Prophylactic use of recombinant activated factor VII decreased the incidence of mediastinal exploration and the duration of intensive care unit stay. A 4.3% incidence of thrombotic complications was observed in this study. The efficacious dose of recombinant activated factor VII is much less in adults compared to children. Prophylactic use of recombinant activated factor VII decreases the dose required, the incidence of mediastinal exploration, and intensive care unit stay, with no survival benefit.

  17. Prolonged Prothrombin Time After Recombinant Activated Factor VII Therapy in Critically Bleeding Trauma Patients Is Associated With Adverse Outcomes

    DTIC Science & Technology

    2010-07-01

    using the FVII coagulant activity (FVII:C) assay, a one- stage assay using thromboplastin tissue factor , which quantifies FVII clotting activity in...and the resultant production of dysfunctional factors II, VII, and X. This study focused on PT specifically because this measure examines the TF...ORIGINAL ARTICLE Prolonged Prothrombin Time After Recombinant Activated Factor VII Therapy in Critically Bleeding Trauma Patients Is Associated With

  18. Age-related changes in factor VII proteolysis in vivo.

    PubMed

    Ofosu, F A; Craven, S; Dewar, L; Anvari, N; Andrew, M; Blajchman, M A

    1996-08-01

    Previous studies have reported that pre-operative plasmas of patients over the age of 40 years who developed post-operative deep vein thrombosis (DVT) had approximately twice the amount of proteolysed factor VII found in plasmas of patients in whom prophylaxis with heparin or low M(r) heparin was successful. These and other studies also reported higher concentrations of thrombin-antithrombin III in pre- and post-operative plasmas of patients who developed post-operative thrombosis than in plasmas of patients in whom prophylaxis was successful. Whether the extent of factor VII proteolysis seen in the patients who developed post-operative DVT is related to the severity of their disease or age is not known. This report investigated age-related changes in the concentrations of total factor VII protein, factor VII zymogen, factor VIIa, tissue factor pathway inhibitor, thrombin-antithrombin III, and prothrombin fragment 1 + 2 in normal plasmas and the relationships between these parameters. With the exception of thrombin-antithrombin III, statistically significant increases in the concentrations of these parameters with age were found. Additionally, the differences between the concentrations of total factor VII protein and factor VII zymogen, an index factor VII proteolysis in vivo, were statistically significant only for individuals over age 40. Using linear regression analysis, a significant correlation was found to exist between the concentrations of plasma factor VIIa and prothrombin fragment 1 + 2. Since factor VIIa-tissue factor probably initiates coagulation in vivo, we hypothesize that the elevated plasma factor VIIa (reflecting a less tightly regulated tissue factor activity and therefore increased thrombin production in vivo) accounts for the high risk for post-operative thrombosis seen in individuals over the age of 40.

  19. Acquired factor VII deficiency associated with acute myeloid leukemia.

    PubMed

    Anoun, Soumaya; Lamchahab, Mouna; Oukkache, Bouchra; Qachouh, Maryam; Benchekroun, Said; Quessar, Asmaa

    2015-04-01

    Isolated acquired factor VII deficiency is a rare coagulopathy. It has been reported in 31 patients with malignancy, sepsis, postoperatively, aplastic anemia, and during bone marrow transplantation. We discuss, through a new case of acquired factor VII deficiency, the characteristics of this disease when it is associated with acute myeloid leukemia. Acquired factor VII deficiency in hematological diseases can be caused by intensive chemotherapy, infections, or hepatic dysfunction. The best treatment in developing countries remains corticosteroids associated with plasma exchange, frozen plasma, and antibiotics.

  20. Factor VII deficiency: a single-center experience.

    PubMed

    Salcioglu, Zafer; Akcay, Arzu; Sen, Hulya Sayilan; Aydogan, Gonul; Akici, Ferhan; Tugcu, Deniz; Ayaz, Nuray Aktay; Baslar, Zafer

    2012-11-01

    Congenital factor VII deficiency is the most common form of rare coagulation factor deficiencies. This article presents a retrospective evaluation of 73 factor VII deficiency cases that had been followed at our center. The study consisted of 48 males and 25 females (2 months-19 years). Thirty-one (42.5%) of them were asymptomatic. Out of symptomatic patients, 17 had severe clinical symptoms, whereas 8 presented with moderate and 17 with mild symptoms. The symptoms listed in order of frequency were as follows: epistaxis, petechia or ecchymose, easy bruising, and oral cavity bleeding. The genotype was determined in 8 patients. Recombinant activated factor VII (rFVIIa) was used to treat 49 bleeding episodes in 8 patients after 2002. In 2 patients with repeated central nervous system bleeding prophylaxis with rFVIIa was administered. No allergic and thrombotic events were observed during both treatment and prophylaxis courses. Antibody occurrence was not detected in the patients during treatment.

  1. Tissue Factor-Factor VII Complex As a Key Regulator of Ovarian Cancer Phenotypes.

    PubMed

    Koizume, Shiro; Miyagi, Yohei

    2015-01-01

    Tissue factor (TF) is an integral membrane protein widely expressed in normal human cells. Blood coagulation factor VII (fVII) is a key enzyme in the extrinsic coagulation cascade that is predominantly secreted by hepatocytes and released into the bloodstream. The TF-fVII complex is aberrantly expressed on the surface of cancer cells, including ovarian cancer cells. This procoagulant complex can initiate intracellular signaling mechanisms, resulting in malignant phenotypes. Cancer tissues are chronically exposed to hypoxia. TF and fVII can be induced in response to hypoxia in ovarian cancer cells at the gene expression level, leading to the autonomous production of the TF-fVII complex. Here, we discuss the roles of the TF-fVII complex in the induction of malignant phenotypes in ovarian cancer cells. The hypoxic nature of ovarian cancer tissues and the roles of TF expression in endometriosis are discussed. Arguments will be extended to potential strategies to treat ovarian cancers based on our current knowledge of TF-fVII function.

  2. Factor VII Deficiency: Clinical Phenotype, Genotype and Therapy.

    PubMed

    Napolitano, Mariasanta; Siragusa, Sergio; Mariani, Guglielmo

    2017-03-28

    Factor VII deficiency is the most common among rare inherited autosomal recessive bleeding disorders, and is a chameleon disease due to the lack of a direct correlation between plasma levels of coagulation Factor VII and bleeding manifestations. Clinical phenotypes range from asymptomatic condition-even in homozygous subjects-to severe life-threatening bleedings (central nervous system, gastrointestinal bleeding). Prediction of bleeding risk is thus based on multiple parameters that challenge disease management. Spontaneous or surgical bleedings require accurate treatment schedules, and patients at high risk of severe hemorrhages may need prophylaxis from childhood onwards. The aim of the current review is to depict an updated summary of clinical phenotype, laboratory diagnosis, and treatment of inherited Factor VII deficiency.

  3. Factor VII Deficiency: Clinical Phenotype, Genotype and Therapy

    PubMed Central

    Napolitano, Mariasanta; Siragusa, Sergio; Mariani, Guglielmo

    2017-01-01

    Factor VII deficiency is the most common among rare inherited autosomal recessive bleeding disorders, and is a chameleon disease due to the lack of a direct correlation between plasma levels of coagulation Factor VII and bleeding manifestations. Clinical phenotypes range from asymptomatic condition—even in homozygous subjects—to severe life-threatening bleedings (central nervous system, gastrointestinal bleeding). Prediction of bleeding risk is thus based on multiple parameters that challenge disease management. Spontaneous or surgical bleedings require accurate treatment schedules, and patients at high risk of severe hemorrhages may need prophylaxis from childhood onwards. The aim of the current review is to depict an updated summary of clinical phenotype, laboratory diagnosis, and treatment of inherited Factor VII deficiency. PMID:28350321

  4. Composition, apparatus, and process, for sorption of gaseous compounds of group II-VII elements

    DOEpatents

    Tom, Glenn M.; McManus, James V.; Luxon, Bruce A.

    1991-08-06

    Scavenger compositions are disclosed, which have utility for effecting the sorptive removal of hazardous gases containing Group II-VII elements of the Periodic Table, such as are widely encountered in the manufacture of semiconducting materials and semiconductor devices. Gas sorption processes including the contacting of Group II-VII gaseous compounds with such scavenger compositions are likewise disclosed, together with critical space velocity contacting conditions pertaining thereto. Further described are gas contacting apparatus, including mesh structures which may be deployed in gas contacting vessels containing such scavenger compositions, to prevent solids from being introduced to or discharged from the contacting vessel in the gas stream undergoing treatment. A reticulate heat transfer structure also is disclosed, for dampening localized exothermic reaction fronts when gas mixtures comprising Group II-VII constituents are contacted with the scavenger compositions in bulk sorption contacting vessels according to the invention.

  5. Blood glucose may condition factor VII levels in diabetic and normal subjects.

    PubMed

    Ceriello, A; Giugliano, D; Quatraro, A; Dello Russo, P; Torella, R

    1988-12-01

    Increased factor VII levels have been reported in Type 1 (insulin-dependent) diabetic subjects. A direct correlation between fasting plasma glucose and factor VII level was found to exist in both diabetic and normal subjects. Induced-hyperglycaemia was able to increase factor VII levels in both diabetic patients and normal control subjects while, when euglycaemia was achieved in diabetic patients, factor VII values returned to normal range. This study shows that the level of factor VII may be directly conditioned by circulating blood glucose and, therefore, stresses the role of hyperglycaemia in conditioning coagulation abnormalities in diabetes mellitus.

  6. The effects of three factor VII polymorphisms on factor VII coagulant levels in healthy Singaporean Chinese, Malay and Indian newborns.

    PubMed

    Quek, S C; Low, P S; Saha, N; Heng, C K

    2006-11-01

    Factor VII (FVII) is an independent risk factor for coronary artery disease. Three polymorphisms of the factor VII gene (F7) were studied in a group of healthy newborns comprising 561 Chinese, 398 Malays and 226 Asian Indians from Singapore. The allele frequencies of 3 polymorphisms (R353Q, Promoter 0/10bp Del/Ins and Intron 7) in the FVII gene were ascertained through genotyping by polymerase chain reaction and restriction digestion of amplified fragments. In Chinese the minor allele frequencies are Q: 0.04, Ins: 0.03, R7: 0.44; Malays, Q: 0.06, Ins: 0.10, R7: 0.41; and Indians, Q: 0.25, Ins: 0.23, R7: 0.43. Strong linkage disequilibrium (Delta > 0.7) is observed between the 0/10 bp and the R353Q sites in all ethnic groups. We conclude that: (i) the prevalence of the minor Q and Ins alleles of the R353Q and 0/10 bp polymorphisms are significantly higher in the Indian newborns than the Chinese and Malays; (ii) the Q allele is significantly associated (p = 0.01) with a lower plasma FVII coagulant level in the Indian and Malay neonates; and this polymorphism explains up to 3.8% of the variance in FVII coagulant levels; (iii) there is no significant difference in allele frequencies of the three polymorphisms between neonates with and without family histories of CAD.

  7. Interrelation between factor VII, prekallikrein, and hyperfibrinolysis in advanced cirrhosis.

    PubMed Central

    Violi, F; Alessandri, C; Ferro, D; Saliola, M; Cordova, C; Musca, A; Balsano, F

    1989-01-01

    Factor VII and prekallikrein activities were studied in 37 patients with liver cirrhosis who were in a decompensated state. Sixteen of them died 30-70 days after admission; 21 survived and were discharged after 30-80 days. Seven who died and six survivors had signs of hyperfibrinolysis: factor VII activity differentiated the two groups independently of the presence of hyperfibrinolysis. The presence of hyperfibrinolysis significantly reduced prekallikrein activity, which did not differentiate clearly survivors from non-survivors. Long term follow up of survivors showed a good correlation between factor VII and prekallikrein activities with long term survival. Hyperfibrinolysis seemed to influence the clinical course of patients: 87% of patients with hyperfibrinolysis who died had fatal haemorrhagic episodes. Low factor VII activity may be a precursor of terminal liver insufficiency. PMID:2613916

  8. Effect of N-acetylcysteine on the accuracy of the prothrombin time assay of plasma coagulation factor II+VII+X activity in subjects infused with the drug. Influence of time and temperature.

    PubMed

    Thorsen, Sixtus; Teisner, Ane; Jensen, Søren Astrup; Philips, Malou; Dalhoff, Kim; Bendtsen, Flemming

    2009-01-01

    The prothrombin time (PT) assay of factor II+VII+X activity is an important predictor of liver damage in paracetamol poisoned patients. It complicates interpretation of results that the antidote, acetylcysteine (NAC) depresses this activity. The aim was to investigate if NAC influences the accuracy of the plasma PT assay. The accuracy of Nycotest PT was studied using plasma added NAC in vitro and plasma from subjects infused with NAC. The latter results were compared with those obtained by analysis of PT by CoaguChek S. Therapeutic NAC concentrations added to plasma in vitro decreased factor II+VII+X activity at 37 degrees C in a time-dependent manner. This effect was quenched at temperatures <24 degrees C. Activity lost at 37 degrees C could partly be recovered by subsequent incubation at 5 or 20 degrees C. Incubation at 37 degrees C prior to assay led to a significant additional depression of factor II+VII+X activity in plasma from subjects infused with NAC during the first 3h of infusion indicating that it contained reactive NAC. The risk that this NAC interfered with the accuracy of the PT assay was considered minimal with samples stored below 24 degrees C. This was supported by similarity of results obtained by analysis of appropriately stored plasma and simultaneously drawn blood by CoaguChek S. Residual reactive NAC does not interfere with the accuracy of the PT assay of plasma stored below 24 degrees C, but NAC-induced loss in activity at 37 degrees C may be partly recovered during subsequent storage below 24 degrees C.

  9. Association of ACE and FACTOR VII gene variability with the risk of coronary heart disease in north Indian population.

    PubMed

    Sobti, R C; Maithil, Nishi; Thakur, Hitender; Sharma, Yashpaul; Talwar, K K

    2010-08-01

    The angiotensin converting enzyme (ACE) is a key factor in the production of angiotensin II and in the degradation of bradykinin. Chronic exposure to high levels of circulating and tissue ACE predispose to vascular wall thickening and atherosclerosis. Factor VII (FACTOR VII) is the first enzyme in the extrinsic pathway of the blood coagulation system and plays a key role in hemostasis; it also contributes to the occurrence of thrombotic events. In this study, we have examined the association of ACE and FACTOR VII gene in coronary heart disease patients (n = 300) and their age-matched controls (n = 300). Genotyping was done by PCR-RFLP method. No significant difference was observed in the distribution of I/D genotypes of ACE between cases and controls. In case of FACTOR VII R353Q polymorphism, there was not much difference in the distribution of alleles. AA genotype had protective effect for CHD (OR 0.56, 95% CI 0.37-0.83, P = 0.001). In case of FACTOR VII VNTR, there was difference in the distribution of alleles, H6 (73.5) and H7 (25.5) in cases, and H6 (70.5) and H7 (30.5) in controls. H6H7 and H7H7 genotypes had a protective effect for CHD with OR 0.27, 95% CI 0.18-0.41, P < 0.001, and OR 0.18, 95% CI 0.09-0.36, P < 0.001. Our study showed D allele of ACE to be associated with marginal risk of CHD, AA genotype of FACTOR VII R353Q and H6H7 and H7H7 genotypes of FACTOR VII VNTR showed protective effect for CHD.

  10. Is prophylaxis required for delivery in women with factor VII deficiency?

    PubMed Central

    Baumann Kreuziger, Lisa M.; Morton, Colleen T.; Reding, Mark T.

    2013-01-01

    Introduction Factor VII (fVII) deficiency is a rare congenital bleeding disorder in which fVII activity level and bleeding tendency do not completely correlate. Pregnancy and delivery present a significant hemostatic challenge to women with fVII deficiency. Treatment with recombinant factor VIIa (rfVIIa) carries a thrombotic risk and the literature is unclear whether prophylaxis is necessary prior to delivery. Aim To define management, hemorrhagic and thrombotic complications of pregnant women with fVII deficiency through a systematic review. Methods Medical databases (PubMed, MEDLINE, CINAHL, Academic Search Premier, Cochrane Library, Web of Science and Scopus) were searched using “factor VII deficiency” and “pregnancy” or “surgery.” Overall 34 articles, 4 abstracts, and 3 institutional cases were reviewed. Results Literature from 1953–2011 reported 94 live births from 62 women with fVII deficiency. The median fVII activity was 5.5%. Hemostatic prophylaxis was used in 32% of deliveries. Without prophylaxis, 40 vaginal deliveries and 16 cesarean sections were completed. The odds of receiving prophylaxis were 2.9 times higher in women undergoing cesarean section compared to vaginal delivery. Post-partum hemorrhage occurred in 10% of deliveries with prophylaxis and 13% of deliveries without prophylaxis. The fVII level did not significantly differ between women who did and did not receive prophylaxis. Conclusion We present the only systematic review of the management of pregnancy in fVII deficient women. No difference in post-partum hemorrhage was seen in deliveries with and without prophylaxis. Therefore we recommend that rfVIIa be available in the case of hemorrhage or surgical intervention, but not as mandatory prophylaxis. PMID:23607277

  11. Is prophylaxis required for delivery in women with factor VII deficiency?

    PubMed

    Baumann Kreuziger, L M; Morton, Colleen T; Reding, Mark T

    2013-11-01

    Factor VII (fVII) deficiency is a rare congenital bleeding disorder in which fVII activity level and bleeding tendency do not completely correlate. Pregnancy and delivery present a significant haemostatic challenge to women with fVII deficiency. Treatment with recombinant factor VIIa (rfVIIa) carries a thrombotic risk and the literature is not clear whether prophylaxis is necessary prior to delivery. The aim of this study was to define management, haemorrhagic and thrombotic complications of pregnant women with fVII deficiency through a systematic review. Medical databases (PubMed, MEDLINE, CINAHL, Academic Search Premier, Cochrane Library, Web of Science and Scopus) were searched using "factor VII deficiency" and "pregnancy" or "surgery." Overall 34 articles, four abstracts, and three institutional cases were reviewed. Literature from 1953 to 2011 reported 94 live births from 62 women with fVII deficiency. The median fVII activity was 5.5%. Haemostatic prophylaxis was used in 32% of deliveries. Without prophylaxis, 40 vaginal deliveries and 16 caesarean sections were completed. The odds of receiving prophylaxis were 2.9 times higher in women undergoing caesarean section compared to vaginal delivery. Post-partum haemorrhage occurred in 10% of deliveries with prophylaxis and 13% of deliveries without prophylaxis. The fVII level did not significantly differ between women who did and did not receive prophylaxis. We present the only systematic review of the management of pregnancy in fVII deficient women. No difference in post-partum haemorrhage was seen in deliveries with and without prophylaxis. Therefore, we recommend that rfVIIa be available in the case of haemorrhage or surgical intervention, but not as mandatory prophylaxis. © 2013 John Wiley & Sons Ltd.

  12. Serendipitous Discovery of Factor VII Deficiency and the Ensuing Dilemma.

    PubMed

    Umakanthan, Jayadev M; Dhakal, Prajwal; Gundabolu, Krishna; Koepsell, Scott A; Baljevic, Muhamed

    2018-03-01

    Congenital factor VII deficiency is a challenging disorder to manage, as it is associated with varied genotypes that do not clinically correlate with a bleeding phenotype. Individuals with severe factor VII deficiency (FVII: c <1%) might be asymptomatic, while patients with moderate deficiency (FVII: c level >5%) may experience severe hemorrhages. In modern medicine, due to extensive routine pre-operative laboratory testing, clinically asymptomatic patients without any bleeding history might be incidentally discovered, raising clinical dilemmas. Careful consideration of bleeding versus thrombosis risk has to be made in such cases, especially in the elderly. Clinical history of no prior bleeding complications may be a reassuring factor. Minimal required replacement dosing of recombinant activated factor VII can be given peri-operatively in such situations, with close monitoring.

  13. Coagulation factor VII is regulated by androgen receptor in breast cancer.

    PubMed

    Naderi, Ali

    2015-02-01

    Androgen receptor (AR) is widely expressed in breast cancer; however, there is limited information on the key molecular functions and gene targets of AR in this disease. In this study, gene expression data from a cohort of 52 breast cancer cell lines was analyzed to identify a network of AR co-expressed genes. A total of 300 genes, which were significantly enriched for cell cycle and metabolic functions, showed absolute correlation coefficients (|CC|) of more than 0.5 with AR expression across the dataset. In this network, a subset of 35 "AR-signature" genes were highly co-expressed with AR (|CC|>0.6) that included transcriptional regulators PATZ1, NFATC4, and SPDEF. Furthermore, gene encoding coagulation factor VII (F7) demonstrated the closest expression pattern with AR (CC=0.716) in the dataset and factor VII protein expression was significantly associated to that of AR in a cohort of 209 breast tumors. Moreover, functional studies demonstrated that AR activation results in the induction of factor VII expression at both transcript and protein levels and AR directly binds to a proximal region of F7 promoter in breast cancer cells. Importantly, AR activation in breast cancer cells induced endogenous factor VII activity to convert factor X to Xa in conjunction with tissue factor. In summary, F7 is a novel AR target gene and AR activation regulates the ectopic expression and activity of factor VII in breast cancer cells. These findings have functional implications in the pathobiology of thromboembolic events and regulation of factor VII/tissue factor signaling in breast cancer. Copyright © 2014 Elsevier Inc. All rights reserved.

  14. Prophylactic treatment of hereditary severe factor VII deficiency in pregnancy.

    PubMed

    Pfrepper, Christian; Siegemund, Annelie; Hildebrandt, Sven; Kronberg, Juliane; Scholz, Ute; Niederwieser, Dietger

    2017-09-01

    : Severe hereditary factor VII deficiency is a rare bleeding disorder and may be associated with a severe bleeding phenotype. We describe a pregnancy in a 33-year-old woman with compound heterozygous factor VII deficiency and a history of severe menorrhagia and mucocutaneous bleedings. After discontinuation of contraceptives, menstruation was covered with recombinant activated factor VII (rFVIIa), and during pregnancy, rFVIIa had to be administered in first trimester in doses ranging from 15 to 90 μg/kg per day because of recurrent retroplacental hematomas and vaginal bleedings. Thrombin generation was measured in first trimester at different doses of rFVIIa and showed an increase in lag time when doses of less than 30 μg/kg/day were administered, whereas time to thrombin peak and peak thrombin were not influenced. A low-dose rFVIIa prophylactic treatment of 15 μg/kg every other day in the late second and in the third trimester was sufficient to allow a successful childbirth in this patient with severe factor VII deficiency.

  15. Self-production of tissue factor-coagulation factor VII complex by ovarian cancer cells.

    PubMed

    Yokota, N; Koizume, S; Miyagi, E; Hirahara, F; Nakamura, Y; Kikuchi, K; Ruf, W; Sakuma, Y; Tsuchiya, E; Miyagi, Y

    2009-12-15

    Thromboembolic events are a major complication in ovarian cancer patients. Tissue factor (TF) is frequently overexpressed in ovarian cancer tissue and correlates with intravascular thrombosis. TF binds to coagulation factor VII (fVII), changing it to its active form, fVIIa. This leads to activation of the extrinsic coagulation cascade. fVII is produced by the liver and believed to be supplied from blood plasma at the site of coagulation. However, we recently showed that ovarian cancer cells express fVII transcripts under normoxia and that this transcription is inducible under hypoxia. These findings led us to hypothesise that ovarian cancer cells are intrinsically associated with TF-fVIIa coagulation activity, which could result in thrombosis. In this study, we examined whether ectopically expressed fVII could cause thrombosis by means of immunohistochemistry, RT-PCR, western blotting and flow cytometry. Ectopic fVII expression occurs frequently in ovarian cancers, particularly in clear cell carcinoma. We further showed that ovarian cancer cells express TF-fVIIa on the cell surface under normoxia and that this procoagulant activity is enhanced by hypoxic stimuli. Moreover, we showed that ovarian cancer cells secrete microparticles (MPs) with TF-fVIIa activity. Production of this procoagulant secretion is enhanced under hypoxia. These results raise the possibility that cancer cell-derived TF-fVIIa could cause thrombotic events in ovarian cancer patients.

  16. Speciation analysis of Mn(II)/Mn(VII) using Fe3O4@ionic liquids-β-cyclodextrin polymer magnetic solid phase extraction coupled with ICP-OES.

    PubMed

    Chen, Songqing; Qin, Xingxiu; Gu, Weixi; Zhu, Xiashi

    2016-12-01

    Ionic liquids-β-cyclodextrin polymer (ILs-β-CDCP) was attached on Fe 3 O 4 nanoparticles to prepare magnetic solid phase extraction agent (Fe 3 O 4 @ILs-β-CDCP). The properties and morphology of Fe 3 O 4 @ILs-β-CDCP were characterized by Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction(XRD), size distribution and magnetic analysis. A new method of magnetic solid phase extraction (MSPE) coupled to ICP-OES for the speciation of Mn(II)/Mn(VII) in water samples was established. The results showed that Mn(VII) and total manganese [Mn(II)+Mn(VII)] were quantitatively extracted after adjusting aqueous sample solution to pH 6.0 and 10.0, respectively. Mn(II) was calculated by subtraction of Mn(VII) from total manganese. Fe 3 O 4 @ILs-β-CDCP showed a higher adsorption capacity toward Mn(II) and Mn(VII). Several factors, such as the pH value, extraction temperature and sample volume, were optimized to achieve the best extraction efficiency. Moreover, the adsorption ability of Fe 3 O 4 @ILs-β-CDCP would not be significantly lower after reusing of 10 times. The accuracy of the developed method was confirmed by analyzing certified reference materials (GSB 07-1189-2000), and by spiking spring water, city water and lake water samples. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. Effects of Recombinant Activated Factor VII in Traumatic Nonsurgical Intracranial Hemorrhage

    DTIC Science & Technology

    2006-09-01

    with inhibitors to factors VIII and IX, and it is ap- proved in Europe for the treatment of patients with acquired hemophilia, congenital FVII deficiency...GARY P. WRATTEN SURGICAL SYMPOSIUM Effects of Recombinant Activated Factor VII in Traumatic Nonsurgical Intracranial Hemorrhage Christopher E. White...OBJECTIVE: To determine whether treatment with recombi- nant activated factor VII (rFVIIa) will prevent progression of bleeding in nonsurgical

  18. Pathogenetic role of Factor VII deficiency and thrombosis in cross-reactive material positive patients.

    PubMed

    Girolami, A; Sambado, L; Bonamigo, E; Ferrari, S; Lombardi, A M

    2013-12-01

    Congenital Factor VII (FVII) deficiency can be divided into two groups: cases of "true" deficiency, or cross-reactive material (CRM) negative and variants that are cross-reactive material positive.The first form is commonly recognized as Type I condition whereas the second one is known as Type II. FVII deficiency has been occasionally associated with thrombotic events, mainly venous. The reasons underlying this peculiar manifestation are unknown even though in the majority of associated patients thrombotic risk factors are present. The purpose of the present study was to investigate if a thrombotic event was more frequent in Type I or in Type II defect.The majority of patients with FVII deficiency and thrombosis belong to Type II defects. In the following paper we discuss the possible role of the dysfunctional FVII cross-reaction material as a contributory cause for the occurrence of thrombosis.

  19. Factor VII deficiency: a novel missense variant and genotype-phenotype correlation in patients from Southern Italy.

    PubMed

    Tiscia, Giovanni; Favuzzi, Giovanni; Chinni, Elena; Colaizzo, Donatella; Fischetti, Lucia; Intrieri, Mariano; Margaglione, Maurizio; Grandone, Elvira

    2017-01-01

    This study aimed at attempting to correlate genotype and phenotype in factor VII deficiency. Here, we present molecular and clinical findings of 10 patients with factor VII deficiency. From 2013 to 2016, 10 subjects were referred to our center because of a prolonged prothrombin time identified during routine or presurgery examinations or after a laboratory assessment of a bleeding episode. Mutation characterization was performed using the bioinformatics applications PROMO, SIFT, and Polyphen-2. Structural changes in the factor VII protein were analyzed using the SPDB viewer tool. Of the 10 variants we identified, 1 was responsible for a novel missense change (c.1199G>C, p.Cys400Ser); in 2 cases we identified the c.-54G>A and c.509G>A (p.Arg170His) polymorphic variants in the 5'-upstream region of the factor VII gene and exon 6, respectively. To our knowledge, neither of these polymorphic variants has been described previously in factor VII-deficient patients. In silico predictions showed differences in binding sites for transcription factors caused by the c.-54G>A variant and a probable damaging effect of the p.Cys400Ser missense change on factor VII active conformation, leading to breaking of the Cys400-Cys428 disulfide bridge. Our findings further suggest that, independently of factor VII levels and of variants potentially affecting factor VII levels, environmental factors, e.g., trauma, could heavily influence the clinical phenotype of factor VII-deficient patients.

  20. Tissue factor is an angiogenic-specific receptor for factor VII-targeted immunotherapy and photodynamic therapy.

    PubMed

    Hu, Zhiwei; Cheng, Jijun; Xu, Jie; Ruf, Wolfram; Lockwood, Charles J

    2017-02-01

    Identification of target molecules specific for angiogenic vascular endothelial cells (VEC), the inner layer of pathological neovasculature, is critical for discovery and development of neovascular-targeting therapy for angiogenesis-dependent human diseases, notably cancer, macular degeneration and endometriosis, in which vascular endothelial growth factor (VEGF) plays a central pathophysiological role. Using VEGF-stimulated vascular endothelial cells (VECs) isolated from microvessels, venous and arterial blood vessels as in vitro angiogenic models and unstimulated VECs as a quiescent VEC model, we examined the expression of tissue factor (TF), a membrane-bound receptor on the angiogenic VEC models compared with quiescent VEC controls. We found that TF is specifically expressed on angiogenic VECs in a time-dependent manner in microvessels, venous and arterial vessels. TF-targeted therapeutic agents, including factor VII (fVII)-IgG1 Fc and fVII-conjugated photosensitizer, can selectively bind angiogenic VECs, but not the quiescent VECs. Moreover, fVII-targeted photodynamic therapy can selectively and completely eradicate angiogenic VECs. We conclude that TF is an angiogenic-specific receptor and the target molecule for fVII-targeted therapeutics. This study supports clinical trials of TF-targeted therapeutics for the treatment of angiogenesis-dependent diseases such as cancer, macular degeneration and endometriosis.

  1. Topical application of recombinant activated factor VII during cesarean delivery for placenta previa.

    PubMed

    Schjoldager, Birgit T B G; Mikkelsen, Emmeli; Lykke, Malene R; Præst, Jørgen; Hvas, Anne-Mette; Heslet, Lars; Secher, Niels J; Salvig, Jannie D; Uldbjerg, Niels

    2017-06-01

    During cesarean delivery in patients with placenta previa, hemorrhaging after removal of the placenta is often challenging. In this condition, the extraordinarily high concentration of tissue factor at the placenta site may constitute a principle of treatment as it activates coagulation very effectively. The presumption, however, is that tissue factor is bound to activated factor VII. We hypothesized that topical application of recombinant activated factor VII at the placenta site reduces bleeding without affecting intravascular coagulation. We included 5 cases with planned cesarean delivery for placenta previa. After removal of the placenta, the surgeon applied a swab soaked in recombinant activated factor VII containing saline (1 mg in 246 mL) to the placenta site for 2 minutes; this treatment was repeated once if the bleeding did not decrease sufficiently. We documented the treatment on video recordings and measured blood loss. Furthermore, we determined hemoglobin concentration, platelet count, international normalized ratio, activated partial thrombin time, fibrinogen (functional), factor VII:clot, and thrombin generation in peripheral blood prior to and 15 minutes after removal of the placenta. We also tested these blood coagulation variables in 5 women with cesarean delivery planned for other reasons. Mann-Whitney test was used for unpaired data. In all 5 cases, the uterotomy was closed under practically dry conditions and the median blood loss was 490 (range 300-800) mL. There were no adverse effects of recombinant activated factor VII and we did not measure factor VII to enter the circulation. Neither did we observe changes in thrombin generation, fibrinogen, activated partial thrombin time, international normalized ratio, and platelet count in the peripheral circulation (all P values >.20). This study indicates that in patients with placenta previa, topical recombinant activated factor VII may diminish bleeding from the placenta site without initiation

  2. Lack of bleeding in patients with severe factor VII deficiency.

    PubMed

    Barnett, J Mark; Demel, Kurt C; Mega, Anthony E; Butera, James N; Sweeney, Joseph D

    2005-02-01

    Factor VII deficiency, although rare, is now recognized as the most common autosomal recessive inherited factor deficiency. It is usually considered to be associated with bleeding only in the severely affected subject and heterozygotes (>10%) are not considered at risk. The general recommendation for surgery is to achieve a FVII level in excess of 15% (0.15 1U/mL). We present three cases of severe factor VII deficiency, each of whom appeared hemostatically competent based on clinical history. Subject 1 is a 33 year-old African-American female with a baseline FVII of <1%, who had a fractured tibia requiring open reduction with internal fixation without any FVII replacement and subsequently underwent successful laparoscopic knee surgery with a factor VII level measured at 6%. Subject 2 is a 58 year-old African-American female with a factor VII level of 9% who underwent an elective left total hip replacement without any factor replacement and had no excessive bleeding, but who sustained a pulmonary embolism postoperatively. Subject 3 is a 19-year-old African-American male with a baseline FVII of 1% with a history of active participation in football without noticeable injury and who underwent an emergent appendectomy without bleeding. These three cases represent individuals with the severe form of FVII deficiency who did not exhibit excessive bleeding when challenged with surgical procedures. The clinical history would appear the most valuable tool in predicting the likelihood of bleeding in these patients, and we suggest that the presumption that all patients with severe FVII deficiency should receive replacement therapy before surgical procedures may not be valid in all cases. Copyright 2005 Wiley-Liss, Inc.

  3. Age-dependent regulation of ERF-VII transcription factor activity in Arabidopsis thaliana.

    PubMed

    Giuntoli, Beatrice; Shukla, Vinay; Maggiorelli, Federica; Giorgi, Federico M; Lombardi, Lara; Perata, Pierdomenico; Licausi, Francesco

    2017-10-01

    The Group VII Ethylene Responsive Factors (ERFs-VII) RAP2.2 and RAP2.12 have been mainly characterized with regard to their contribution as activators of fermentation in plants. However, transcriptional changes measured in conditions that stabilize these transcription factors exceed the mere activation of this biochemical pathway, implying additional roles performed by the ERF-VIIs in other processes. We evaluated gene expression in transgenic Arabidopsis lines expressing a stabilized form of RAP2.12, or hampered in ERF-VII activity, and identified genes affected by this transcriptional regulator and its homologs, including some involved in oxidative stress response, which are not universally induced under anaerobic conditions. The contribution of the ERF-VIIs in regulating this set of genes in response to chemically induced or submergence-stimulated mitochondria malfunctioning was found to depend on the plant developmental stage. A similar age-dependent mechanism also restrained ERF-VII activity upon the core-hypoxic genes, independently of the N-end rule pathway, which is accounted for the control of the anaerobic response. To conclude, this study shed new light on a dual role of ERF-VII proteins under submergence: as positive regulators of the hypoxic response and as repressors of oxidative-stress related genes, depending on the developmental stage at which plants are challenged by stress conditions. © 2017 John Wiley & Sons Ltd.

  4. Factors Influencing Title VII Bilingual Program Institutionalization.

    ERIC Educational Resources Information Center

    Lewis, Gerald R.; And Others

    1985-01-01

    This study of the primary restraining and driving forces that influence Title VII bilingual education programs found the external environment, the local community, to be the main factor influencing institutionalization and self-renewal. The internal environment--the local school, and the local school's organization or central office, school board,…

  5. Prophylaxis in congenital factor VII deficiency: indications, efficacy and safety. Results from the Seven Treatment Evaluation Registry (STER).

    PubMed

    Napolitano, Mariasanta; Giansily-Blaizot, Muriel; Dolce, Alberto; Schved, Jean F; Auerswald, Guenter; Ingerslev, Jørgen; Bjerre, Jens; Altisent, Carmen; Charoenkwan, Pimlak; Michaels, Lisa; Chuansumrit, Ampaiwan; Di Minno, Giovanni; Caliskan, Umran; Mariani, Guglielmo

    2013-04-01

    Because of the very short half-life of factor VII, prophylaxis in factor VII deficiency is considered a difficult endeavor. The clinical efficacy and safety of prophylactic regimens, and indications for their use, were evaluated in factor VII-deficient patients in the Seven Treatment Evaluation Registry. Prophylaxis data (38 courses) were analyzed from 34 patients with severe factor VII deficiency (<1-45 years of age, 21 female). Severest phenotypes (central nervous system, gastrointestinal, joint bleeding episodes) were highly prevalent. Twenty-one patients received recombinant activated factor VII (24 courses), four received plasma-derived factor VII, and ten received fresh frozen plasma. Prophylactic schedules clustered into "frequent" courses (three times weekly, n=23) and "infrequent" courses (≤ 2 times weekly, n=15). Excluding courses for menorrhagia, "frequent" and "infrequent" courses produced 18/23 (78%) and 5/12 (41%) "excellent" outcomes, respectively; relative risk, 1.88; 95% confidence interval, 0.93-3.79; P=0.079. Long term prophylaxis lasted from 1 to >10 years. No thrombosis or new inhibitors occurred. In conclusion, a subset of patients with factor VII deficiency needed prophylaxis because of severe bleeding. Recombinant activated factor VII schedules based on "frequent" administrations (three times weekly) and a 90 μg/kg total weekly dose were effective. These data provide a rationale for long-term, safe prophylaxis in factor VII deficiency.

  6. Cost effectiveness of recombinant activated factor VII for the control of bleeding in patients with severe blunt trauma injuries in the United Kingdom.

    PubMed

    Morris, S; Ridley, S; Munro, V; Christensen, M C

    2007-01-01

    The aim of this study was to assess the lifetime cost effectiveness of recombinant activated factor VII vs placebo as adjunctive therapy for control of bleeding in patients with severe blunt trauma in the UK. We developed a cost-effectiveness model based on patient level data from a 30-day international, randomised, placebo-controlled Phase II trial. The data were supplemented with secondary data from UK sources to estimate lifetime costs and benefits. The model produced a baseline estimate of the incremental cost per life year gained with recombinant activated factor VII relative to placebo of 12 613 UK pounds. The incremental cost per quality adjusted life year gained was 18 825 UK pounds. These estimates are sensitive to the choice of discount rate and health state utility values used. Preliminary results suggest that relative to placebo, recombinant activated factor VII may be a cost-effective therapy to the UK National Health Service.

  7. Life-threatening bleeding in a case of autoantibody-induced factor VII deficiency.

    PubMed

    Okajima, K; Ishii, M

    1999-02-01

    A male patient presented with life-threatening bleeding induced by autoantibody-induced factor VII (F.VII) deficiency. This patient had macroscopic hematuria, skin ecchymosis, gastrointestinal bleeding, and a neck hematoma that was causing disturbed respiration. He developed acute renal failure and acute hepatic failure, probably due to obstruction of the ureters and the biliary tract, respectively. Although activated partial thromboplastin time was normal, prothrombin time (PT) was remarkably prolonged at 71.8 seconds compared to 14.0 seconds in a normal control. Both the immunoreactive level of F.VII antigen and the F.VII activity of the patient's plasma samples were < 1.0% of normal. Although an equal part of normal plasma was added to the patient's plasma, PT was not corrected. The patient's plasma inhibited F.VII activity. These findings suggested the presence of a plasma inhibitor for F.VII. After administration of large doses of methylprednisolone, PT was gradually shortened and plasma levels of F.VII increased over time. Bleeding, acute renal failure, and acute hepatic failure improved markedly following the steroid treatment. These observations suggest that life-threatening bleeding can be induced by autoantibody-induced F.VII deficiency and that immunosuppressive therapy using large doses of steroid can be successful in inhibiting the production of the autoantibody.

  8. Ultraviolet Fe VII absorption and Fe II emission lines of central stars of planetary nebulae

    NASA Technical Reports Server (NTRS)

    Cheng, Kwang-Ping; Feibelman, Walter A.; Bruhweiler, Frederick C.

    1991-01-01

    The SWP camera of the IUE satellite was used in the high-dispersion mode to search for Fe VII absorption and Fe II high-excitation emission lines in five additional very hot central stars of planetary nebulae. Some of the Fe VII lines were detected at 1208, 1239, and 1332 A in all the objects of this program, LT 5, NGC 6058, NGC 7094, A43, and Lo 1 (= K1-26), as well as some of the Fe II emission lines at A 1360, 1776, 1869, 1881, 1884, and 1975 A. Two additional objects, NGC 2867 and He 2-131, were obtained from the IUE archive and were evaluated. The present study probably exhausts the list of candidates that are sufficiently bright and hot to be reached with the high-dispersion mode of the IUE.

  9. Ultraviolet Fe VII absorption and Fe II emission lines of central stars of planetary nebulae

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Cheng, Kwang-Ping; Feibelman, W.A.; Bruhweiler, F.C.

    1991-08-01

    The SWP camera of the IUE satellite was used in the high-dispersion mode to search for Fe VII absorption and Fe II high-excitation emission lines in five additional very hot central stars of planetary nebulae. Some of the Fe VII lines were detected at 1208, 1239, and 1332 A in all the objects of this program, LT 5, NGC 6058, NGC 7094, A43, and Lo 1 (= K1-26), as well as some of the Fe II emission lines at A 1360, 1776, 1869, 1881, 1884, and 1975 A. Two additional objects, NGC 2867 and He 2-131, were obtained from themore » IUE archive and were evaluated. The present study probably exhausts the list of candidates that are sufficiently bright and hot to be reached with the high-dispersion mode of the IUE. 17 refs.« less

  10. Stability of prothrombin and factor VII in freeze-dried plasma

    PubMed Central

    Brozović, M.; Gurd, L. J.; Robertson, I.; Bangham, D. R.

    1971-01-01

    The stability of prothrombin and factor VII was studied using accelerated degradation tests in three preparations of freeze-dried pooled normal plasmas. In a previous report (Brozović, Gurd, Robertson, and Bangham, 1971) factor X was shown to be relatively unstable in these preparations of freeze-dried plasma: it was calculated that up to 8% of the original factor X activity would be lost after 10 years at −20°C, up to 54% at 4°C, and up to 90% at room temperature. The losses of factor VII activity were estimated to be negligible at −20°C, between 2 and 18% at 4°C, and between 20 and 70% of the original activity at 20°C, after 10 years of storage. Prothrombin was found to be less stable than factor VII: the expected loss in 10 years at −20°C may be up to 4%, at 4°C up to 30%, and at 20°C up to 83% of the initial activity. These findings indicate that in freeze-dried plasma prothrombin as well as factor X may be insufficiently stable for plasma to serve as long-term reference material for the standardization of the one-stage prothrombin time. Moreover, the loss of prothrombin and factor X in freeze-dried plasma stored at 4°C may be so high that when it is required to preserve these factors it may be necessary to store freeze-dried plasma at lower temperatures. PMID:5130534

  11. Nattokinase decreases plasma levels of fibrinogen, factor VII, and factor VIII in human subjects.

    PubMed

    Hsia, Chien-Hsun; Shen, Ming-Ching; Lin, Jen-Shiou; Wen, Yao-Ke; Hwang, Kai-Lin; Cham, Thau-Ming; Yang, Nae-Cherng

    2009-03-01

    Nattokinase, a serine proteinase from Bacillus subtilis, is considered to be one of the most active functional ingredients found in natto. In this study, we hypothesized that nattokinase could reduce certain factors of blood clotting and lipids that are associated with an increase risk for cardiovascular disease (CVD). Thus, an open-label, self-controlled clinical trial was conducted on subjects of the following groups: healthy volunteers (Healthy Group), patients with cardiovascular risk factors (Cardiovascular Group), and patients undergoing dialysis (Dialysis Group). All subjects ingested 2 capsules of nattokinase (2000 fibrinolysis units per capsule) daily orally for 2 months. The laboratory measurements were performed on the screening visit and, subsequently, regularly after the initiation of the study. The intent-to-treat analysis was performed on all 45 enrolled subjects. By use of mixed model analysis, a significant time effect, but not group effect, was observed in the change from baseline of fibrinogen (P = .003), factor VII (P < .001), and factor VIII (P < .001), suggesting that the plasma levels of the 3 coagulation factors continuously declined during intake; also, the extents of decrease were similar between groups. After 2 months of administration, fibrinogen, factor VII, and factor VIII decreased 9%, 14%, and 17%, respectively, for the Healthy Group; 7%, 13%, and 19%, respectively, for the Cardiovascular Group; and 10%, 7%, and 19%, respectively, for the Dialysis Group, whereas blood lipids were unaffected by nattokinase. No significant changes of uric acid or notable adverse events were observed in any of the subjects. In summary, this study showed that oral administration of nattokinase could be considered as a CVD nutraceutical by decreasing plasma levels of fibrinogen, factor VII, and factor VIII.

  12. A rare combination: congenital factor VII deficiency with Chiari malformation.

    PubMed

    Bay, Ali; Aktekin, Elif; Erkutlu, Ibrahim

    2015-12-01

    Congenital factor (VII) deficiency is a rare bleeding disorder. We present a patient with congenital FVII deficiency and congenital hydrocephalus who underwent a ventriculoperitoneal shunt operation and needed no prophylaxis after the procedure.

  13. Evaluation of off-label recombinant activated factor VII for multiple indications in children.

    PubMed

    Reiter, Pamela D; Valuck, Robert J; Taylor, Ruston S

    2007-07-01

    Despite a paucity of safety and efficacy data, the use of recombinant activated factor VII in children for off-label indications has now surpassed its use in hemophilia. A retrospective chart review was conducted of 46 subjects (age, 6.7 +/- 6 years; weight, 26 +/- 20 kg) who received recombinant activated factor VII for nonhemophiliac indications between January 1, 2004, and September 1, 2005. Indications for use included prevention (n = 6) or treatment (n = 40) of bleeding due to general surgery, hepatic failure, gastrointestinal bleeding, severe traumatic brain injury, bone marrow transplant, cardiac, acetaminophen overdose, and multiorgan system failure. Decreases in prothrombin time, partial thromboplastin time, and international normalized ratio were observed. No inappropriate thrombotic events were noted. Administration of recombinant activated factor VII was associated with a reduction in coagulation markers without obvious adverse thrombotic events at cost of $4189 per dose. These findings should be confirmed in a prospective trial.

  14. Synthesis and characterization of (18)F-labeled active site inhibited factor VII (ASIS).

    PubMed

    Erlandsson, Maria; Nielsen, Carsten H; Jeppesen, Troels E; Kristensen, Jesper B; Petersen, Lars C; Madsen, Jacob; Kjaer, Andreas

    2015-05-15

    Activated factor VII blocked in the active site with Phe-Phe-Arg-chloromethyl ketone (active site inhibited factor VII (ASIS)) is a 50-kDa protein that binds with high affinity to its receptor, tissue factor (TF). TF is a transmembrane glycoprotein that plays an important role in, for example, thrombosis, metastasis, tumor growth, and tumor angiogenesis. The aim of this study was to develop an (18)F-labeled ASIS derivative to assess TF expression in tumors. Active site inhibited factor VII was labeled using N-succinimidyl-4-[(18)F]fluorobenzoate, and the [(18)F]ASIS was purified on a PD-10 desalting column. The radiochemical yield was 25 ± 6%, the radiochemical purity was >97%, and the pseudospecific radioactivity was 35 ± 9 GBq/µmol. The binding efficacy was evaluated in pull-down experiments, which monitored the binding of unlabeled ASIS and [(18)F]ASIS to TF and to a specific anti-factor VII antibody (F1A2-mAb). No significant difference in binding efficacy between [(18)F]ASIS and ASIS could be detected. Furthermore, [(18)F]ASIS was relatively stable in vitro and in vivo in mice. In conclusion, [(18)F]ASIS has for the first time been successfully synthesized as a possible positron emission tomography tracer to image TF expression levels. In vivo positron emission tomography studies to evaluate the full potential of [(18)F]ASIS are in progress. Copyright © 2015 John Wiley & Sons, Ltd.

  15. Pharmacodynamics of recombinant activated factor VII and plasma-derived factor VII in a cohort of severe FVII deficient patients.

    PubMed

    van Geffen, Mark; Mathijssen, Natascha C J; Holme, Pål A; Laros-van Gorkom, Britta A P; van Kraaij, Marian G J; Masereeuw, Roselinde; Peyvandi, Flora; van Heerde, Waander L

    2013-07-01

    Recombinant activated factor VII (rFVIIa) and plasma-derived factor VII (pdFVII) are used to prevent bleedings in severe FVII deficient patients, despite their short half-lifes. It is suggested that FVII levels of 15-20 IU/dL are sufficient to maintain hemostasis. We analyzed the pharmacodynamic effects of FVII substitution therapy in the Nijmegen Hemostasis Assay (NHA) that simultaneously measures thrombin and plasmin generation. Ten severe FVII deficient patients were treated with 20 μg/kg rFVIIa or 25 IU/kg pdFVII in a cross-over design. Thrombin generation lag-time (TG-LT) was identified as an effect-response parameter. Pharmacodynamic analysis using a maximum effect model showed 50% reduction of the TG-LT effect at ~2 IU/dL FVII activity for both rFVIIa and pdFVII. The FVII activity to obtain TG-LT comparable to the upper limit of normal range in healthy controls (4 min) was given by the effective concentration (ECnormal), showing sufficient hemostasis at 3-4 IU/dL FVII activity. No association was seen between FVII activity and other thrombin or plasmin generation parameters as measured by NHA. In conclusion, 3-4 IU/dL FVII activity seems sufficient to maintain hemostasis in patients with severe FVII deficiency during prophylaxis. These data may suggest a potential value for measurement of TG-LT in the monitoring of FVII(a) therapy. Copyright © 2013 Elsevier Ltd. All rights reserved.

  16. Administration of recombinant activated factor VII in the intensive care unit after complex cardiovascular surgery: clinical and economic outcomes.

    PubMed

    Uber, Walter E; Toole, John M; Stroud, Martha R; Haney, Jason S; Lazarchick, John; Crawford, Fred A; Ikonomidis, John S

    2011-06-01

    Refractory bleeding after complex cardiovascular surgery often leads to increased length of stay, cost, morbidity, and mortality. Recombinant activated factor VII administered in the intensive care unit can reduce bleeding, transfusion, and surgical re-exploration. We retrospectively compared factor VII administration in the intensive care unit with reoperation for refractory bleeding after complex cardiovascular surgery. From 1501 patients who underwent cardiovascular procedures between December 2003 and September 2007, 415 high-risk patients were identified. From this cohort, 24 patients were divided into 2 groups based on whether they either received factor VII in the intensive care unit (n = 12) or underwent reoperation (n = 12) for refractory bleeding. Preoperative and postoperative data were collected to compare efficacy, safety, and economic outcomes. In-hospital survival for both groups was 100%. Factor VII was comparable with reoperation in achieving hemostasis, with both groups demonstrating decreases in chest tube output and need for blood products. Freedom from reoperation was achieved in 75% of patients receiving factor VII, whereas reoperation was effective in achieving hemostasis alone in 83.3% of patients. Prothrombin time, international normalized ratio, and median operating room time were significantly less (P < .05) in patients who received factor VII. Both groups had no statistically significant differences in other efficacy, safety, or economic outcomes. Factor VII administration in the intensive care unit appears comparable with reoperation for refractory bleeding after complex cardiovascular surgical procedures and might represent an alternative to reoperation in selected patients. Future prospective, randomized controlled trials might further define its role. Copyright © 2011 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.

  17. Factor VII and protein C are phosphatidic acid-binding proteins.

    PubMed

    Tavoosi, Narjes; Smith, Stephanie A; Davis-Harrison, Rebecca L; Morrissey, James H

    2013-08-20

    Seven proteins in the human blood clotting cascade bind, via their GLA (γ-carboxyglutamate-rich) domains, to membranes containing exposed phosphatidylserine (PS), although with membrane binding affinities that vary by 3 orders of magnitude. Here we employed nanodiscs of defined phospholipid composition to quantify the phospholipid binding specificities of these seven clotting proteins. All bound preferentially to nanobilayers in which PS headgroups contained l-serine versus d-serine. Surprisingly, however, nanobilayers containing phosphatidic acid (PA) bound substantially more of two of these proteins, factor VIIa and activated protein C, than did equivalent bilayers containing PS. Consistent with this finding, liposomes containing PA supported higher proteolytic activity by factor VIIa and activated protein C toward their natural substrates (factors X and Va, respectively) than did PS-containing liposomes. Moreover, treating activated human platelets with phospholipase D enhanced the rates of factor X activation by factor VIIa in the presence of soluble tissue factor. We hypothesize that factor VII and protein C bind preferentially to the monoester phosphate of PA because of its accessibility and higher negative charge compared with the diester phosphates of most other phospholipids. We further found that phosphatidylinositol 4-phosphate, which contains a monoester phosphate attached to its myo-inositol headgroup, also supported enhanced enzymatic activity of factor VIIa and activated protein C. We conclude that factor VII and protein C bind preferentially to monoester phosphates, which may have implications for the function of these proteases in vivo.

  18. Mutation in the factor VII hepatocyte nuclear factor 4α-binding site contributes to factor VII deficiency.

    PubMed

    Zheng, Xing-Wu; Kudaravalli, Rama; Russell, Theresa T; DiMichele, Donna M; Gibb, Constance; Russell, J Eric; Margaritis, Paris; Pollak, Eleanor S

    2011-10-01

    Severe coagulant factor VII (FVII) deficiency in postpubertal dizygotic twin males results from two point mutations in the FVII gene, a promoter region T→C transition at -60 and a His-to-Arg substitution at amino acid 348; both mutations prevent persistence of plasma functional FVII. This report documents longitudinal laboratory measurements from infancy to adulthood of FVII coagulant activity (FVII:C) in the twin FVII-deficient patients; it also details specific biochemical analyses of the -60 T→C mutation. The results revealed FVII:C levels of less than 1% in infancy that remain severely decreased through puberty and into adulthood. In-vitro analyses utilizing hepatocyte nuclear factor 4α (HNF4α) co-transfection and a chromatin immunoprecipitation assay indicate that the -60 T→C mutation severely diminishes functional interaction between the FVII promoter and transcription factor HNF4α. The importance of interaction between the FVII gene and HNF4α in normal FVII expression provides an in-vivo illustration of the regulated expression of an autosomal gene encoding a coagulation protein. The constancy of FVII:C and peripubertal patient symptomatology reported here illustrates androgen-independent expression in contrast to expression with an analogous mutation in the promoter region of the gene encoding coagulation FIX.

  19. Speciation of Mn(II), Mn(VII) and total manganese in water and food samples by coprecipitation-atomic absorption spectrometry combination.

    PubMed

    Citak, Demirhan; Tuzen, Mustafa; Soylak, Mustafa

    2010-01-15

    A speciation procedure based on the coprecipitation of manganese(II) with zirconium(IV) hydroxide has been developed for the investigation of levels of manganese species. The determination of manganese levels was performed by flame atomic absorption spectrometry (FAAS). Total manganese was determined after the reduction of Mn(VII) to Mn(II) by ascorbic acid. The analytical parameters including pH, amount of zirconium(IV), sample volume, etc., were investigated for the quantitative recoveries of manganese(II). The effects of matrix ions were also examined. The recoveries for manganese(II) were in the range of 95-98%. Preconcentration factor was calculated as 50. The detection limit for the analyte ions based on 3 sigma (n=21) was 0.75 microg L(-1) for Mn(II). The relative standard deviation was found to be lower than 7%. The validation of the presented procedure was performed by analysis of certified reference material having different matrices, NIST SRM 1515 (Apple Leaves) and NIST SRM 1568a (Rice Flour). The procedure was successfully applied to natural waters and food samples.

  20. Fe(II)- and Sulfide-Facilitated Reduction of 99Tc(VII)O4- in Microbially Reduced Hyporheic Zone Sediments

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Lee, Ji-Hoon; Zachara, John M.; Fredrickson, Jim K.

    Redox-reactive, biogeochemical phases generated by reductive microbial activity in hyporheic zone sediments from a dynamic groundwater-river interaction zone were evaluated for their ability to reduce soluble pertechnetate [99Tc(VII)O4-] to less soluble Tc(IV). The sediments were bioreduced by indigenous microorganisms that were stimulated by organic substrate addition in synthetic groundwater with or without sulfate. In most treatments, 20 µmol L-1 initial aqueous Tc(VII) was reduced to near or below detection (3.82×10-9 mol L-1) over periods of days to months in suspensions of variable solids concentrations. Native sediments containing significant lithogenic Fe(II) in various phases were, in contrast, unreactive with Tc(VII). Themore » reduction rates in the bioreduced sediments increased with increases in sediment mass, in proportion to weak acid-extractable Fe(II) and sediment-associated sulfide (AVS). The rate of Tc(VII) reduction was first order with respect to both aqueous Tc(VII) concentration and sediment mass, but correlations between specific reductant concentrations and reaction rate were not found. X-ray microprobe measurements revealed a strong correlation between Tc hot spots and Fe-containing mineral particles in the sediment. However, only a portion of Fe-containing particles were Tc-hosts. The Tc-hot spots displayed a chemical signature (by EDXRF) similar to pyroxene. The application of autoradiography and electron microprobe allowed further isolation of Tc-containing particles that were invariably found to be ca 100 µm aggregates of primary mineral material embedded within a fine-grained phyllosilicate matrix. EXAFS spectroscopy revealed that the Tc(IV) within these were a combination of a Tc(IV)O2-like phase and Tc(IV)-Fe surface clusters, with a significant fraction of a TcSx-like phase in sediments incubated with SO42-. AVS was implicated as a more selective reductant at low solids concentration even though its concentration was below

  1. Fe(II)- and sulfide-facilitated reduction of 99Tc(VII)O4- in microbially reduced hyporheic zone sediments

    NASA Astrophysics Data System (ADS)

    Lee, Ji-Hoon; Zachara, John M.; Fredrickson, James K.; Heald, Steve M.; McKinley, James P.; Plymale, Andrew E.; Resch, Charles T.; Moore, Dean A.

    2014-07-01

    Redox-reactive, biogeochemical phases generated by reductive microbial activity in hyporheic zone sediments from a dynamic groundwater-river interaction zone were evaluated for their ability to reduce soluble pertechnetate [99Tc(VII)O4-] to less soluble Tc(IV). The sediments were bioreduced by indigenous microorganisms that were stimulated by organic substrate addition in synthetic groundwater with or without sulfate. In most treatments, 20 μmol L-1 initial aqueous Tc(VII) was reduced to near or below detection (3.82 × 10-9 mol L-1) over periods of days to months in suspensions of variable solids concentrations. Native sediments containing significant lithogenic Fe(II) in various phases were, in contrast, unreactive with Tc(VII). The reduction rates in the bioreduced sediments increased with increases in sediment mass, in proportion to weak acid-extractable Fe(II) and sediment-associated sulfide (AVS). The rate of Tc(VII) reduction was first order with respect to both aqueous Tc(VII) concentration and sediment mass, but correlations between specific reductant concentrations and reaction rate were not found. X-ray microprobe measurements revealed a strong correlation between Tc hot spots and Fe-containing mineral particles in the sediment. However, only a portion of Fe-containing particles were Tc-hosts. The Tc-hot spots displayed a chemical signature (by EDXRF) similar to pyroxene. The application of autoradiography and electron microprobe allowed further isolation of Tc-containing particles that were invariably found to be ca 100 μm aggregates of primary mineral material embedded within a fine-grained phyllosilicate matrix. EXAFS spectroscopy revealed that the Tc(IV) within these were a combination of a Tc(IV)O2-like phase and Tc(IV)-Fe surface clusters, with a significant fraction of a TcSx-like phase in sediments incubated with SO42-. AVS was implicated as a more selective reductant at low solids concentration even though its concentration was below that

  2. Case report: a 70-year-old man with undiagnosed factor VII deficiency presented with acute ischemic stroke.

    PubMed

    Ip, Hing-Lung; Chan, Anne Yin-Yan; Ng, Kit-Chung; Soo, Yannie Oi-Yan; Wong, Lawrence Ka-Sing

    2013-11-01

    Factor VII deficiency is an uncommon coagulation disorder that patient usually presents with bleeding diathesis, but thrombotic event has been reported. We report a case of unusual clinical presentation in a patient with undiagnosed factor VII deficiency who presented with acute ischemic stroke. Copyright © 2013 National Stroke Association. Published by Elsevier Inc. All rights reserved.

  3. Neuronal carbonic anhydrase VII provides GABAergic excitatory drive to exacerbate febrile seizures

    PubMed Central

    Ruusuvuori, Eva; Huebner, Antje K; Kirilkin, Ilya; Yukin, Alexey Y; Blaesse, Peter; Helmy, Mohamed; Jung Kang, Hyo; El Muayed, Malek; Christopher Hennings, J; Voipio, Juha; Šestan, Nenad; Hübner, Christian A; Kaila, Kai

    2013-01-01

    Brain carbonic anhydrases (CAs) are known to modulate neuronal signalling. Using a novel CA VII (Car7) knockout (KO) mouse as well as a CA II (Car2) KO and a CA II/VII double KO, we show that mature hippocampal pyramidal neurons are endowed with two cytosolic isoforms. CA VII is predominantly expressed by neurons starting around postnatal day 10 (P10). The ubiquitous isoform II is expressed in neurons at P20. Both isoforms enhance bicarbonate-driven GABAergic excitation during intense GABAA-receptor activation. P13–14 CA VII KO mice show behavioural manifestations atypical of experimental febrile seizures (eFS) and a complete absence of electrographic seizures. A low dose of diazepam promotes eFS in P13–P14 rat pups, whereas seizures are blocked at higher concentrations that suppress breathing. Thus, the respiratory alkalosis-dependent eFS are exacerbated by GABAergic excitation. We found that CA VII mRNA is expressed in the human cerebral cortex before the age when febrile seizures (FS) occur in children. Our data indicate that CA VII is a key molecule in age-dependent neuronal pH regulation with consequent effects on generation of FS. PMID:23881097

  4. A hypothesis: factor VII governs clot formation, tissue repair and apoptosis.

    PubMed

    Coleman, Lewis S

    2007-01-01

    A hypothesis: thrombin is a "Universal Enzyme of Energy Transduction" that employs ATP energy in flowing blood to activate biochemical reactions and cell effects in both hemostasis and tissue repair. All cells possess PAR-1 (thrombin) receptors and are affected by thrombin elevations, and thrombin effects on individual cell types are determined by their unique complement of PAR-1 receptors. Disruption of the vascular endothelium (VE) activates a tissue repair mechanism (TRM) consisting of the VE, tissue factor (TF), and circulating Factors VII, IX and X that governs localized thrombin elevations to activate clot formation and cellular effects that repair tissue damage. The culmination of the repair process occurs with the restoration of the VE followed by declines in thrombin production that causes Apoptosis ("programmed cell death") in wound-healing fibroblasts, which functions as a mechanism to draw wound edges together. The location and magnitude of TRM activity governs the location and magnitude of Factor VIII activity and clot formation, but the large size of Factor VIII prevents it from penetrating the clot formed by its activity, so that its effects are self-limiting. Factors VII, IX and X function primarily as tissue repair enzymes, while Factor VIII and Factor XIII are the only serine protease enzymes in the "Coagulation Cascade" that are exclusively associated with hemostasis.

  5. Continuous infusion of recombinant activated factor VII for bleeding control after lobectomy in a patient with inherited factor VII deficiency.

    PubMed

    Miyata, Naoko; Isaka, Mitsuhiro; Kojima, Hideaki; Maniwa, Tomohiro; Takahashi, Shoji; Takamiya, Osamu; Ohde, Yasuhisa

    2016-03-01

    Inherited factor VII (FVII) deficiency is a rare recessive inherited coagulation disorder with limited available information, especially in patients undergoing major thoracic surgery. In addition, an optimal management strategy for the disease has not been defined. We herein report a case involving a 61-year-old man with asymptomatic FVII deficiency who underwent a right middle and lower lobectomy to treat lung cancer. To the best of our knowledge, the present report is the first to describe the use of recombinant activated FVII continuous infusion for bleeding control after a major thoracic surgery in a patient with inherited FVII deficiency.

  6. Coagulation factor VII variants resistant to inhibitory antibodies.

    PubMed

    Branchini, Alessio; Baroni, Marcello; Pfeiffer, Caroline; Batorova, Angelika; Giansily-Blaizot, Muriel; Schved, Jean F; Mariani, Guglielmo; Bernardi, Francesco; Pinotti, Mirko

    2014-11-01

    Replacement therapy is currently used to prevent and treat bleeding episodes in coagulation factor deficiencies. However, structural differences between the endogenous and therapeutic proteins might increase the risk for immune complications. This study was aimed at identifying factor (F)VII variants resistant to inhibitory antibodies developed after treatment with recombinant activated factor VII (rFVIIa) in a FVII-deficient patient homozygous for the p.A354V-p.P464Hfs mutation, which predicts trace levels of an elongated FVII variant in plasma. We performed fluorescent bead-based binding, ELISA-based competition as well as fluorogenic functional (activated FX and thrombin generation) assays in plasma and with recombinant proteins. We found that antibodies displayed higher affinity for the active than for the zymogen FVII (half-maximal binding at 0.54 ± 0.04 and 0.78 ± 0.07 BU/ml, respectively), and inhibited the coagulation initiation phase with a second-order kinetics. Isotypic analysis showed a polyclonal response with a large predominance of IgG1. We hypothesised that structural differences in the carboxyl-terminus between the inherited FVII and the therapeutic molecules contributed to the immune response. Intriguingly, a naturally-occurring, poorly secreted and 5-residue truncated FVII (FVII-462X) escaped inhibition. Among a series of truncated rFVII molecules, we identified a well-secreted and catalytically competent variant (rFVII-464X) with reduced binding to antibodies (half-maximal binding at 0.198 ± 0.003 BU/ml) as compared to the rFVII-wt (0.032 ± 0.002 BU/ml), which led to a 40-time reduced inhibition in activated FX generation assays. Taken together our results provide a paradigmatic example of mutation-related inhibitory antibodies, strongly support the FVII carboxyl-terminus as their main target and identify inhibitor-resistant FVII variants.

  7. Microwave assisted synthesis of novel acridine-acetazolamide conjugates and investigation of their inhibition effects on human carbonic anhydrase isoforms hCA I, II, IV and VII.

    PubMed

    Ulus, Ramazan; Aday, Burak; Tanç, Muhammet; Supuran, Claudiu T; Kaya, Muharrem

    2016-08-15

    4-Amino-N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)benzamide was condensed with cyclic-1,3-diketones (dimedone and cyclohexane-1,3-dione) and aromatic aldehydes under microwave irradiation, leading to a series of acridine-acetazolamide conjugates. The new compounds were investigated as inhibitors of carbonic anhydrases (CA, EC 4.2.1.1), and more precisely cytosolic isoforms hCA I, II, VII and membrane-bound one hCA IV. All investigated isoforms were inhibited in low micromolar and nanomolar range by the new compounds. hCA IV and VII were inhibited with KIs in the range of 29.7-708.8nM (hCA IV), and of 1.3-90.7nM (hCA VII). For hCA I and II the KIs were in the range of 6.7-335.2nM (hCA I) and of 0.5-55.4nM (hCA II). The structure-activity relationships (SAR) for the inhibition of these isoforms with the acridine-acetazolamide conjugates reported here were delineated. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. R353Q polymorphism in the factor VII gene and cardiovascular risk in Heterozygous Familial Hypercholesterolemia: a case-control study.

    PubMed

    Criado-García, Juan; Fuentes, Francisco; Cruz-Teno, Cristina; García-Rios, Antonio; Jiménez-Morales, Anabel; Delgado-Lista, Javier; Mata, Pedro; Alonso, Rodrigo; López-Miranda, José; Pérez-Jiménez, Francisco

    2011-04-09

    Heterozygous Familial Hypercholesterolemia (FH) is a genetic disorder characterized by a high risk of cardiovascular disease. Certain polymorphisms of the factor VII gene have been associated with the development of coronary artery disease and there is a known association between factor VII levels and polymorphic variants in this gene. To date, no study has evaluated the association between factor VII and coronary artery disease in patients with FH. This case-control study comprised 720 patients (546 with FH and 174 controls). We determined the prevalence and allele frequencies of the R353Q polymorphism of factor VII, the plasma levels of factor VII antigen (FVII Ag) and whether they could be predictive factors for cardiovascular risk. 75% (410) of the patients with FH were RR, 23% (127) RQ and 1.6% (9) QQ; in the control group 75.3% (131) were RR, 21.3% (37) RQ and 3.4% (6) QQ (p = 0.32). No statistically significant associations were observed in the distribution of genotypes and allele frequencies between case (FH) and control groups. Nor did we find differences when we evaluated the relationship between the R353Q polymorphism and cardiovascular risk (including coronary disease, ischemic stroke and peripheral arterial disease), either in the univariate analysis or after adjustment for sex, age, arterial hypertension, body mass index, xanthomas, diabetes, smoking, HDLc and LDLc and lipid-lowering treatment. The FVII Ag concentrations behaved in a similar fashion, with no differences for the interaction between controls and those with FH (RR vs. RQ/QQ; p = 0.96). In the subgroup of patients with FH no association was found among cardiovascular disease, genotype and FVII Ag levels (RR vs. RQ/QQ; p = 0.97). Our study did not find a direct relationship between cardiovascular risk in patients with Heterozygous Familial Hypercholesterolemia, the R353Q polymorphism of factor VII and FVII Ag levels.

  9. A role for very low-dose recombinant activated factor VII in refractory bleeding after cardiac surgery: Lessons from an observational study.

    PubMed

    Hoffmann, Till; Assmann, Alexander; Dierksen, Angelika; Roussel, Elisabeth; Ullrich, Sebastian; Lichtenberg, Artur; Albert, Alexander; Sixt, Stephan

    2018-04-18

    Although off-label use of recombinant activated factor VII against refractory bleeding is incorporated in current guideline recommendations, safety concerns persist predominantly with respect to thromboembolic complications. We analyzed the safety and efficacy of recombinant activated factor VII at a very low dose in cardiosurgical patients with refractory bleeding. This prospective study includes 1180 cardiosurgical patients at risk of bleeding. Goal-directed substitution was based on real-time laboratory testing and clinical scoring of the bleeding intensity. All patients who fulfilled the criteria for enhanced risk of bleeding (n = 281) were consequently included in the present analysis. Patients in whom refractory bleeding developed despite substitution with specific hemostatic compounds (n = 167) received a single shot of very low-dose recombinant activated factor VII (≤20 μg/kg). Mortality and risk of thromboembolic complications, and freedom from stroke and acute myocardial infarction in particular, were analyzed (vs patients without recombinant activated factor VII) by multivariable logistic and Cox regression analyses, as well as Kaplan-Meier estimates. There was no increase in rates of mortality (30-day mortality 4.2% vs 7.0% with P = .418; follow-up survival 85.6% at 13.0 [interquartile range, 8.4-15.7] months vs 80.7% at 10.2 [interquartile range, 7.2-16.1] months with P = .151), thromboembolic complications (6.6% vs 9.6% with P = .637), renal insufficiency, need for percutaneous coronary intervention, duration of ventilation, duration of hospital stay, or rehospitalization in patients receiving very low-dose recombinant activated factor VII compared with patients not receiving recombinant activated factor VII. Complete hemostasis without any need for further hemostatic treatment was achieved after very low-dose recombinant activated factor VII administration in the majority of patients (up to 88.6% vs 0% with P < .001). The key results

  10. Prophylactic Level VII Nodal Dissection as a Prognostic Factor in Papillary Thyroid Carcinoma: a Pilot Study of 27 Patients.

    PubMed

    Fayek, Ihab Samy

    2015-01-01

    Prognostic value of prophylactic level VII nodal dissection in papillary thyroid carcinoma has been highlighted. A total of 27 patients with papillary thyroid carcinoma with N0 neck underwent total thyroidectomy with level VI and VII nodal dissection through same collar neck incision. Multicentricity, bilaterality, extrathyroidal extension, level VI and VII lymph nodes were studied as separate and independent prognostic factors for DFS at 24 months. 21 females and 6 males with a mean age of 34.6 years old, tumor size was 5-24 mm. (mean 12.4 mm.), multicentricity in 11 patients 2-4 foci (mean 2.7), bilaterality in 8 patients and extrathyroidal extension in 8 patients. Dissected level VI LNs 2-8 (mean 5 LNs) and level VII LNs 1-4 (mean 1.9). Metastatic level VI LNs 0-3 (mean 1) and level VII LNs 0-2 (mean 0.5). Follow-up from 6-51 months (mean 25.6) with 7 patients showed recurrence (3 local and 4 distant). Cumulative DFS at 24 months was 87.8% and was significantly affected in relation to bilaterality (p-value<0.001), extrathyroidal extension (p-value<0.001), level VI positive ((p-value<0.001) and level VII positive ((p-value<0.001) LNs. No recurrences were detected during the follow-up period in the absence of level VI and level VII nodal involvement. Level VII prophylactic nodal dissection is an important and integral prognostic factor in papillary thyroid carcinoma. A larger multicenter study is crucial to reach a satisfactory conclusion about the necessity and safety of this approach.

  11. In vitro effects of recombinant activated factor VII on thrombin generation and coagulation following inhibition of platelet procoagulant activity by prasugrel.

    PubMed

    Mazzeffi, Michael; Szlam, Fania; Jakubowski, Joseph A; Tanaka, Kenichi A; Sugidachi, Atsuhiro; Levy, Jerrold H

    2013-07-01

    Prasugrel is a thienopyridyl P2Y12 antagonist with potent antiplatelet effects. At present, little is known about its effects on thrombin generation or what strategies may emergently reverse its anticoagulant effects. In the current study we evaluated whether recombinant activated factor VII may reverse prasugrel induced effects and increase thrombin generation in an in vitro model. The effect of prasugrel active metabolite, PAM (R-138727), was evaluated on platelet aggregation, thrombin generation, and rotational thromboelastometry parameters using blood from 20 healthy volunteers. Additionally, we evaluated the effects of adenosine diphosphate (ADP) and recombinant activated factor VII on restoring these parameters towards baseline values. PAM reduced maximum platelet aggregation and led to platelet disaggregation. It also decreased peak thrombin, increased lag time, and increased time to peak thrombin. Treatment with recombinant activated factor VII restored all three parameters of thrombin generation towards baseline. ADP decreased lag time and time to peak thrombin, but had no effect on peak thrombin. When recombinant activated factor VII and ADP were combined they had a greater effect on thrombin parameters than either drug alone. PAM also increased thromboelastometric clotting time and clot formation time, but had no effect on maximum clot firmness. Treatment with either recombinant activated factor VII or ADP restored these values towards baseline. Recombinant activated factor VII restores thrombin generation in the presence of PAM. In patients taking prasugrel with life-threatening refractory bleeding it has the potential to be a useful therapeutic approach. Additional clinical studies are needed to validate our findings. Copyright © 2013 Elsevier Ltd. All rights reserved.

  12. Heparanase enhances the generation of activated factor X in the presence of tissue factor and activated factor VII.

    PubMed

    Nadir, Yona; Brenner, Benjamin; Fux, Liat; Shafat, Itay; Attias, Judith; Vlodavsky, Israel

    2010-11-01

    Heparanase is an endo-β-D-glucuronidase dominantly involved in tumor metastasis and angiogenesis. Recently, we demonstrated that heparanase is involved in the regulation of the hemostatic system. Our hypothesis was that heparanase is directly involved in activation of the coagulation cascade. Activated factor X and thrombin were studied using chromogenic assays, immunoblotting and thromboelastography. Heparanase levels were measured by enzyme-linked immunosorbent assay. A potential direct interaction between tissue factor and heparanase was studied by co-immunoprecipitation and far-western assays. Interestingly, addition of heparanase to tissue factor and activated factor VII resulted in a 3- to 4-fold increase in activation of the coagulation cascade as shown by increased activated factor X and thrombin production. Culture medium of human embryonic kidney 293 cells over-expressing heparanase and its derivatives increased activated factor X levels in a non-enzymatic manner. When heparanase was added to pooled normal plasma, a 7- to 8-fold increase in activated factor X level was observed. Subsequently, we searched for clinical data supporting this newly identified role of heparanase. Plasma samples from 35 patients with acute leukemia at presentation and 20 healthy donors were studied for heparanase and activated factor X levels. A strong positive correlation was found between plasma heparanase and activated factor X levels (r=0.735, P=0.001). Unfractionated heparin and an inhibitor of activated factor X abolished the effect of heparanase, while tissue factor pathway inhibitor and tissue factor pathway inhibitor-2 only attenuated the procoagulant effect. Using co-immunoprecipitation and far-western analyses it was shown that heparanase interacts directly with tissue factor. Overall, our results support the notion that heparanase is a potential modulator of blood hemostasis, and suggest a novel mechanism by which heparanase increases the generation of activated

  13. Effective treatment of chemoresistant breast cancer in vitro and in vivo by a factor VII-targeted photodynamic therapy.

    PubMed

    Duanmu, J; Cheng, J; Xu, J; Booth, C J; Hu, Z

    2011-04-26

    The purpose of this study was to test a novel, dual tumour vascular endothelial cell (VEC)- and tumour cell-targeting factor VII-targeted Sn(IV) chlorin e6 photodynamic therapy (fVII-tPDT) by targeting a receptor tissue factor (TF) as an alternative treatment for chemoresistant breast cancer using a multidrug resistant (MDR) breast cancer line MCF-7/MDR. The TF expression by the MCF-7/MDR breast cancer cells and tumour VECs in MCF-7/MDR tumours from mice was determined separately by flow cytometry and immunohistochemistry using anti-human or anti-murine TF antibodies. The efficacy of fVII-tPDT was tested in vitro and in vivo and was compared with non-targeted PDT for treatment of chemoresistant breast cancer. The in vitro efficacy was determined by a non-clonogenic assay using crystal violet staining for monolayers, and apoptosis and necrosis were assayed to elucidate the underlying mechanisms. The in vivo efficacy of fVII-tPDT was determined in a nude mouse model of subcutaneous MCF-7/MDR tumour xenograft by measuring tumour volume. To our knowledge, this is the first presentation showing that TF was expressed on tumour VECs in chemoresistant breast tumours from mice. The in vitro efficacy of fVII-tPDT was 12-fold stronger than that of ntPDT for MCF-7/MDR cancer cells, and the mechanism of action involved induction of apoptosis and necrosis. Moreover, fVII-tPDT was effective and safe for the treatment of chemoresistant breast tumours in the nude mouse model. We conclude that fVII-tPDT is effective and safe for the treatment of chemoresistant breast cancer, presumably by simultaneously targeting both the tumour neovasculature and chemoresistant cancer cells. Thus, this dual-targeting fVII-tPDT could also have therapeutic potential for the treatment of other chemoresistant cancers.

  14. Synthesis and biological evaluation of novel aromatic and heterocyclic bis-sulfonamide Schiff bases as carbonic anhydrase I, II, VII and IX inhibitors.

    PubMed

    Akocak, Suleyman; Lolak, Nabih; Nocentini, Alessio; Karakoc, Gulcin; Tufan, Anzel; Supuran, Claudiu T

    2017-06-15

    A series of sixteen novel aromatic and heterocyclic bis-sulfonamide Schiff bases were prepared by conjugation of well known aromatic and heterocyclic aminosulfonamide carbonic anhydrase (CA, EC 4.2.1.1) inhibitor pharmacophores with aromatic and heterocyclic bis-aldehydes. The obtained bis-sulfonamide Schiff bases were investigated as inhibitors of four selected human (h) CA isoforms, hCA I, hCA II, hCA VII and hCA IX. Most of the newly synthesized compounds showed a good inhibitory profile against isoforms hCA II and hCA IX, also showing moderate selectivity against hCA I and VII. Several efficient lead compounds were identified among this bis-sulfonamide Schiff bases with low nanomolar to sub-nanomolar activity against hCA II (K i s ranging between 0.4 and 861.1nM) and IX (K i s between 0.5 and 933.6nM). Since hCA II and hCA IX are important drug targets (antiglaucoma and anti-tumor agents), these isoform-selective inhibitors may be considered of interest for various biomedical applications. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. Contribution of tertiary amino groups to Re(VII) biosorption on modified corn stalk: competitiveness and regularity.

    PubMed

    Lou, Zhenning; Zhao, Ziyi; Li, Yexia; Shan, Weijun; Xiong, Ying; Fang, Dawei; Yue, Shuang; Zang, Shuliang

    2013-04-01

    The effects of basic strength and steric hindrance of gels modified by dimethylamine, diethylamine, di-n-octylamine and di-2-ethylhexylamine, respectively, on rhenium (Re(VII)) adsorption capacity and selectivity were discussed. By comparing with the adsorption of other coexisting metals, such as Mo(VI), Cu(II), Pb(II), Fe(III), Zn(II), Mn(VII) and Ni(II), the gel modified by di-n-octylamine (DNOA-OCS) showed a high affinity for Re(VII) at higher hydrochloric acid concentration (C(H)(+)≥1.0 mol L(-1)), and the maximum adsorption capacity was 98.69 mg g(-1). This article not only described the adsorption behavior but also suggested isotherms, kinetics and thermodynamics of Re(VII) onto the DNOA-OCS gel in an aqueous medium using several models. Further study on adsorption of rhenium in a fixed-bed column packed with the DNOA-OCS gel under continuous and recirculating modes could confirm that the corn stalk gel modified by di-n-octylamine could be used as the adsorbent of Re(VII) from Mo-containing wastewater. Copyright © 2013 Elsevier Ltd. All rights reserved.

  16. 77 FR 5396 - Recordkeeping and Reporting Requirements Under Title VII, the ADA, and GINA

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-02-03

    ... Requirements Under Title VII, the ADA, and GINA AGENCY: Equal Employment Opportunity Commission. ACTION: Final... rule, extends its existing recordkeeping requirements under title VII of the Civil Rights Act of 1964 (Title VII) and the Americans with Disabilities Act (ADA) to entities covered by title II of the Genetic...

  17. Management of factor VII-deficient patients undergoing joint surgeries--preliminary results of locally developed treatment regimen.

    PubMed

    Windyga, J; Zbikowski, P; Ambroziak, P; Baran, B; Kotela, I; Stefanska-Windyga, E

    2013-01-01

    Inherited factor VII (FVII) deficiency is a rare coagulation disorder with variable haemorrhagic manifestations. In severely affected cases spontaneous haemarthroses leading to advanced arthropathy have been observed. Such cases may require surgery. Therapeutic options for bleeding prevention in FVII deficient patients undergoing surgery comprise various FVII preparations but the use of recombinant activated factor VII (rFVIIa) seems to be the treatment of choice. To present the outcome of orthopaedic surgery under haemostatic coverage of rFVIIa administered according to the locally established treatment regimen in five adult patients with FVII baseline plasma levels below 10 IU dL(-1). Two patients required total hip replacement (THR); three had various arthroscopic procedures. Recombinant activated factor VII was administered every 8 h on day of surgery (D0) followed by every 12-24 h for the subsequent 9-14 days, depending on the type of surgery. Factor VII plasma coagulation activity (FVII:C) was determined daily with no predefined therapeutic target levels. Doses of rFVIIa on D0 ranged from 18 to 37 μg kg(-1) b.w. and on the subsequent days--from 13 to 30 μg kg(-1) b.w. Total rFVIIa dose per procedure ranged from 16 to 37.5 mg, and the total number of doses per procedure was 16-31. None of our patients developed excessive bleeding including those in whom FVII:C trough levels returned nearly to the baseline level on the first post-op day. Preliminary results demonstrate that rFVIIa administered according to our treatment regimen is an effective and safe haemostatic agent for hypoproconvertinaemia patients undergoing orthopaedic surgery. © 2012 Blackwell Publishing Ltd.

  18. Japanese family with congenital factor VII deficiency.

    PubMed

    Sakakibara, Kanae; Okayama, Yoshiki; Fukushima, Kenji; Kaji, Shunsaku; Muraoka, Michiko; Arao, Yujiro; Shimada, Akira

    2015-10-01

    Congenital factor VII (FVII) deficiency is a rare bleeding disorder with autosomal recessive inheritance. The present female patient was diagnosed with congenital FVII deficiency because of low hepaplastin test (HPT), although vitamin K was given. Heterozygous p.A191T mutation was detected in the peripheral blood, and the same mutation was also found in the mother and sister. To the best of our knowledge, this is the fourth reported case of p.A191T mutation of FVII in the literature and the first to be reported in Japan. FVII coagulation activity (FVII:C) in asymptomatic heterozygous carriers is mildly reduced. Therefore, some patients may not be accurately diagnosed with congenital FVII deficiency. In infants with low HPT without vitamin K deficiency, congenital FVII deficiency should be considered. © 2015 Japan Pediatric Society.

  19. R353Q polymorphism in the factor VII gene and cardiovascular risk in Heterozygous Familial Hypercholesterolemia: a case-control study

    PubMed Central

    2011-01-01

    Background Heterozygous Familial Hypercholesterolemia (FH) is a genetic disorder characterized by a high risk of cardiovascular disease. Certain polymorphisms of the factor VII gene have been associated with the development of coronary artery disease and there is a known association between factor VII levels and polymorphic variants in this gene. To date, no study has evaluated the association between factor VII and coronary artery disease in patients with FH. Results This case-control study comprised 720 patients (546 with FH and 174 controls). We determined the prevalence and allele frequencies of the R353Q polymorphism of factor VII, the plasma levels of factor VII antigen (FVII Ag) and whether they could be predictive factors for cardiovascular risk. 75% (410) of the patients with FH were RR, 23% (127) RQ and 1.6% (9) QQ; in the control group 75.3% (131) were RR, 21.3% (37) RQ and 3.4% (6) QQ (p = 0.32). No statistically significant associations were observed in the distribution of genotypes and allele frequencies between case (FH) and control groups. Nor did we find differences when we evaluated the relationship between the R353Q polymorphism and cardiovascular risk (including coronary disease, ischemic stroke and peripheral arterial disease), either in the univariate analysis or after adjustment for sex, age, arterial hypertension, body mass index, xanthomas, diabetes, smoking, HDLc and LDLc and lipid-lowering treatment. The FVII Ag concentrations behaved in a similar fashion, with no differences for the interaction between controls and those with FH (RR vs. RQ/QQ; p = 0.96). In the subgroup of patients with FH no association was found among cardiovascular disease, genotype and FVII Ag levels (RR vs. RQ/QQ; p = 0.97). Conclusions Our study did not find a direct relationship between cardiovascular risk in patients with Heterozygous Familial Hypercholesterolemia, the R353Q polymorphism of factor VII and FVII Ag levels. PMID:21477332

  20. The Effect of Recombinant Activated Factor VII on Mortality in Combat-Related Casualties With Severe Trauma and Massive Transfusion

    DTIC Science & Technology

    2008-02-01

    The Effect of Recombinant Activated Factor VII on Mortality in Combat-Related Casualties With Severe Trauma and Massive Transfusion Philip C...REPORT TYPE 3. DATES COVERED 00-00-2007 to 00-00-2007 4. TITLE AND SUBTITLE The Effect of Recombinant Activated Factor VII on Mortality in Combat...Boffard study,17 the effect of rFVIIa on 24-hour blood product ad- ministration was only determined for patients who lived for at least 24 hours

  1. Enhanced Functional Recombinant Factor VII Production by HEK 293 Cells Stably Transfected with VKORC1 where the Gamma-Carboxylase Inhibitor Calumenin is Stably Suppressed by shRNA Transfection

    PubMed Central

    Wajih, Nadeem; Owen, John; Wallin, Reidar

    2008-01-01

    Introduction Recombinant members of the vitamin K-dependent protein family (factors IX and VII and protein C) have become important pharmaceuticals in treatment of bleeding disorders and sepsis. However, because the in vivo γ-carboxylation system in stable cell lines used for transfection has a limited capacity of post translational γ carboxylation, the recovery of fully γ-carboxylated and functional proteins is low. Materials and Methods In this work we have engineered recombinant factor VII producing HEK 293 cells to stably overexpress VKORC1, the reduced vitamin K γ-carboxylase cofactor and in addition stably silenced the γ-carboxylase inhibitory protein calumenin. Results and Conclusions Stable cell lines transfected with only a factor VII cDNA had a 9% production of functional recombinant factor VII. On the other hand, these recombinant factor VII producing cells when engineered to overexpress VKORC1 and having calumenin stably suppressed more than 80% by shRNA expression, produced 68% functional factor VII. The technology presented should be applicable to all vertebrae members of the vitamin K-dependent protein family and should lower the production cost of the clinically used factors VII, IX and protein C. PMID:18177690

  2. Enhanced functional recombinant factor VII production by HEK 293 cells stably transfected with VKORC1 where the gamma-carboxylase inhibitor calumenin is stably suppressed by shRNA transfection.

    PubMed

    Wajih, Nadeem; Owen, John; Wallin, Reidar

    2008-01-01

    Recombinant members of the vitamin K-dependent protein family (factors IX and VII and protein C) have become important pharmaceuticals in treatment of bleeding disorders and sepsis. However, because the in vivo gamma-carboxylation system in stable cell lines used for transfection has a limited capacity of post translational gamma-carboxylation, the recovery of fully gamma-carboxylated and functional proteins is low. In this work we have engineered recombinant factor VII producing HEK 293 cells to stably overexpress VKORC1, the reduced vitamin K gamma-carboxylase cofactor and in addition stably silenced the gamma-carboxylase inhibitory protein calumenin. Stable cell lines transfected with only a factor VII cDNA had a 9% production of functional recombinant factor VII. On the other hand, these recombinant factor VII producing cells when engineered to overexpress VKORC1 and having calumenin stably suppressed more than 80% by shRNA expression, produced 68% functional factor VII. The technology presented should be applicable to all vertebrae members of the vitamin K-dependent protein family and should lower the production cost of the clinically used factors VII, IX and protein C.

  3. Management of Surgical Third Lower Molar Extraction and Postoperative Progress in Patients With Factor VII Deficiency: A Clinical Protocol and Focus on This Rare Pathologic Entity.

    PubMed

    Passarelli, Pier Carmine; Pasquantonio, Guido; D'Addona, Antonio

    2017-10-01

    The purpose of the present study was to analyze the management of surgical third molar extraction and postoperative progress in patients with a diagnosis of factor VII deficiency. Close collaboration between the oral-maxillofacial surgeon and hematologist will allow the team to categorize the risk and operate safely, thereby minimizing the incidence and severity of intraoperative and postoperative complications. The present retrospective study included 7 patients with factor VII deficiency who had undergone third lower molar surgery. Their factor VII deficiency ranged from 10.5 to 21.0%. Recombinant activated factor VII (rFVIIa) (coagulation factor VIIa [recombinant]; NovoSeven RT; Novo Nordisk, Bagsvaerd, Denmark) was transfused intravenously in a single dose of 25 μg/kg body weight, 30 minutes before surgical extractions. After the surgery, betamethasone, an analgesic, and an ice pack were administered. Pretreatment with recombinant activated factor VII resulted in excellent hemostasis. No hemorrhagic complications and no postoperative major bleeding were observed. The extraction of the third lower molar appears to be a safe procedure for patients with factor VII deficiency when appropriate prophylaxis with rFVIIa is used. Copyright © 2017 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

  4. Pathogenesis of lumbar spine disease in mucopolysaccharidosis VII

    PubMed Central

    Smith, Lachlan J; Baldo, Guilherme; Wu, Susan; Liu, Yuli; Whyte, Michael P; Giugliani, Roberto; Elliott, Dawn M; Haskins, Mark E; Ponder, Katherine P

    2012-01-01

    Mucopolysaccharidosis type VII (MPS VII) is characterized by deficient β-glucuronidase (GUSB) activity, which leads to accumulation of chondroitin, heparan and dermatan sulfate glycosaminoglycans (GAGs), and multisystemic disease. MPS VII patients can develop kypho-scoliotic deformity and spinal cord compression due to disease of intervertebral discs, vertebral bodies, and associated tissues. We have previously demonstrated in MPS VII dogs that intervertebral discs degenerate, vertebral bodies have irregular surfaces, and vertebral body epiphyses have reduced calcification, but the pathophysiological mechanisms underlying these changes are unclear. We hypothesized that some of these manifestations could be due to upregulation of destructive proteases, possibly via the binding of GAGs to Toll-like receptor 4 (TLR4), as has been proposed for other tissues in MPS models. In this study, the annulus fibrosus of the intervertebral disc of 6 month-old MPS VII dogs had cathepsin B and K activities that were 117- and 2-fold normal, respectively, which were associated with elevations in mRNA levels for cathepsins as well as TLR4. The epiphyses of MPS VII dogs had a marked elevation in mRNA for the cartilage-associated gene collagen II, consistent with a developmental delay in the conversion of the cartilage to bone in this region. A spine from a human patient with MPS VII exhibited similar increased cartilage in the vertebral bodies adjacent to the end plates, disorganization of the intervertebral discs, and irregular vertebral end plate morphology. These data suggest that the pathogenesis of destructive changes in the spine in MPS VII may involve upregulation of cathepsins. Inhibition of destructive proteases, such as cathepsins, might reduce spine disease in patients with MPS VII or related disorders. PMID:22513347

  5. Human extrahepatic portal vein obstruction correlates with decreased factor VII and protein C transcription but increased hepatocyte proliferation.

    PubMed

    Chiu, Bill; Melin-Aldana, Hector; Superina, Riccardo A

    2007-10-01

    A 3-year-old girl developed extrahepatic portal vein obstruction (EHPVO) after a liver transplant. She had sequelae of portal hypertension that required another transplantation. The circumstances allowed for comparison of liver-dependent coagulation factor production between the second donor liver and the explanted liver with EHPVO. Liver samples from the explanted first graft and the second transplant were obtained. Fresh tissue was used to perform reverse transcription-polymerase chain reaction with primers against factors V, VII, as well as VIII, protein C, and paraffin-embedded sections for hepatocyte proliferation using Ki-67 antibody as well as for apoptosis using TUNEL assay. The transcription of factor VII and that of protein C were decreased in the explant as compared with the newly transplanted liver (factor VII, 77% of the donor; protein C, 88% of the donor). The transcription of factor V and that of factor VIII were unchanged. The explant had a greater percentage of proliferating hepatocytes than the new organ (0.85% +/- 0.75% vs 0.11% +/- 0.21%). The percentage of apoptotic cells was similar between the 2 livers (0.09% +/- 0.13% vs 0.09% +/- 0.13%). Idiopathic EHPVO is associated with a reduction in liver-dependent coagulation factor transcription and an increase in hepatocyte proliferation. Portal blood flow deprivation alters hepatic homeostasis and initiates mechanisms that attempt to restore liver-dependent coagulation factors.

  6. Positive Feedback Loops for Factor V and Factor VII Activation Supply Sensitivity to Local Surface Tissue Factor Density During Blood Coagulation

    PubMed Central

    Balandina, A.N.; Shibeko, A.M.; Kireev, D.A.; Novikova, A.A.; Shmirev, I.I.; Panteleev, M.A.; Ataullakhanov, F.I.

    2011-01-01

    Blood coagulation is triggered not only by surface tissue factor (TF) density but also by surface TF distribution. We investigated recognition of surface TF distribution patterns during blood coagulation and identified the underlying molecular mechanisms. For these investigations, we employed 1), an in vitro reaction-diffusion experimental model of coagulation; and 2), numerical simulations using a mathematical model of coagulation in a three-dimensional space. When TF was uniformly immobilized over the activating surface, the clotting initiation time in normal plasma increased from 4 min to >120 min, with a decrease in TF density from 100 to 0.7 pmol/m2. In contrast, surface-immobilized fibroblasts initiated clotting within 3–7 min, independently of fibroblast quantity and despite a change in average surface TF density from 0.5 to 130 pmol/m2. Experiments using factor V-, VII-, and VIII-deficient plasma and computer simulations demonstrated that different responses to these two TF distributions are caused by two positive feedback loops in the blood coagulation network: activation of the TF–VII complex by factor Xa, and activation of factor V by thrombin. This finding suggests a new role for these reactions: to supply sensitivity to local TF density during blood coagulation. PMID:22004734

  7. (99)Tc(VII) Retardation, Reduction, and Redox Rate Scaling in Naturally Reduced Sediments.

    PubMed

    Liu, Yuanyuan; Liu, Chongxuan; Kukkadapu, Ravi K; McKinley, James P; Zachara, John; Plymale, Andrew E; Miller, Micah D; Varga, Tamas; Resch, Charles T

    2015-11-17

    An experimental and modeling study was conducted to investigate pertechnetate (Tc(VII)O4(-)) retardation, reduction, and rate scaling in three sediments from Ringold formation at U.S. Department of Energy's Hanford site, where (99)Tc is a major contaminant in groundwater. Tc(VII) was reduced in all the sediments in both batch reactors and diffusion columns, with a faster rate in a sediment containing a higher concentration of HCl-extractable Fe(II). Tc(VII) migration in the diffusion columns was reductively retarded with retardation degrees correlated with Tc(VII) reduction rates. The reduction rates were faster in the diffusion columns than those in the batch reactors, apparently influenced by the spatial distribution of redox-reactive minerals along transport paths that supplied Tc(VII). X-ray computed tomography and autoradiography were performed to identify the spatial locations of Tc(VII) reduction and transport paths in the sediments, and results generally confirmed the newly found behavior of reaction rate changes from batch to column. The results from this study implied that Tc(VII) migration can be reductively retarded at Hanford site with a retardation degree dependent on reactive Fe(II) content and its distribution in sediments. This study also demonstrated that an effective reaction rate may be faster in transport systems than that in well-mixed reactors.

  8. Purification and Autoactivation Method for Recombinant Coagulation Factor VII.

    PubMed

    Granovski, Vladimir; Freitas, Marcela C C; Abreu-Neto, Mario Soares; Covas, Dimas T

    2018-01-01

    Recombinant coagulation factor VII is a very important and complex protein employed for treatment of hemophiliac patients (hemophilia A/B) who develop inhibitors antibodies to conventional treatments (FVIII and FIX). The rFVII is a glycosylated molecule and circulates in plasma as zymogen of 50 kDa. When activated the molecule is cleaved to 20-30 kDa and has a half-life of about 3 h, needing to be processed fast and efficiently until freeze-drying. Here, we describe a very simple and fast purification sequence for rFVII using affinity FVII Select resin and a dialysis system that can be easily scaled up.

  9. A review of recombinant factor VII for refractory bleeding in nonhemophilic trauma patients.

    PubMed

    Barletta, Jeffrey F; Ahrens, Christine L; Tyburski, James G; Wilson, Robert F

    2005-03-01

    Recombinant factor VII (rFVII) is an attractive agent to control refractory, coagulopathic bleeding in patients following major surgery. The purpose of this review is to evaluate the published experiences of rFVII in adult, nonhemophilic, surgical and trauma patients. A computerized literature search was conducted to identify articles pertaining to rFVII use for refractory bleeding in adult, nonhemophilic, surgical patients. The selected articles were reviewed and the applicable data was analyzed. A total of 117 patients were found in 8 case series and 24 case reports. Overall, rFVII was effective in restoring hemostasis in 99/117 (85%) patients with 76/99 (77%) surviving to hospital discharge. In trauma patients, hemostasis was achieved in 20/26 (77%) patients and 17/20 (85%) survived. There were 5 (4%) thromboembolic events observed in the 117 cases and much disparity was noted with the initial dose. Severe acidosis affected the activity of rFVII. Recombinant factor VII is an effective therapeutic agent for achieving hemostasis in nonhemophilic surgical patients. Published clinical experiences, however, are limited to small case series and case reports.

  10. Double heterozygous mutations Gln100Leu and His348Gln of the F7 gene in a patient with factor VII deficiency.

    PubMed

    Li, Min; Zheng, Fangxiu; Jin, Yanhui; Wang, Mingshan; Zhu, Liqing; Yang, Lihong

    2013-03-01

    A 25-year-old Chinese woman who had a history of easy bruising was admitted to hospital due to uncontrolled epistaxis. She showed factor VII activity level of 2% and factor VII antigen level of 4% of the normal value. We detected a novel missense mutation g.8355 A>T (p.Gln100Leu) in the second epidermal growth factor-like (EGF) domain and a g.11482 T>G (p.His348Gln) in the catalytic domain. Although the Gln100 residue is close to the junction of EGF-2 domain with the serine protease domain, we infer that the substitution of polar negatively charged Gln residue at the position 100 with introduction of nonpolar Leu residue may be likely to perturb proper folding, resulting in decreasing factor VII activity.

  11. A comparison between recombinant activated factor VII (Aryoseven) and Novoseven in patients with congenital factor VII deficiency.

    PubMed

    Faranoush, M; Abolghasemi, Hassan; Toogeh, Gh; Karimi, M; Eshghi, P; Managhchi, M; Hoorfar, H; Dehdezi, B Keikhaei; Mehrvar, A; Khoeiny, B; Kamyar, K; Heshmat, R; Baghaeipour, M R; Mirbehbahani, N B; Fayazfar, R; Ahmadinejad, M; Naderi, M

    2015-11-01

    In order to establish the efficacy and biosimilar nature of AryoSeven to NovoSeven in the treatment of congenital factor VII (FVII) deficiency, patients received either agent at 30 μg/kg, intravenously per week for 4 weeks, in a randomized fashion. The primary aim was to compare FVII:coagulation activity (FVII:C), 20 minutes after recombinant activated FVII (rFVIIa) injection, in the 2 groups. A secondary measure was self-reported bleeding. The median interquartile baseline range of the plasma level of activated FVII (FVIIa) activity in the 2 groups was 1.6 (1.1-14.0) IU/dL and 5.0 (1.1-25.5) IU/dL. All patients achieved levels of FVIIa (FVII:C) >30 IU/dL, 20 minutes after the injection of rFVIIa. Bleeding was similar between the 2 groups, with a comparable decrease in severity and frequency compared to the last month prior to treatment. AryoSeven is similar to NovoSeven in increasing postinjection FVIIa activity as well as in clinical safety and efficacy. © The Author(s) 2014.

  12. Cerebral Venous Sinus Thrombosis in a Patient with Undiagnosed Factor VII Deficiency.

    PubMed

    Qadir, Hira; Rashid, Anila; Adil, Salman Naseem

    2017-09-01

    Factor VII (FVII) deficiency is one of the rare inherited bleeding disorders. Thrombosis has been occasionally described in inherited FVII deficiency. Here, we report a young female with undiagnosed FVII deficiency who presented with cerebral venous sinus thrombosis (CVST). Oral contraceptive pill was found to be prothrombotic risk factor. The CVSToccurred in spite of the congenital FVII deficiency indicating that no definitive antithrombotic protection is assured by this defect. Low molecular weight heparin and anti-Xa assay were found to be safe choice of anticoagulation and monitoring, respectively, in this patient.

  13. Tissue factor-dependent vascular endothelial growth factor production by human fibroblasts in response to activated factor VII.

    PubMed

    Ollivier, V; Bentolila, S; Chabbat, J; Hakim, J; de Prost, D

    1998-04-15

    The transmembrane protein tissue factor (TF) is the cell surface receptor for coagulation factor VII (FVII) and activated factor VII (FVIIa). Recently, TF has been identified as a regulator of angiogenesis, tumor growth, and metastasis. This study was designed to link the binding of FVII(a) to its receptor, TF, with the subsequent triggering of angiogenesis through vascular endothelial growth factor (VEGF) production by human lung fibroblasts. We report that incubation of fibroblasts, which express constitutive surface TF, with FVII(a) induces VEGF synthesis. FVII(a)-induced VEGF secretion, assessed by a specific enzyme-linked immunosorbent assay, was time- and concentration-dependent. VEGF secretion was maximal after 24 hours of incubation of the cells with 100 nmol/L FVII(a) and represented a threefold induction of the basal VEGF level. Reverse transcriptase-polymerase chain reaction analysis of VEGF detected three mRNA species of 180, 312, and 384 bp corresponding, respectively, to VEGF121, VEGF165, and VEGF189. A 2.5- to 3.5-fold increase was observed for the 180- and 312-bp transcripts at 12 and 24 hours, respectively. FVII(a)-dependent VEGF production was inhibited by a pool of antibodies against TF, pointing to the involvement of this receptor. On specific active-site inhibition with dansyl-glutamyl-glycinyl-arginyl chloromethyl ketone, FVIIa lost 70% of its capacity to elicit VEGF production. Consistent with this, the native form (zymogen) of FVII only had a 1.8-fold stimulating effect. Protein tyrosine kinase and protein kinase C are involved in signal transduction leading to VEGF production, as shown by the inhibitory effects of genistein and GF 109203X. The results of this study indicate that TF is essential for VIIa-induced VEGF production by human fibroblasts and that its role is mainly linked to the proteolytic activity of the TF-VIIa complex.

  14. Mechanism of action of recombinant activated factor VII: an update.

    PubMed

    Hedner, Ulla

    2006-01-01

    Bleeding episodes in patients with hemophilia and inhibitors must be managed using agents that are hemostatically active in the absence of factor VIII or IX. Activated prothrombin complex concentrates have long been used in this context. However, the search for safer and more effective agents has led to the development of recombinant activated factor VII (rFVIIa; NovoSeven, Novo Nordisk, Bagsvaerd, Denmark). This paper presents an update on the mechanism of action of rFVIIa, and describes how pharmacologic doses of this agent enhance thrombin production and thus contribute to the development of a stable, lysis-resistant fibrin plug at the site of vessel damage. This mechanism explains the reported efficacy of rFVIIa in a range of clinical situations characterized by impaired thrombin generation.

  15. Safety update on the use of recombinant activated factor VII in approved indications.

    PubMed

    Neufeld, Ellis J; Négrier, Claude; Arkhammar, Per; Benchikh el Fegoun, Soraya; Simonsen, Mette Duelund; Rosholm, Anders; Seremetis, Stephanie

    2015-06-01

    This updated safety review summarises the large body of safety data available on the use of recombinant activated factor VII (rFVIIa) in approved indications: haemophilia with inhibitors, congenital factor VII (FVII) deficiency, acquired haemophilia and Glanzmann's thrombasthenia. Accumulated data up to 31 December 2013 from clinical trials as well as post-marketing data (registries, literature reports and spontaneous reports) were included. Overall, rFVIIa has shown a consistently favourable safety profile, with no unexpected safety concerns, in all approved indications. No confirmed cases of neutralising antibodies against rFVIIa have been reported in patients with congenital haemophilia, acquired haemophilia or Glanzmann's thrombasthenia. The favourable safety profile of rFVIIa can be attributed to the recombinant nature of rFVIIa and its localised mechanism of action at the site of vascular injury. Recombinant FVIIa activates factor X directly on the surface of activated platelets, which are present only at the site of injury, meaning that systemic activation of coagulation is avoided and the risk of thrombotic events (TEs) thus reduced. Nonetheless, close monitoring for signs and symptoms of TE is warranted in all patients treated with any pro-haemostatic agent, including rFVIIa, especially the elderly and any other patients with concomitant conditions and/or predisposing risk factors to thrombosis. Copyright © 2015 Elsevier Ltd. All rights reserved.

  16. Recombinant activated factor VII in cardiac surgery: a systematic review.

    PubMed

    Warren, Oliver; Mandal, Kaushik; Hadjianastassiou, Vassilis; Knowlton, Lisa; Panesar, Sukhmeet; John, Kokotsakis; Darzi, Ara; Athanasiou, Thanos

    2007-02-01

    Postoperative hemorrhage is a common complication in cardiac surgery, and it is associated with a considerable increase in morbidity, mortality, and cost. Recombinant activated factor VII (rFVIIa) is an emerging hemostatic agent, increasingly used in cardiac surgery. This article systematically reviews the evidence regarding the efficacy, safety, and cost of rFVIIa in this setting. Although definitive evidence from randomized controlled trials is lacking, the use of rFVIIa in patients experiencing refractory postoperative hemorrhage seems promising and relatively safe. However further research is required to definitively establish its clinical utility in the postoperative cardiac patient.

  17. Isolated acquired factor VII deficiency: review of the literature.

    PubMed

    Mulliez, Sylvie M N; Devreese, Katrien M J

    2016-04-01

    Isolated acquired factor VII (FVII) deficiency is a rare haemorrhagic disorder. We report what is currently known about the pathogenesis, clinical features, diagnosis, treatment and prognosis of acquired FVII deficiency. We performed a literature search and included all articles published between 1980 and August 2015. Acquired FVII deficiency has been reported in 42 patients. There are well-established clinical diseases associated with acquired FVII deficiency, most notably infections, malignancy and haematological stem cell transplantation. The exact pathogenesis of the diseases is still unknown, but different pathophysiological hypotheses have been suggested. The clinical manifestation of acquired FVII deficiency varies greatly in severity; asymptomatic course as well as severe life-threatening bleeding diathesis and fatal bleedings have been described.

  18. Fish as bioreactors: transgene expression of human coagulation factor VII in fish embryos.

    PubMed

    Hwang, Gyulin; Müller, Ferenc; Rahman, M Aziz; Williams, Darren W; Murdock, Paul J; Pasi, K John; Goldspink, Geoffrey; Farahmand, Hamid; Maclean, Norman

    2004-01-01

    A plasmid containing human coagulation factor VII (hFVII) complementary DNA regulated by a cytomegalovirus promoter was microinjected into fertilized eggs of zebrafish, African catfish, and tilapia. The active form of hFVll was detected in the fish embryos by various assays. This positive expression of human therapeutic protein in fish embryos demonstrates the possibility of exploitation of transgenic fish as bioreactors.

  19. The Crystal Structure of a hCA VII Variant Provides Insights into the Molecular Determinants Responsible for Its Catalytic Behavior.

    PubMed

    Buonanno, Martina; Di Fiore, Anna; Langella, Emma; D'Ambrosio, Katia; Supuran, Claudiu T; Monti, Simona Maria; De Simone, Giuseppina

    2018-05-24

    Although important progress has been achieved in understanding the catalytic mechanism of Carbonic Anhydrases, a detailed picture of all factors influencing the catalytic efficiency of the various human isoforms is still missing. In this paper we report a detailed structural study and theoretical pKa calculations on a hCA VII variant. The obtained data were compared with those already known for another thoroughly investigated cytosolic isoform, hCA II. Our structural studies show that in hCA VII the network of ordered water molecules, which connects the zinc bound solvent molecule to the proton shuttle His64, is altered compared to hCA II, causing a reduction of the catalytic efficiency. Theoretical calculations suggest that changes in solvent network are related to the difference in pKa of the proton shuttle in the two enzymes. The residue that plays a major role in determining the diverse pKa values of the proton shuttle is the one in position four, namely His for hCA II and Gly for hCA VII. This residue is located on the protein surface, outside of the active site cavity. These findings are in agreement with our previous studies that highlighted the importance of histidines on the protein surface of hCA II (among which His4) as crucial residues for the high catalytic efficiency of this isoform.

  20. Isotypic analysis of antibodies against activated Factor VII in patients with Factor VII deficiency using the x-MAP technology.

    PubMed

    Pfeiffer, Caroline; Mathieu-Dupas, Eve; Logghe, Pauline; Lissalde-Lavigne, Géraldine; Balicchi, Julien; Caliskan, Umran; Valentin, Thomas; Laune, Daniel; Molina, Franck; Schved, Jean François; Giansily-Blaizot, Muriel

    2016-05-01

    While the immune response to hemophilic factors in hemophilia has been widely studied, little is known about the development of anti-Factor VII (FVII) antibodies in FVII deficiency. We developed a robust technique based on the x-MAP technology to detect the presence of antibodies against FVII and characterize their isotype and validated this method using blood samples from 100 patients with FVII deficiency (median FVII clotting activity [FVII:C]: 6%) and 95 healthy controls. Anti-FVII antibodies were detected in patients but also in some controls, although the concentration of total immunoglobulin G (IgGt) and IgG1 and IgG4 subclasses was significantly different between groups. The IgG1 subclass concentrations remained significantly different also when only untreated patients were compared with controls. This difference could partially be related to the F7 genotype, particularly in patients harboring the p.Arg139Gln mutation. This x-MAP-based method might be useful for assessing the immunogenicity of novel FVII compounds and of activated FVII (FVIIa) concentrates. Further prospective studies are needed to better understand the clinical relevance of these antibodies in the management of patients with FVII deficiency. Copyright © 2016 Elsevier Ltd. All rights reserved.

  1. Recombinant activated factor VII: 30 years of research and innovation.

    PubMed

    Hedner, Ulla

    2015-06-01

    Recombinant activated factor VII (rFVIIa) was initially developed to treat bleeding episodes in patients with congenital haemophilia and inhibitors. The story of its development began in the 1970s, when FVIIa was identified as one of the activated coagulation factors that has minimal potential for inducing thromboembolic side-effects. Extensive research over the last 30 years has greatly increased our knowledge of the characteristics of FVII, its activation, and the mechanisms by which rFVIIa restores haemostasis. In haemophilia, the haemostatic effect of rFVIIa is mediated via binding to thrombin-activated platelets at the site of injury, thereby enhancing thrombin generation also in the absence of factor (F) VIII or FIX. The mechanism of action of rFVIIa has also allowed its successful use in other clinical scenarios characterised by impaired thrombin generation, and its licensed uses have now been extended to acquired haemophilia, congenital FVII deficiency and Glanzmann's thrombasthenia. Copyright © 2015 Elsevier Ltd. All rights reserved.

  2. Elevated prothrombin time on routine preoperative laboratory results in a healthy infant undergoing craniosynostosis repair: Diagnosis and perioperative management of congenital factor VII deficiency.

    PubMed

    Jones, Kareen L; Greenberg, Robert S; Ahn, Edward S; Kudchadkar, Sapna R

    2016-01-01

    Congenital factor VII deficiency is a rare bleeding disorder with high phenotypic variability. It is critical that children with congenital Factor VII deficiency be identified early when high-risk surgery is planned. Cranial vault surgery is common for children with craniosynostosis, and these surgeries are associated with significant morbidity mostly secondary to the risk of massive blood loss. A two-month old infant who presented for elective craniosynostosis repair was noted to have an elevated prothrombin time (PT) with a normal activated partial thromboplastin time (aPTT) on preoperative labs. The infant had no clinical history or reported family history of bleeding disorders, therefore a multidisciplinary decision was made to repeat the labs under general anesthesia and await the results prior to incision. The results confirmed the abnormal PT and the case was canceled. Hematologic workup during admission revealed factor VII deficiency. The patient underwent an uneventful endoscopic strip craniectomy with perioperative administration of recombinant Factor VIIa. Important considerations for perioperative laboratory evaluation and management in children with factor VII deficiency are discussed. Anesthetic and surgical management of the child with factor VII deficiency necessitates meticulous planning to prevent life threatening bleeding during the perioperative period. A thorough history and physical examination with a high clinical suspicion are vital in preventing hemorrhage during surgeries in children with coagulopathies. Abnormal preoperative lab values should always be confirmed and addressed before proceeding with high-risk surgery. A multidisciplinary discussion is essential to optimize the risk-benefit ratio during the perioperative period. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  3. Successful synthesis of active human coagulation factor VII by co-expression of mammalian gamma-glutamyl carboxylase and modification of vit.K cycle in Drosophila Schneider S2 cells.

    PubMed

    Nagahashi, Kotomi; Umemura, Kazuo; Kanayama, Naohiro; Iwaki, Takayuki

    2017-04-01

    Mammalian gamma-glutamyl carboxylase and reduced vitamin K are indispensable for synthesis of mature mammalian vitamin K dependent proteins including some of blood coagulation factors (factors II, VII, IX, and X). It was well known that Drosophila melanogaster expressed gamma-glutamyl carboxylase and possessed a vit.K cycle although native substrates for them have not been identified yet. Despite the potential capability of gamma carboxylation in D. melanogaster derived cells such as S2 cells, Drosophila gamma-glutamyl carboxylase failed to gamma carboxylate a peptide fused to the human coagulation factor IX propeptide. Thus, it had been believed that the Drosophila system was not adequate to synthesize mammalian vit.K dependent proteins. Indeed, we previously attempted to synthesize biologically active factor VII in S2 cells although we were not able to obtain it. However, recently, a successful transient expression of biologically active human factor IX from S2 cells was reported. In the present study, several expression vectors which enable expressing mammalian GGCX, VKORC1, and/or PDIA2 along with F7 were developed. S2 cells transfected with pMKA85, pMAK86, and pMAK219 successfully synthesized active FVII. Thus, mammalian GGCX was indispensable to synthesize active FVII while mammalian VKORC1 and PDIA2 were not critical but supportive factors for S2 cells.

  4. Clinical course of sly syndrome (mucopolysaccharidosis type VII)

    PubMed Central

    Montaño, Adriana M; Lock-Hock, Ngu; Steiner, Robert D; Graham, Brett H; Szlago, Marina; Greenstein, Robert; Pineda, Mercedes; Gonzalez-Meneses, Antonio; Çoker, Mahmut; Bartholomew, Dennis; Sands, Mark S; Wang, Raymond; Giugliani, Roberto; Macaya, Alfons; Pastores, Gregory; Ketko, Anastasia K; Ezgü, Fatih; Tanaka, Akemi; Arash, Laila; Beck, Michael; Falk, Rena E; Bhattacharya, Kaustuv; Franco, José; White, Klane K; Mitchell, Grant A; Cimbalistiene, Loreta; Holtz, Max; Sly, William S

    2016-01-01

    Background Mucopolysaccharidosis VII (MPS VII) is an ultra-rare disease characterised by the deficiency of β-glucuronidase (GUS). Patients’ phenotypes vary from severe forms with hydrops fetalis, skeletal dysplasia and mental retardation to milder forms with fewer manifestations and mild skeletal abnormalities. Accurate assessments on the frequency and clinical characteristics of the disease have been scarce. The aim of this study was to collect such data. Methods We have conducted a survey of physicians to document the medical history of patients with MPS VII. The survey included anonymous information on patient demographics, family history, mode of diagnosis, age of onset, signs and symptoms, severity, management, clinical features and natural progression of the disease. Results We collected information on 56 patients from 11 countries. Patients with MPS VII were classified based on their phenotype into three different groups: (1) neonatal non-immune hydrops fetalis (NIHF) (n=10), (2) Infantile or adolescent form with history of hydrops fetalis (n=13) and (3) Infantile or adolescent form without known hydrops fetalis (n=33). Thirteen patients with MPS VII who had the infantile form with history of hydrops fetalis and survived childhood, had a wide range of clinical manifestations from mild to severe. Five patients underwent bone marrow transplantation and one patient underwent enzyme replacement therapy with recombinant human GUS. Conclusions MPS VII is a pan-ethnic inherited lysosomal storage disease with considerable phenotypical heterogeneity. Most patients have short stature, skeletal dysplasia, hepatosplenomegaly, hernias, cardiac involvement, pulmonary insufficiency and cognitive impairment. In these respects it resembles MPS I and MPS II. In MPS VII, however, one unique and distinguishing clinical feature is the unexpectedly high proportion of patients (41%) that had a history of NIHF. Presence of NIHF does not, by itself, predict the eventual severity

  5. Primary prophylaxis for children with severe congenital factor VII deficiency - Clinical and laboratory assessment.

    PubMed

    Kuperman, A A; Barg, A A; Fruchtman, Y; Shaoul, E; Rosenberg, N; Kenet, G; Livnat, T

    2017-09-01

    Severe congenital factor VII (FVII) deficiency is a rare bleeding disorder. Prophylaxis with replacement therapy has been suggested to patients, yet the most beneficial dosing regimens and therapy intervals are still to be defined. Due to the lack of evidence-based data, we hereby present our experience with long-term administration and monitoring primary prophylaxis in children with severe FVII deficiency and an extremely high bleeding risk. Four children with familial FVII deficiency, treated by prophylactic recombinant activated factor VII (rFVIIa), 15-30μg/kg/dose, given 2-3 times weekly since infancy, are discussed. Clinical follow up and monitoring laboratory assays, including thrombin generation, measured at various time points after prophylactic rFVIIa administration are presented. Among our treated patients neither FVII activity nor thrombin generation parameters (both already declined 24h post rFVIIa administration) were able to predict the impact of prophylaxis, and could not be used as surrogate markers in order to assess the most beneficial treatment frequency. However, the long clinical follow-up and comprehensive laboratory assessment performed, have shown that early primary prophylaxis as administered in our cohort was safe and effective. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Inhibitor development after liver transplantation in congenital factor VII deficiency.

    PubMed

    See, W-S Q; Chang, K-O; Cheuk, D K-L; Leung, Y-Y R; Chan, G C-F; Chan, S-C; Ha, S-Y

    2016-09-01

    Congenital factor VII (FVII) deficiency is the commonest type of the rare bleeding disorders. Very few cases of congenital FVII deficiency developed inhibitor and liver transplant is considered as definitive treatment. In the literature, twelve patients with congenital FVII deficiency developed inhibitors. Two had spontaneous resolution of inhibitors and one did not respond to high dose recombinant factor VIIa (rFVIIa) and died. Regarding liver transplant in congenital FVII patients, seven patients underwent liver transplant with good prognosis. We report a 5-year-old girl with confirmed severe congenital FVII deficiency since neonatal period. She suffered from recurrent intracranial bleeding despite rFVIIa replacement. After auxiliary liver transplant at the age of 4, she continued to show persistent deranged clotting profile and was found to have inhibitor towards FVII. Interestingly, she was still responsive to rFVIIa replacement. © 2016 John Wiley & Sons Ltd.

  7. The safety and efficacy of the administration of recombinant activated factor VII in major surgery and trauma patients.

    PubMed

    Wilson, Stephen J; Bellamy, Mark C; Giannoudis, Peter V

    2005-05-01

    Recombinant activated Factor VII (rFVIIa) has been successfully used in the treatment of haemophilia A and B with associated inhibitors for some years. Activated Factor VII binds to activated platelets independently of tissue factor. The resulting stimulation of an exaggerated early thrombin burst at sites of vascular injury makes it an attractive potential treatment for massive, uncontrolled bleeding associated with surgery and trauma. This article describes the evidence relating to surgery and trauma. The lack of large, controlled trials of rFVIIa means that a definitive recommendation regarding its use cannot be made at present. However, in the context of clearly defined protocols and balanced treatment strategies, rFVIIa may have a role in traumatic bleeding. Large scale, randomised controlled trials in trauma are required, as is further work on the safety profile of rFVIIa with an independent international safety monitoring committee.

  8. Upregulation of the coagulation factor VII gene during glucose deprivation is mediated by activating transcription factor 4.

    PubMed

    Cronin, Katherine R; Mangan, Thomas P; Carew, Josephine A

    2012-01-01

    Constitutive production of blood coagulation proteins by hepatocytes is necessary for hemostasis. Stressful conditions trigger adaptive cellular responses and delay processing of most proteins, potentially affecting plasma levels of proteins secreted exclusively by hepatocytes. We examined the effect of glucose deprivation on expression of coagulation proteins by the human hepatoma cell line, HepG2. Expression of coagulation factor VII, which is required for initiation of blood coagulation, was elevated by glucose deprivation, while expression of other coagulation proteins decreased. Realtime PCR and ELISA demonstrated that the relative percentage expression +/- SD of steady-state F7 mRNA and secreted factor VII antigen were significantly increased (from 100+/-15% to 188+/-27% and 100+/-8.8% to 176.3+/-17.3% respectively, p<0.001) at 24 hr of treatment. The integrated stress response was induced, as indicated by upregulation of transcription factor ATF4 and of additional stress-responsive genes. Small interfering RNAs directed against ATF4 potently reduced basal F7 expression, and prevented F7 upregulation by glucose deprivation. The response of the endogenous F7 gene was replicated in reporter gene assays, which further indicated that ATF4 effects were mediated via interaction with an amino acid response element in the F7 promoter. Our data indicated that glucose deprivation enhanced F7 expression in a mechanism reliant on prior ATF4 upregulation primarily due to increased transcription from the ATF4 gene. Of five coagulation protein genes examined, only F7 was upregulated, suggesting that its functions may be important in a systemic response to glucose deprivation stress.

  9. Synthesis and biological evaluation of histamine Schiff bases as carbonic anhydrase I, II, IV, VII, and IX activators.

    PubMed

    Akocak, Suleyman; Lolak, Nabih; Vullo, Daniela; Durgun, Mustafa; Supuran, Claudiu T

    2017-12-01

    A series of 20 histamine Schiff base was synthesised by reaction of histamine, a well known carbonic anhydrase (CA, E.C 4.2.2.1.) activator pharmacophore, with substituted aldehydes. The obtained histamine Schiff bases were assayed as activators of five selected human (h) CA isozymes, the cytosolic hCA I, hCA II, and hCA VII, the membrane-anchored hCA IV and transmembrane hCA IX. Some of these compounds showed efficient activity (in the nanomolar range) against the cytosolic isoform hCA VII, which is a key CA enzyme involved in brain metabolism. Moderate activity was observed against hCA I and hCA IV (in the nanomolar to low micromolar range). The structure-activity relationship for activation of these isoforms with the new histamine Schiff bases is discussed in detail based on the nature of the aliphatic, aromatic, or heterocyclic moiety present in the aldehyde fragment of the molecule, which may participate in diverse interactions with amino acid residues at the entrance of the active site, where activators bind, and which is the most variable part among the different CA isoforms.

  10. High Dose, Prolonged Epsilon Aminocaproic Acid Infusion, and Recombinant Factor VII for Massive Postoperative Retroperitoneal Hemorrhage following Splenectomy.

    PubMed

    Lee, Alex T; Barnes, Christopher R; Jain, Shweta; Pauldine, Ronald

    2016-01-01

    The antifibrinolytic agent ε -aminocaproic acid is used to decrease procedural blood loss in a variety of high risk surgeries. The utility of recombinant factor VII administration in massive hemorrhage has also been reported in a variety of settings, though the impact in a surgical context remains unclear. We describe the case of a patient who underwent massive open splenectomy and developed diffuse retroperitoneal bleeding on postoperative day one. Massive transfusion was initiated, but attempts to control hemorrhage with surgical and interventional radiology approaches were unsuccessful, as was recombinant factor VII administration. Commencement of a high dose aminocaproic acid infusion was followed by a prominent rise in fibrinogen levels and stabilization of the hemorrhage. Indications, dosages, and adverse effects of ε -aminocaproic acid as described in the literature are reviewed.

  11. High Dose, Prolonged Epsilon Aminocaproic Acid Infusion, and Recombinant Factor VII for Massive Postoperative Retroperitoneal Hemorrhage following Splenectomy

    PubMed Central

    Barnes, Christopher R.; Jain, Shweta; Pauldine, Ronald

    2016-01-01

    The antifibrinolytic agent ε-aminocaproic acid is used to decrease procedural blood loss in a variety of high risk surgeries. The utility of recombinant factor VII administration in massive hemorrhage has also been reported in a variety of settings, though the impact in a surgical context remains unclear. We describe the case of a patient who underwent massive open splenectomy and developed diffuse retroperitoneal bleeding on postoperative day one. Massive transfusion was initiated, but attempts to control hemorrhage with surgical and interventional radiology approaches were unsuccessful, as was recombinant factor VII administration. Commencement of a high dose aminocaproic acid infusion was followed by a prominent rise in fibrinogen levels and stabilization of the hemorrhage. Indications, dosages, and adverse effects of ε-aminocaproic acid as described in the literature are reviewed. PMID:27957347

  12. [Our experience with recombinant activated factor VII (NovoSeven) in the high risk cardiosurgical patients with bleeding complication].

    PubMed

    Miskolczi, Szabolcs; Vaszily, Miklós; Papp, Csaba; Péterffy, Arpád

    2008-01-01

    Haemorrhagic complications significantly increase mortality and cost of treatment in cardiac surgery. A few years ago recombinant activated factor VII has been introduced to decrease such complications. In our department recombinant activated factor VII has been used in 11 patients between 2004 and 2007. Nine of them underwent a combined (simultaneous CABG and valve replacement) high risk surgery with long aortic cross clamp time and long extracorporeal circulation time. One patient underwent a repeat coronary artery bypass operation and one was operated for aortic dissection. The average dose given was 6.5 mg (2.4-9.6 mg). The average amount of bleeding without NovoSeven given was 5440 ml, however it was only 987 ml when NovoSeven was used. Nine of the patients were completely recovered and discharged from hospital, but two of them died in the postoperative period for delayed use of the recombinant factor VII-a and for severe co-morbidities (bowel ischaemia, cirrhosis of the liver). NovoSeven given in the proper time and dose significantly reduces bleeding following cardiac surgery, even if it cannot be stopped surgically. Using recombinant factor VIIa can save life in case of severe non-surgical diffuse bleeding or in case of suture insufficiency caused by friable soft tissues following high risk combined surgery with extremely long aortic cross clamp time and extracorporeal circulation time. Significant delay in the use of NovoSeven should be avoided because the temporary reduction of bleeding usually does not change fatal outcome.

  13. Benchmarking Atomic Data for Astrophysics: Be-like Ions between B II and Ne VII

    NASA Astrophysics Data System (ADS)

    Wang, Kai; Chen, Zhan Bin; Zhang, Chun Yu; Si, Ran; Jönsson, Per; Hartman, Henrik; Gu, Ming Feng; Chen, Chong Yang; Yan, Jun

    2018-02-01

    Large-scale self-consistent multiconfiguration Dirac–Hartree–Fock and relativistic configuration interaction calculations are reported for the n≤slant 6 levels in Be-like ions from B II to Ne VII. Effects from electron correlation are taken into account by means of large expansions in terms of a basis of configuration state functions, and a complete and accurate data set of excitation energies; lifetimes; wavelengths; electric dipole, magnetic dipole, electric quadrupole, and magnetic quadrupole line strengths; transition rates; and oscillator strengths for these levels is provided for each ion. Comparisons are made with available experimental and theoretical results. The uncertainty of excitation energies is assessed to be 0.01% on average, which makes it possible to find and rule out misidentifications and aid new line identifications involving high-lying levels in astrophysical spectra. The complete data set is also useful for modeling and diagnosing astrophysical plasmas.

  14. Use of global assays to understand clinical phenotype in congenital factor VII deficiency.

    PubMed

    Greene, L A; Goldenberg, N A; Simpson, M L; Villalobos-Menuey, E; Bombardier, C; Acharya, S S; Santiago-Borrero, P J; Cambara, A; DiMichele, D M

    2013-09-01

    Congenital factor VII (FVII) deficiency is characterized by genotypic variability and phenotypic heterogeneity. Traditional screening and factor assays are unable to reliably predict clinical bleeding phenotype and guide haemorrhage prevention strategy. Global assays of coagulation and fibrinolysis may better characterize overall haemostatic balance and aid in haemorrhagic risk assessment. We evaluated the ability of novel global assays to better understand clinical bleeding severity in congenital FVII deficiency. Subjects underwent central determination of factor VII activity (FVII:C) as well as clot formation and lysis (CloFAL) and simultaneous thrombin and plasmin generation (STP) global assay analysis. A bleeding score was assigned to each subject through medical chart review. Global assay parameters were analysed with respect to bleeding score and FVII:C. Subgroup analyses were performed on paediatric subjects and subjects with FVII ≥ 1 IU dL(-1). CloFAL fibrinolytic index (FI2 ) inversely correlated with FVII:C while CloFAL maximum amplitude (MA) and STP maximum velocity of thrombin generation (VT max) varied directly with FVII:C. CloFAL FI2 directly correlated with bleeding score among subjects in both the total cohort and paediatric subcohort, but not among subjects with FVII ≥ 1 IU dL(-1) . Among subjects with FVII ≥ 1 IU dL(-1), STP time to maximum velocity of thrombin generation and time to maximum velocity of plasmin generation inversely correlated with bleeding score. These preliminary findings suggest a novel potential link between a hyperfibrinolytic state in bleeding severity and congenital FVII deficiency, an observation that should be further explored. © 2013 John Wiley & Sons Ltd.

  15. Upregulation of the Coagulation Factor VII Gene during Glucose Deprivation Is Mediated by Activating Transcription Factor 4

    PubMed Central

    Cronin, Katherine R.; Mangan, Thomas P.; Carew, Josephine A.

    2012-01-01

    Background Constitutive production of blood coagulation proteins by hepatocytes is necessary for hemostasis. Stressful conditions trigger adaptive cellular responses and delay processing of most proteins, potentially affecting plasma levels of proteins secreted exclusively by hepatocytes. We examined the effect of glucose deprivation on expression of coagulation proteins by the human hepatoma cell line, HepG2. Methodology/Principal Findings Expression of coagulation factor VII, which is required for initiation of blood coagulation, was elevated by glucose deprivation, while expression of other coagulation proteins decreased. Realtime PCR and ELISA demonstrated that the relative percentage expression +/− SD of steady-state F7 mRNA and secreted factor VII antigen were significantly increased (from 100+/−15% to 188+/−27% and 100+/−8.8% to 176.3+/−17.3% respectively, p<0.001) at 24 hr of treatment. The integrated stress response was induced, as indicated by upregulation of transcription factor ATF4 and of additional stress-responsive genes. Small interfering RNAs directed against ATF4 potently reduced basal F7 expression, and prevented F7 upregulation by glucose deprivation. The response of the endogenous F7 gene was replicated in reporter gene assays, which further indicated that ATF4 effects were mediated via interaction with an amino acid response element in the F7 promoter. Conclusions/Significance Our data indicated that glucose deprivation enhanced F7 expression in a mechanism reliant on prior ATF4 upregulation primarily due to increased transcription from the ATF4 gene. Of five coagulation protein genes examined, only F7 was upregulated, suggesting that its functions may be important in a systemic response to glucose deprivation stress. PMID:22848420

  16. Molecular cloning, characterization and expression analysis of coagulation factor VII gene in grass carp (Ctenopharyngodon idella).

    PubMed

    Liu, Qiaolin; Xu, Baohong; Xiao, Tiaoyi; Su, Jianming; Zhong, Lei

    2013-08-01

    Coagulation factor VII has been studied in several species but, to date, not in grass carp (Ctenopharyngodon idella), a commercially important freshwater fish found in China. In this study, the full-length cDNA of grass carp coagulation factor VII (GcCFVII) was cloned using a RACE-Ready cDNA Kit, grass carp were challenged with a hemorrhagic virus, and temporal expression profiles of GcCFVII in the thymus, gills, liver, spleen, and head kidney were examined at 0 h, 24 h, 48 h, 72 h, 96 h, and 138 h using fluorescence quantitative PCR. The results showed the 1480 bp GcCFVII to contain three conservative motifs: Gla, EGF-CA, and Tryp-SPc, similar to other species. Phylogenetic analysis showed the evolution of GcCFVII gene to be consistent with the evolution of the species. After viral challenge, GcCFVII expression in five tissues of grass carp showed different patterns of fluctuation. These results provide a solid basis for further investigation of GcCFVII and its relationship with grass carp hemorrhage. Copyright © 2013 Elsevier Ltd. All rights reserved.

  17. Preparing to use vehicle infrastructure integration (VII) in transportation operations : phase II.

    DOT National Transportation Integrated Search

    2009-01-01

    Vehicle infrastructure integration (VII) is an emerging approach intended to create an enabling communication capability to support vehicle-to-vehicle and vehicle-to-infrastructure communications for safety and mobility applications. The Virginia Dep...

  18. Factor VII Tokushima: the first case of factor VII Cys22Gly with the development of myocardial infarction in the proband receiving recombinant factor VIIa replacement therapy.

    PubMed

    Shigekiyo, Toshio; Sekimoto, Etsuko; Shibata, Hironobu; Ozaki, Shuji; Okumura, Takanobu; Fujinaga, Hiroyuki; Shibata, Hiroshi; Aihara, Ken-ichi; Akaike, Masashi

    2015-12-01

    An 81-year-old man was referred to our department because of suspected factor VII (FVII) deficiency. His FVII activity was under 1%, whereas the FVII activity levels of his son and granddaughter were 65 and 109%, respectively. The nucleotide at position 3886 of his FVII gene was homozygous for G. A single T to G substitution results in the replacement of wild-type Cys at residue 22 by Gly. His son was heterozygous for G and T at position 3886, whereas his granddaughter was homozygous for wild-type T. These results suggest that he was homozygous for FVII Cys22Gly. He underwent radiofrequency ablation (RFA) for hepatocellular carcinoma, receiving 20 μg/kg of recombinant FVIIa prior to RFA and 10 μg/kg of recombinant FVIIa twice after RFA. He showed no bleeding tendency; however, a myocardial infarction was diagnosed and percutaneous coronary intervention was performed.

  19. Survey of Land-Grant Colleges and Universities. Bulletin, 1930, No. 9. Volume II. [Part VII - Index

    ERIC Educational Resources Information Center

    Office of Education, United States Department of the Interior, 1930

    1930-01-01

    The attached document covers the concluding sections of the second volume of the Survey of Land-Grant Colleges and Universities: Part VII through the index. Part VII, Extension services, is divided into the following sections: (1) Introduction; (2) Position and objectives of Smith-Lever cooperative extension; (3) Administrative organization of…

  20. Rare coagulation disorders: fibrinogen, factor VII and factor XIII.

    PubMed

    de Moerloose, P; Schved, J-F; Nugent, D

    2016-07-01

    Rare coagulation disorders (RCDs) include the inherited deficiencies of fibrinogen, factor (F) II, FV, combined FV and VIII, FVII, FX, combined FVII and X, FXI, FXIII and combined congenital deficiency of vitamin K-dependent factors (VKCFDs). Despite their rarity, a deep comprehension of all these disorders is essential to really understand haemostasis. Indeed, even if they share some common features each RCD has some particularity which makes it unique. In this review, we focus on three disorders: fibrinogen, FVII and FXIII. © 2016 John Wiley & Sons Ltd.

  1. Chronic sleep deprivation markedly reduces coagulation factor VII expression

    PubMed Central

    Pinotti, Mirko; Bertolucci, Cristiano; Frigato, Elena; Branchini, Alessio; Cavallari, Nicola; Baba, Kenkichi; Contreras-Alcantara, Susana; Ehlen, J. Christopher; Bernardi, Francesco; Paul, Ketema N.; Tosini, Gianluca

    2010-01-01

    Chronic sleep loss, a common feature of human life in industrialized countries, is associated to cardiovascular disorders. Variations in functional parameters of coagulation might contribute to explain this relationship. By exploiting the mouse model and a specifically designed protocol, we demonstrated that seven days of partial sleep deprivation significantly decreases (−30.5%) the thrombin generation potential in plasma evaluated upon extrinsic (TF/FVIIa pathway) but not intrinsic activation of coagulation. This variation was consistent with a decrease (−49.8%) in the plasma activity levels of factor VII (FVII), the crucial physiologicalal trigger of coagulation, which was even more pronounced at the liver mRNA level (−85.7%). The recovery in normal sleep conditions for three days completely restored thrombin generation and FVII activity in plasma. For the first time, we demonstrate that chronic sleep deprivation on its own reduces, in a reversible manner, the FVII expression levels, thus influencing the TF/FVIIa activation pathway efficiency. PMID:20418241

  2. Warfarin dose requirement in Turkish patients: the influences of patient characteristics and polymorphisms in CYP2C9, VKORC1 and factor VII.

    PubMed

    Yildirim, E; Erol, K; Birdane, A

    2014-01-01

    To determine the contribution of cytochrome P4502C9 (CYP2C9), vitamin K epoxide reductase (VKORC1) and factor VII genotypes, age, body mass index (BMI), international normalized ratio (INR) and other individual patient characteristics on warfarin dose requirements in an adult Turkish population. Blood samples were collected from 101 Turkish patients. Genetic analyses for CYP2C9*2 and *3, VKORC1 -1639 G>A and factor VII -401 G>T polymorphisms were performed. Age, INR, BMI values and other individual patient characteristics were also recorded. The mean daily warfarin dosage was significantly higher in patients with the CYP2C9*1/*1 genotype than in the CYP2C9*2/*2 and CYP2C9*1/*3 groups (p ≤ 0.05). With respect to the VKORC1 -1639 G>A polymorphism, the mean warfarin daily dose requirement was higher in the wild type group compared to the heterozygous group (p≤0.001). The mean daily dose requirement for patients with the GG form of factor VII was significantly higher than that of patients with the TT genotype (p ≤ 0.05). Age, gender, BMI, INR had no statistically significant correlation with warfarin dose (p ≥ 0.05). Polymorphisms in CYP2C9, VKORC1 and factor VII did partially affect daily warfarin dose requirements, while age, gender, BMI and INR do not. However, further case-control studies with a larger study size and different genetic loci are needed to confirm our study.

  3. [Significant decrease in factor VII activity by tissue thromboplastin derived from rabbit brain in a patient with congenital factor VII deficiency (FVII Padua)].

    PubMed

    Sekiya, Akiko; Morishita, Eriko; Maruyama, Keiko; Asakura, Hidesaku; Nakao, Shinji; Ohtake, Shigeki

    2012-03-01

    Congenital factor VII (FVII) deficiency is a bleeding disorder that requires optimal hemostatic management for each case due to its wide variety of bleeding symptoms. We experienced a patient with inherited FVII deficiency who demonstrated different FVII activities depending on tissue thromboplastins used for assays. An 82-year-old woman without any episodes of abnormal bleeding was found to have different FVII activities of 1.4% and 32% when assayed using thromboplastins from rabbit brain and human placenta, respectively. DNA sequencing analysis revealed a homozygous missense mutation of G10828A (FVII Padua) that caused an amino acid substitution of Arg304 to Gln (R304Q). Carriers of 304Q alleles are usually clinically asymptomatic and do not require FVII replacement therapies even in cases of homozygotes. In case a prolonged prothrombin time or reduced FVII activity is detected, re-examination using thromboplastins of other sources can be helpful for preliminary diagnosis of R304Q, in order to prevent unnecessary FVII replacement therapies.

  4. [Haplotype Analysis of Coagulation Factor VII Gene in a Patient with Congenital Coagulation Factor VII Deficiency with Heterozygous p.Arg337Cys Mutation and o.Aro413Gin Polymorphism..

    PubMed

    Suzuki, Keijiro; Yoshioka, Tomoko; Obara, Takehiro; Suwabe, Akira

    2016-05-01

    Congenital coagulation factor VII (FVII) deficiency is a rare hemorrhagic disease with an autosomal reces- sive inheritance pattern. We analyzed coagulation factor VII gene (F7) of a patient with FVII deficiency and used expression studies to investigate the effect of a missense mutation on FVII secretion. The proband, a 69-year-old Japanese woman, had a history of postpartum bleeding and excessive bleeding after dental extrac- tion. She was found to have mildly increased PT-INR (1.17) before an ophthalmic operation. FVII activity and antigen were reduced (29.0% and 32.8%). Suspecting that the proband was FVII deficient, we analyzed F7 of the patient. Sequence analysis revealed that the patient was heterozygous for a point mutation (p.Arg337Cys) in the catalytic domain and polymorphisms: the decanucleotide insertion at the promoter re- gion, dimorphism (c.525C >T) in exon 5, and p.Arg413Gln in exon 8. Haplotype analysis clarified that p.Arg337Cys was located on the p.Arg413 allele (Ml allele). The other allele had the p.Arg413Gln polymor- phism(M2 allele) which is known to produce less FVII. Expression studies revealed that p.Arg337Cys causes impairment of FVII secretion. Insufficient secretion of FVII arising from both the p.Arg337Cys/M1 allele and the p.Arg337/M2 allele might lower the FVII level of this patient(<50%). The FVII level in a heterozygous FVII deficient patient might be influenced by F7 polymorphisms on the normal allele. There- fore, genetic analyses are important for the diagnosis of heterozygous FVII deficiency.

  5. Ischemic stroke in a patient with moderate to severe inherited factor VII deficiency.

    PubMed

    Reddy, Manasa; Tawfik, Bernard; Gavva, Chakri; Yates, Sean; De Simone, Nicole; Hofmann, Sandra L; Rambally, Siayareh; Sarode, Ravi

    2016-12-01

    Thrombosis is known to occur in patients with rare inherited bleeding disorders, usually in the presence of a thrombotic risk factor such as surgery and/or factor replacement therapy, but sometimes spontaneously. We present the case of a 72-year-old African American male diagnosed with congenital factor VII (FVII) deficiency after presenting with ischemic stroke, presumably embolic, in the setting of atherosclerotic carotid artery stenosis. The patient had an international normalized ratio (INR) of 2.0 at presentation, with FVII activity of 6% and normal Extem clotting time in rotational thromboelastometry. He was treated with aspirin (325 mg daily) and clopidogrel (75 mg daily) with no additional bleeding or thrombotic complications throughout his admission. This case provides further evidence that moderate to severe FVII deficiency does not protect against thrombosis. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Increasing plasma fibrinogen, but unchanged levels of intraplatelet cyclic nucleotides, plasma endothelin-1, factor VII, and neopterin during cholesterol lowering with fluvastatin.

    PubMed

    Gottsäter, A; Anwaar, I; Lind, P; Mattiasson, I; Lindgärde, F

    1999-04-01

    Lipid-lowering statin treatment reduces cardiovascular morbidity and mortality and improves endothelial function in patients with hypercholesterolemia. The aim of the present study was to evaluate plasma levels of fibrinogen, factor VII, and the macrophage-derived inflammatory mediator neopterin during lipid lowering. In addition, the endothelial production of platelet antiaggregatory and vasodilatory factors such as nitric oxide and prostacyclin, and vasoconstrictive factors such as endothelin-1, was assessed. Plasma fibrinogen, factor VII, endothelin-1, and the neopterin and intraplatelet nitric oxide and prostacyclin mediators cyclic 3'-5'guanosine monophosphate (cGMP) and cyclic 3'-5'adenosine monophosphate (cAMP) were measured before and 6 months after the institution of treatment with fluvastatin in 17 patients (eight men and nine women, median age 60 years) with vascular disease and previously untreated hypercholesterolemia. After 6 months, a decrease of 1.62 mmol/l [1.26-2.18 (19%); P < 0.01] was noted in levels of total cholesterol, and a decrease of 1.70 mmol/l [1.52-2.30 (28%); P < 0.01] in levels of low-density lipoprotein cholesterol. Plasma levels of fibrinogen had increased [from 4.81 g/l (4.26-5.27) to 5.17 g/l (4.81-5.67); P < 0.05], whereas no significant changes had occurred in intraplatelet levels of cGMP [decrease by 0.05 pmol/10(9) platelets (-0.17 to 0.24); NS], cAMP [decrease by 0.13 pmol/10(9) platelets (-0.37 to 0.86); NS], plasma endothelin-1 [decrease by 0.05 pg/ml (-0.60 to 0.70); NS], plasma factor VII [from 1.14 IE/ml (0.58-1.38) to 1.22 IE/ml (0.96-1.46); NS], or plasma neopterin [from 8.6 nmol/l (7.1-11.5) to 8.7 nmol/l (7.9-11.3); NS]. In conclusion, during cholesterol-lowering treatment with fluvastatin, plasma levels of fibrinogen increased whereas intraplatelet cyclic nucleotide levels and plasma endothelin-1, factor VII and neopterin levels were unchanged.

  7. Beneficial nutritional properties of olive oil: implications for postprandial lipoproteins and factor VII.

    PubMed

    Williams, C M

    2001-08-01

    Previous research concerning protective cardiovascular properties of olive oil has focussed on the beneficial consequences on blood cholesterol levels of substituting dietary saturated fatty acids with oleic acid. Despite evidence implicating raised circulating triglycerides in the postprandial state in the pathogenesis of atherosclerosis and thrombosis, little research had been conducted to investigate effects of monounsaturated fatty acids on postprandial events. In a case control study of southern (n = 30) versus northern European (n = 30) men, significant differences in postprandial triglyceride and apolipoprotein (apo) B-48 response were observed, with evidence of attenuated and potentially beneficial responses in the Southern Europeans. In a randomised controlled study manufactured foods typical of the Northern European food culture, were used to deliver diets rich in either saturated or monounsaturated fatty acids (from olive oil). During the period of the olive oil enriched diet, LDL-cholesterol levels were 15% lower (p < 0.001) than during the saturated fat diet. Postprandial triglyceride response was shifted towards the profile seen in southern European men and the postprandial activation of factor VII, as well as the production of factor VII antigen, was reduced on the olive oil diet. The study demonstrated significant improvements in biomarkers for cardiovascular disease in subjects osed to high olive oil diets (Southern Europeans) or transferred to such diets in the short term (Northern European volunteers). The study produced novel findings with respect to potential mechanisms by which diets high in monounsaturated fatty acids (MUFA) can reduce population risk of cardiovascular disease.

  8. [Molecular genetic analysis for a pedigree with severe hereditary coagulation factor VII deficiency].

    PubMed

    Ding, Qiu-lan; Wang, Hong-li; Wang, Xue-feng; Wang, Ming-shan; Fu, Qi-hua; Wu, Wen-man; Hu, Yi-qun; Wang, Zhen-yi

    2003-10-01

    To identify the genetic mutations of a severe inherited coagulation factor VII (FVII) deficiency pedigree. The diagnosis was validated by coagulant and haemostatic parameters. FVII gene mutations were screened in the propositus and his family members by DNA direct sequencing and confirmed by digestions of the restriction enzymes of the PCR production. Two heterozygous missense mutations were found in the propositus of the pedigree: a G to T transversion at position 9482 in exon 6 and a C to T mutation at position 11348 in exon 8 resulting in the amino acid substitution of Arg152 with Leu and Arg304 with Trp, respectively. A heterozygous single nucleotide deletion (C) at position 11487-11489(CCC) within exon 8 was identified, which predicted the frameshift mutation at position His351 followed by the changes of six corresponding amino acids and appearance of a premature protein caused by stop codon. The heterozygous mutations identified in the proband were derived from his father (Arg152 to Leu) and his mother (Arg304 to Trp mutation) and a heterozygous deletion (C) at position 11487-9(CCC). By tracing the other pedigree members, it was found that his grandmother had a heterozygous mutation of Arg304Trp and a heterozygous polymorphism of Arg353Gln and his grandfather had a heterozygous Arg152Leu mutation. Three heterozygous mutations were found in a pedigree with hereditary coagulation factor VII deficiency. Arg152Leu and deletion C at position 11487-9(CCC) were novel mutations.

  9. [Administration of activated recombinant factor VII (novo seven) for the control of massive bleeding in gynecology].

    PubMed

    Tanchev, S; Pandurski, F; Georgiev, A; Gesheva, Iu; Platikanov, V; Dinov, P

    2004-01-01

    We report our clinical opinion for recombinant activated factor VII (NovoSeven, Novo Nordisk, Copenhagen, Denmark) administration in gynecology patients with massive haemorrhage. 3 women with gynecology deseases and severe bleeding in recieved NovoSeven in bolus IV. The blood loss and laboratory changes in hematology and haemostasis parameters are monitored. The bleeding was ceased in all cases. Decrease in values of Hb, Er and PTT was noted. The use of recombinant factor VIIA in gynecology patients with severe bleeding is effective and safe enough and could be an alternative to the extreme surgical procedures.

  10. A high affinity monoclonal antibody recognizing the light chain of human coagulating factor VII.

    PubMed

    Sarial, Sheila; Asadi, Farzad; Jeddi-Tehrani, Mahmood; Hadavi, Reza; Bayat, Ali Ahmad; Mahmoudian, Jafar; Taghizadeh-Jahed, Masoud; Shokri, Fazel; Rabbani, Hodjattallah

    2012-12-01

    Factor VII (FVII) is a serine protease-coagulating element responsible for the initiation of an extrinsic pathway of clot formation. Here we generated and characterized a high affinity monoclonal antibody that specifically recognizes human FVII. Recombinant human FVII (rh-FVII) was used for the production of a monoclonal antibody using BALB/c mice. The specificity of the antibody was determined by Western blot using plasma samples from human, mouse, sheep, goat, bovine, rabbit, and rat. Furthermore, the antibody was used to detect transiently expressed rh-FVII in BHK21 cell line using Western blot and sandwich ELISA. A mouse IgG1 (kappa chain) monoclonal antibody clone 1F1-B11 was produced against rh-FVII. The affinity constant (K(aff)) of the antibody was calculated to be 6.4×10(10) M(-1). The antibody could specifically recognize an epitope on the light chain of hFVII, with no reactivity with factor VII from several other animals. In addition, transiently expressed rh-FVII in BHK21 cells was recognized by 1F1-B11. The high affinity as well as the specificity of 1F1-B11 for hFVII will facilitate the affinity purification of hFVII and also production of FVII deficient plasma and minimizes the risk of bovine FVII contamination when fetal bovine serum-supplemented media are used for production and subsequent purification of rh-FVII.

  11. Genotype and phenotype relationships in 10 Pakistani unrelated patients with inherited factor VII deficiency.

    PubMed

    Borhany, M; Boijout, H; Pellequer, J-L; Shamsi, T; Moulis, G; Aguilar-Martinez, P; Schved, J-F; Giansily-Blaizot, M

    2013-11-01

    Inherited factor VII (FVII) deficiency is one of the commonest rare bleeding disorders. It is characterized by a wide molecular and clinical heterogeneity and an autosomal recessive pattern of inheritance. Factor VII-deficient patients are still scarcely explored in Pakistan although rare bleeding disorders became quite common as a result of traditional consanguineous marriages. The aim of the study was to give a first insight of F7 gene mutations in Pakistani population. Ten unrelated FVII-deficient patients living in Pakistan were investigated (median FVII:C = 2%; range = 2-37%). A clinical questionnaire was filled out for each patient and direct sequencing was performed on the coding regions, intron/exon boundaries and 5' and 3' untranslated regions of the F7 gene. Nine different mutations (eight missense mutations and one located within the F7 promoter) were identified on the F7 gene. Five of them were novel (p.Cys82Tyr, p.Cys322Ser, p.Leu357Phe, p.Thr410Ala, c-57C>T, the last being predicted to alter the binding site of transcription factor HNF-4). Half of the patients had single mutations in Cys residues involved in disulfide bridges. The p.Cys82Arg mutation was the most frequent in our series. Six of seven patients with FVII:C levels below 10% were homozygous in connection with the high percentage of consanguinity in our series. In addition, we graded the 10 patients according to three previously published classifications for rare bleeding disorders. The use of the bleeding score proposed by Tosetto and co-workers in 2006 appears to well qualify the bleeding tendency in our series. © 2013 John Wiley & Sons Ltd.

  12. Managing incidentally diagnosed isolated factor VII deficiency perioperatively: a brief expert consensus report.

    PubMed

    Sheth, Sujit; Soff, Gerald; Mitchell, Beau; Green, David; Kaicker, Shipra; Fireman, Fernando; Tugal, Oya; Guarini, Ludovico; Giardina, Patricia; Aledort, Louis

    2012-02-01

    While isolated factor VII (FVII) deficiency is being more frequently diagnosed owing to improved preoperative screening procedures, there is no specific guideline for perioperative management of such patients. To complicate the issue, FVII activity levels seem to correlate less well with the risk of hemorrhage than the patient's past and family bleeding history do. We have devised expert consensus recommendations for managing such patients perioperatively, taking into consideration the personal and family bleeding history, the FVII activity level and the inherent bleeding risk of the procedure itself. We hope that clinicians will find this a useful tool in the decision-making process, thereby limiting the use of recombinant factor VIIa to those who need it most, and preventing possible thrombotic complications in those without a strong indication for its use.

  13. Carbonic anhydrase activators. Activation of isoforms I, II, IV, VA, VII, and XIV with L- and D-phenylalanine and crystallographic analysis of their adducts with isozyme II: stereospecific recognition within the active site of an enzyme and its consequences for the drug design.

    PubMed

    Temperini, Claudia; Scozzafava, Andrea; Vullo, Daniela; Supuran, Claudiu T

    2006-05-18

    Activation of six human brain carbonic anhydrases (hCAs, EC 4.2.1.1), hCA I, II, IV, VA, VII, and XIV, with l-/d-phenylalanine was investigated kinetically and by X-ray crystallography. l-Phe was a potent activator of isozymes I, II, and XIV (K(A)s of 13-240 nM), a weaker activator of hCA VA and VII (K(A)s of 9.8-10.9 microM), and a quite inefficient hCA IV activator (K(A) of 52 microM). d-Phe showed good hCA II activatory properties (K(A) of 35 nM), being a moderate hCA VA, VII, and XIV (K(A)s of 4.6-9.7 microM) and a weak hCA I and IV activator (K(A)s of 63-86 microM). X-ray crystallography of the hCA II-l-Phe/d-Phe adducts showed the activators to be anchored at the entrance of the active site, participating in numerous bonds and hydrophobic interactions with amino acid residues His64, Thr200, Trp5, and Pro201. This is the first study showing different binding modes of stereoisomeric activators within the hCA II active site, with consequences for overall proton transfer processes (rate-determining for the catalytic cycle). It also points out differences of activation efficiency between various isozymes with structurally related activators, exploitable for designing alternative proton transfer pathways. CA activators may lead to the design of pharmacologically useful derivatives for the enhancement of synaptic efficacy, which may represent a conceptually new approach for the treatment of Alzheimer's disease, aging, and other conditions in which spatial learning and memory therapy must be enhanced. As the blood and brain concentrations of l-Phe are quite variable (30-73 microM), activity of some brain CAs may strongly be influenced by the level of activator(s) present in such tissues.

  14. Important comments on KERMA factors and DPA cross-section data in ACE files of JENDL-4.0, JEFF-3.2 and ENDF/B-VII.1

    NASA Astrophysics Data System (ADS)

    Konno, Chikara; Tada, Kenichi; Kwon, Saerom; Ohta, Masayuki; Sato, Satoshi

    2017-09-01

    We have studied reasons of differences of KERMA factors and DPA cross-section data among nuclear data libraries. Here the KERMA factors and DPA cross-section data included in the official ACE files of JENDL-4.0, ENDF/B-VII.1 and JEFF-3.2 are examined in more detail. As a result, it is newly found out that the KERMA factors and DPA cross-section data of a lot of nuclei are different among JENDL-4.0, ENDF/B-VII.1 and JEFF-3.2 and reasons of the differences are the followings: 1) large secondary particle production yield, 2) no secondary gamma data, 3) secondary gamma data in files12-15 mt = 3, 4) mt = 103-107 data without mt = 600 s-800 s data in file6. The issue 1) is considered to be due to nuclear data, while the issues 2)-4) seem to be due to NJOY. The ACE files of JENDL-4.0, ENDF/B-VII.1 and JEFF-3.2 with these problems should be revised after correcting wrong nuclear data and NJOY problems.

  15. Emission line spectra of S VII ? S XIV in the 20 ? 75 ? wavelength region

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Lepson, J K; Beiersdorfer, P; Behar, E

    As part of a larger project to complete a comprehensive catalogue of astrophysically relevant emission lines in support of new-generation X-ray observatories using the Lawrence Livermore electron beam ion traps EBIT-I and EBIT-II, the authors present observations of sulfur lines in the soft X-ray and extreme ultraviolet regions. The database includes wavelength measurements with standard errors, relative intensities, and line assignments for 127 transitions of S VII through S XIV between 20 and 75 {angstrom}. The experimental data are complemented with a full set of calculations using the Hebrew University Lawrence Livermore Atomic Code (HULLAC). A comparison of the laboratorymore » data with Chandra measurements of Procyon allows them to identify S VII-S XI lines.« less

  16. Phenotypic and genotypic characterization of four factor VII deficiency patients from central China.

    PubMed

    Liu, Hui; Wang, Hua-Fang; Cheng, Zhi-peng; Wang, Qing-yun; Hu, Bei; Zeng, Wei; Wu, Ying-ying; Guo, Tao; Tang, Liang; Hu, Yu

    2015-06-01

    Hereditary coagulation factor VII deficiency (FVIID) is a rare autosomal, recessive inherited hemorrhagic disorder related to a variety of mutations or polymorphisms throughout the factor VII (FVII) gene (F7). The aims of this study were to characterize the molecular defect of the F7 gene in four unrelated patients with FVIID and to find the genotype-phenotype correlation. All nine exons, exon-intron boundaries, and 5' and 3'-untranslated regions of the F7 gene were amplified by PCR and the purified PCR products were sequenced directly. Suspected mutations were confirmed by another PCR and sequencing of the opposite strand. Family studies were also performed. A total of five unique lesions were identified, including three missense mutations (c.384A>G, c.839A>C, c.1163T>G, predicting p.Tyr128Cys, p.Glu280Ala and p.Phe388Cys substitution, respectively) and two splice junction mutations (c.572-1G>A, c.681+1G>T), among which two (p.Glu280Ala, p.Phe388Cys) were novel. A previously reported mutation p.Tyr128Cys was seen in the homozygous state in two unrelated patients. The other two cases were both compound heterozygotes of a missense mutation and a splicing site mutation. Multiple sequence alignment using DNAMAN analysis showed that all the missense mutations were found in residues that highly conserved across species and vitamin K-dependent serine proteases. Online software Polyphen and SIFT were used to confirm the pathogenic of the missense mutation. p.Tyr128Cys seems to be a hotspot of the F7 gene in ethnic Han Chinese population.

  17. Factor VII R353Q genetic polymorphism is associated with altered warfarin sensitivity among CYP2C9 *1/*1 carriers.

    PubMed

    Mlynarsky, Liat; Bejarano-Achache, Idit; Muszkat, Mordechai; Caraco, Yoseph

    2012-05-01

    Warfarin responsiveness is characterized by marked interindividual variability. A major portion of this variability is attributed to CYP2C9 and VKORC1 polymorphisms, but almost 50% is still unaccounted for. This paper reports the first prospective study on the association between factor VII R353Q polymorphism and warfarin responsiveness during induction. Genotyping for factor VII R353Q and 323D/I polymorphisms was performed in a cohort consisting of 374 patients (198 CYP2C9*1/*1) treated with warfarin who were prospectively followed from warfarin initiation. Compared with *1/*1-R/R and *1/*1-R/Q genotype carriers, *1/*1-Q/Q homozygotes achieved higher International Normalized Ratio (INR) values while consuming lower warfarin doses. The greater sensitivity was illustrated by 82.1% higher Warfarin Sensitivity Index During Induction (WSIDI) (0.14 ± 0.11 vs. 0.08 ± 0.50 mg⁻¹ Mann-Whitney, P = 0.043). Multiple regression analysis consisting of both genetic and nongenetic factors explained 26% of WSIDI variability, with R353Q genetic polymorphism having a modest yet significant effect and accounting for 1.7% of the overall variability. Moreover, the incidence of overanticoagulation (i.e., INR > 4) was 6.94-fold higher among *1/*1-Q/Q vs. *1/*1-R/R&R/Q carriers during warfarin induction (Pearson chi-square, P = 0.005). These findings were not accounted for by a chance difference in the distribution of VKORC1 genotypes. Analysis of these parameters among the entire cohort, including CYP2C9*2 and CYP2C9*3 variant allele carriers, did not reach statistical significance. Warfarin responsiveness during induction was unrelated to factor VII 323D/I genetic polymorphism. The response to warfarin during induction is influenced by factor VII R353Q polymorphism. The prospective use of this polymorphism, along with CYP2C9 and VKORC1, may enhance the accuracy of warfarin loading. However, the impact of R353Q polymorphism on overall warfarin response is subtle, and it is therefore

  18. Immobilization of 99-Technetium (VII) by Fe(II)-Goethite and Limited Reoxidation

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Um, Wooyong; Chang, Hyun-Shik; Icenhower, Jonathan P.

    2011-05-04

    Synthesized goethite was successfully used with addition of Fe(II) to sequester Tc present in both deionized water and simulated off-gas scrubber waste solutions. Pertechnetate concentration in solution decreased immediately when the pH was raised above 7 by addition of sodium hydroxide. Removal of Tc(VII) from solution occurred most likely as a result of heterogeneous surface-catalyzed reduction to Tc(IV) and subsequent co-precipitation onto the goethite. The final Tc-bearing solid was identified as goethite-dominated Fe(III)-(oxy)hydroxide based on XRD analysis, confirming the widespread observation of its characteristic acicular habit by TEM/SEM images. Analysis of the solid precipitate by XAFS showed that the dominantmore » oxidation state of Tc was Tc(IV) and was in octahedral coordination with Tc-O, Fe-O, and Tc-Fe bond distances that are consistent with direct substitution of Tc for Fe in the goethite structure. In some experiments the final Tc-goethite product was subsequently armored with additional layers of freshly precipitated goethite. Successful incorporation of Tc(IV) within the goethite mineral lattice and subsequent goethite armoring can limit re-oxidation of Tc(IV) and its subsequent release from Tc-goethite waste forms, even when the final product is placed in oxidizing environments that typify shallow waste burial facilities.« less

  19. Quantitative PET Imaging of Tissue Factor Expression Using 18F-Labeled Active Site-Inhibited Factor VII.

    PubMed

    Nielsen, Carsten H; Erlandsson, Maria; Jeppesen, Troels E; Jensen, Mette M; Kristensen, Lotte K; Madsen, Jacob; Petersen, Lars C; Kjaer, Andreas

    2016-01-01

    Tissue factor (TF) is upregulated in many solid tumors, and its expression is linked to tumor angiogenesis, invasion, metastasis, and prognosis. A noninvasive assessment of tumor TF expression status is therefore of obvious clinical relevance. Factor VII is the natural ligand to TF. Here we report the development of a new PET tracer for specific imaging of TF using an (18)F-labeled derivative of factor VII. Active site-inhibited factor VIIa (FVIIai) was obtained by inactivation with phenylalanine-phenylalanine-arginine-chloromethyl ketone. FVIIai was radiolabeled with N-succinimidyl 4-(18)F-fluorobenzoate and purified. The corresponding product, (18)F-FVIIai, was injected into nude mice with subcutaneous human pancreatic xenograft tumors (BxPC-3) and investigated using small-animal PET/CT imaging 1, 2, and 4 h after injection. Ex vivo biodistribution was performed after the last imaging session, and tumor tissue was preserved for molecular analysis. A blocking experiment was performed in a second set of mice. The expression pattern of TF in the tumors was visualized by immunohistochemistry and the amount of TF in tumor homogenates was measured by enzyme-linked immunosorbent assay and correlated with the uptake of (18)F-FVIIai in the tumors measured in vivo by PET imaging. The PET images showed high uptake of (18)F-FVIIai in the tumor regions, with a mean uptake of 2.5 ± 0.3 percentage injected dose per gram (%ID/g) (mean ± SEM) 4 h after injection of 7.3-9.3 MBq of (18)F-FVIIai and with an average maximum uptake in the tumors of 7.1 ± 0.7 %ID/g at 4 h. In comparison, the muscle uptake was 0.2 ± 0.01 %ID/g at 4 h. At 4 h, the tumors had the highest uptake of any organ. Blocking with FVIIai significantly reduced the uptake of (18)F-FVIIai from 2.9 ± 0.1 to 1.4 ± 0.1 %ID/g (P < 0.001). The uptake of (18)F-FVIIai measured in vivo by PET imaging correlated (r = 0.72, P < 0.02) with TF protein level measured ex vivo. (18)F-FVIIai is a promising PET tracer for

  20. Similarities and discrepancies in homozygous factor VII defects due to mutations in the region of residues Met298 to Cys310 (exon 8) in the catalytic domain of factor VII.

    PubMed

    Girolami, A; Berti de Marinis, G; Bonamigo, E; Vettore, S

    2011-06-01

    Patients with the Arg304Gln mutation in factor VII Padua (FVII Padua) show discrepant activity levels that depend on the thromboplastin used in the assay system. This report investigates the possibility that residues close to Arg304 (exon 8) show the same discrepant behavior. All available homozygous patients with a mutation in a 13-residue region (preceding and following Arg304) have been evaluated. Only the Arg304Trp mutation showed a discrepancy similar to that shown by the Arg304Gln mutation. Other homozygotes failed to show differences, despite their all being positive for cross-reacting material. Another FVII amino acid residue involved in tissue factor binding and activation is Arg79 (exon 4). No comparison could be carried out because no homozygotes for deficiency in this region have ever been described. The relationship between these 2 residues involved in tissue factor binding and activation has not yet been completely clarified; however, Arg residues 79 and 304 are the only 2 residues definitely shown thus far to be involved in this important function.

  1. Two-incision laparoscopic appendectomy for a severe hemophilia A child patient with coagulation factor VII deficiency

    PubMed Central

    He, Jin Peng; Feng, Jie Xiong

    2017-01-01

    Abstract Rationale: 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. Patient concerns: An 8y7m-old Chinese boy presented with half a day of right sided abdominal pain, fever, nausea, and vomiting. Diagnoses: 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. Interventions: 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. Outcomes: The patient had an uneventful recovery. Lessons: 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. PMID:29019885

  2. Intelsat VII program and the future

    NASA Astrophysics Data System (ADS)

    Madon, P. J.; Sachdev, D. K.

    The evolution of the Intelsat VII spacecraft is discussed. The role of competitive procurement process in this evolution is addressed, and the overall system-level features of the spacecraft are reviewed. The time frame for the five Intelsat VII missions is summarized, and follow-up projects to Intelsat VII are discussed.

  3. Recombinant epidermal growth factor-like domain-1 from coagulation factor VII functionalized iron oxide nanoparticles for targeted glioma magnetic resonance imaging.

    PubMed

    Liu, Heng; Chen, Xiao; Xue, Wei; Chu, Chengchao; Liu, Yu; Tong, Haipeng; Du, Xuesong; Xie, Tian; Liu, Gang; Zhang, Weiguo

    The highly infiltrative and invasive nature of glioma cells often leads to blurred tumor margins, resulting in incomplete tumor resection and tumor recurrence. Accurate detection and precise delineation of glioma help in preoperative delineation, surgical planning and survival prediction. In this study, recombinant epidermal growth factor-like domain-1, derived from human coagulation factor VII, was conjugated to iron oxide nanoparticles (IONPs) for targeted glioma magnetic resonance (MR) imaging. The synthesized EGF1-EGFP-IONPs exhibited excellent targeting ability toward tissue factor (TF)-positive U87MG cells and human umbilical vein endothelial cells in vitro, and demonstrated persistent and efficient MR contrast enhancement up to 12 h for preclinical glioma models with high targeting specificity in vivo. They hold great potential for clinical translation and developing targeted theranostics against brain glioma.

  4. Expanding the versatility of phage display II: improved affinity selection of folded domains on protein VII and IX of the filamentous phage.

    PubMed

    Løset, Geir Åge; Roos, Norbert; Bogen, Bjarne; Sandlie, Inger

    2011-02-24

    Phage display is a leading technology for selection of binders with affinity for specific target molecules. Polypeptides are normally displayed as fusions to the major coat protein VIII (pVIII) or the minor coat protein III (pIII). Whereas pVIII display suffers from drawbacks such as heterogeneity in display levels and polypeptide fusion size limitations, toxicity and infection interference effects have been described for pIII display. Thus, display on other coat proteins such as pVII or pIX might be more attractive. Neither pVII nor pIX display have gained widespread use or been characterized in detail like pIII and pVIII display. Here we present a side-by-side comparison of display on pIII with display on pVII and pIX. Polypeptides of interest (POIs) are fused to pVII or pIX. The N-terminal periplasmic signal sequence, which is required for phage integration of pIII and pVIII and that has been added to pVII and pIX in earlier studies, is omitted altogether. Although the POI display level on pIII is higher than on pVII and pIX, affinity selection with pVII and pIX display libraries is shown to be particularly efficient. Display through pVII and/or pIX represent platforms with characteristics that differ from those of the pIII platform. We have explored this to increase the performance and expand the use of phage display. In the paper, we describe effective affinity selection of folded domains displayed on pVII or pIX. This makes both platforms more attractive alternatives to conventional pIII and pVIII display than they were before.

  5. Expanding the Versatility of Phage Display II: Improved Affinity Selection of Folded Domains on Protein VII and IX of the Filamentous Phage

    PubMed Central

    Løset, Geir Åge; Roos, Norbert; Bogen, Bjarne; Sandlie, Inger

    2011-01-01

    Background Phage display is a leading technology for selection of binders with affinity for specific target molecules. Polypeptides are normally displayed as fusions to the major coat protein VIII (pVIII) or the minor coat protein III (pIII). Whereas pVIII display suffers from drawbacks such as heterogeneity in display levels and polypeptide fusion size limitations, toxicity and infection interference effects have been described for pIII display. Thus, display on other coat proteins such as pVII or pIX might be more attractive. Neither pVII nor pIX display have gained widespread use or been characterized in detail like pIII and pVIII display. Methodology/Principal Findings Here we present a side-by-side comparison of display on pIII with display on pVII and pIX. Polypeptides of interest (POIs) are fused to pVII or pIX. The N-terminal periplasmic signal sequence, which is required for phage integration of pIII and pVIII and that has been added to pVII and pIX in earlier studies, is omitted altogether. Although the POI display level on pIII is higher than on pVII and pIX, affinity selection with pVII and pIX display libraries is shown to be particularly efficient. Conclusions/Significance Display through pVII and/or pIX represent platforms with characteristics that differ from those of the pIII platform. We have explored this to increase the performance and expand the use of phage display. In the paper, we describe effective affinity selection of folded domains displayed on pVII or pIX. This makes both platforms more attractive alternatives to conventional pIII and pVIII display than they were before. PMID:21390283

  6. Determinants of drug costs in hopitalised patients with haemophilia: impact of recombinant activated factor VII.

    PubMed

    Galanaud, Jean Philippe; Pelletier-Fleury, Nathalie; Logerot-Lebrun, Hélène; Lambert, Thierry

    2003-01-01

    To analyse the determinants of anti-haemophilic drug costs in hospitalised patients with haemophilia and to estimate the impact of recombinant activated factor VII (rFVIIa) therapy on this expenditure. The perspective of the study was from the viewpoint of the hospital. A prospective study was carried out. All patients with haemophilia who were hospitalised in 1999 in Bicêtre public hospital, Paris, France were included in the cohort. For each of the 96 patients (154 hospital stays), we estimated the costs of anti-haemophilic drugs (coagulation concentrates) used. Costs were then stratified by different variables (severity of the disease, presence of a circulating inhibitor to coagulation factors, etc.) and a multivariate model was developed to determine the relationship between these variables and total anti-haemophilic drug costs, while controlling for potential confounders. Our study revealed: (i) the independent role of the five following variables in contributing to high anti-haemophilic drug expenditure: presence of a circulating inhibitor to coagulation factors, odds ratio (OR) = 16.9 (95% CI: 4.3-66); severity of the disease (factor VIII or factor IX < or =0.01 IU/mL), OR = 3.7 (95% CI: 1.6-8.6); length of hospital stay >4 days, OR = 8 (95% CI: 2.2-29.4); age >18 years old, OR = 6.2 (95% CI: 1.6-24.5); and surgical reasons for hospitalisation (whether surgery was haemophilia related [OR = 35.7 (95% CI: 7.3-175)] or not [OR = 5.4 (95% CI: 1.3-22.5)]); (ii) the large share that rFVIIa represented in this expenditure on medicines: rFVIIa was used in 20.1% of hospital stays and accounted for 56.2% of the total anti-haemophilic drug costs, which were estimated at 4,384,732 Euros (2000 values). Our data underline the heavy cost of the treatment of haemophilic patients with an inhibitor to coagulation factors. But, to the question of whether the high expenditure linked to rFVIIa utilisation will be balanced out by later benefits, it is not yet possible to reply

  7. Quantitative analysis of the synthesis and secretion of type VII collagen in cultured human dermal fibroblasts with a sensitive sandwich enzyme-linked immunoassay.

    PubMed

    Amano, Satoshi; Ogura, Yuki; Akutsu, Nobuko; Nishiyama, Toshio

    2007-02-01

    Type VII collagen is the major component of anchoring fibrils in the epidermal basement membrane. Its expression has been analyzed by immunostaining or Northern blotting, but rarely at the protein level. In this study, we have quantitatively examined the effects of ascorbic acid and various cytokines/growth factors on the protein synthesis and secretion of type VII collagen by human dermal fibroblasts in culture, using a developed, highly sensitive sandwich enzyme-linked immunoassay with two kinds of specific monoclonal antibodies against the non-collagenous domain-1. Ascorbic acid and its derivative induced a twofold increase in type VII collagen synthesis, and markedly increased the secretion of type VII collagen into the medium when compared with the control culture. This effect was not influenced by the presence of transforming growth factor-beta1 (TGF-beta1). The synthesis of type VII collagen was elevated by TGF-beta1, platelet-derived growth factor, tumor necrosis factor-alpha, and interleukin-1beta, but not by TGF-alpha. Thus, our data indicate that the synthesis and secretion of type VII collagen in human dermal fibroblasts are regulated by ascorbate and the enhancement of type VII collagen gene expression by cytokines/growth factors is accompanied with elevated production of type VII collagen at the protein level.

  8. Recombinant activated factor VII for bleeding in patients without inherited bleeding disorders.

    PubMed

    Selin, S; Tejani, A

    2006-03-01

    (1) Recombinant activated factor VII (rFVIIa) is licensed in Canada for the prevention and treatment of bleeding in hemophiliacs, but it is increasingly used to control bleeding in non-hemophilic patients during surgery, or during treatment for severe trauma or intracerebral hemorrhage (ICH). (2) In one clinical trial, there was a significant reduction in mortality among patients with ICH treated with rFVIIa. In another trial, administration of rFVIIa significantly reduced the number of trauma patients needing massive blood transfusions although there was no significant difference in mortality. (3) Adequately powered randomized controlled trials are needed to clarify the efficacy and safety of rFVIIa for non-bleeding disorder indications. Phase III trials in ICH and trauma are underway. (4) There is potential for non-hemophilic use, particularly if clinical efficacy and cost effectiveness are established.

  9. [Correlation between polymorphisms in the coagulation factor VII gene hypervariable region 4 site and the risk of coronary heart disease in population with different ethnic backgrounds: a Meta-analysis].

    PubMed

    Wang, Li-li; Ma, Bin; Qian, Dun; Pang, Jun; Yao, Ya-li

    2013-12-01

    To assess the correlation between polymorphisms in the coagulation factor VII (F VII)gene hypervariable region 4 (HVR4)site and risk related to coronary heart disease (CHD)in different ethnic populations, especially the Asian populations. Publications up to April 2013, from CBM, CNKI, Wanfang Database,VIP, PubMed, Cochrane Library and Embase were searched to collect data from case-control studies related to F VII gene HVR4 site and CHD in populations from different ethnicities. Quality of studies was evaluated, available data extracted and both RevMan 5.1 and Stata 11.0 softwares were used for Meta-analysis. Fifteen case-control studies were included, involving 3167 cases with CHD group and 3168 cases in the control group. on this Meta-analysis showed that:a)polymorphism of the F VII gene HVR4 site H7/H6+H5 and CHD, b)H7H7/H6H6 + H7H6 and CHD were both slightly correlated between people with different ethnic backgrounds. However, the H6 allele versus H7+H5 allele and CHD showed different results-a high correlation seen in different ethnic groups. H5 allele versus H6+H7 allele and CHD did not appear significant difference(OR = 1.20, 95%CI:0.76-1.90, P = 0.43). Both F VII gene HVR4 polymorphisms H7 allele and the H7H7 genotype might have served as protective factors for CHD in different ethnic groups, H6 allele might serve as a risk factor for CHD, but H5 allele was likely not to be associated with CHD in different ethnic groups.

  10. [Hereditary heterozygous factor VII deficiency in patients undergoing surgery : Clinical relevance].

    PubMed

    Woehrle, D; Martinez, M; Bolliger, D

    2016-10-01

    A hereditary deficiency in coagulation factor VII (FVII) may affect the international normalized ratio (INR) value. However, FVII deficiency is occasionally associated with a tendency to bleed spontaneously. We hypothesized that perioperative substitution with coagulation factor concentrates might not be indicated in most patients. In this retrospective data analysis, we included all patients with hereditary heterozygous FVII deficiency who underwent surgical procedures at the University Hospital Basel between December 2010 and November 2015. In addition, by searching the literature, we identified publications reporting patients with FVII deficiency undergoing surgical procedures without perioperative substitution. We identified 22 patients undergoing 46 surgical procedures, resulting in a prevalence of 1:1500-2000. Coagulation factor concentrates were administered during the perioperative period in 15 procedures (33 %), whereas in the other 31 procedures (66 %), FVII deficiency was not substituted. No postoperative bleeding or thromboembolic events were reported. In addition, we found no differences in pre- and postoperative hemoglobin and coagulation parameters, with the exception of an improved postoperative INR value in the substituted group. In the literature review, we identified five publications, including 125 patients with FVII deficiency, undergoing 213 surgical procedures with no perioperative substitution. Preoperative substitution using coagulation factor concentrates does not seem to be mandatory in patients with an FVII level ≥15 %. For decision-making on preoperative substitution, patient history of an increased tendency to bleed may be more important than the FVII level or increased INR value.

  11. Women with congenital factor VII deficiency: clinical phenotype and treatment options from two international studies.

    PubMed

    Napolitano, M; Di Minno, M N D; Batorova, A; Dolce, A; Giansily-Blaizot, M; Ingerslev, J; Schved, J-F; Auerswald, G; Kenet, G; Karimi, M; Shamsi, T; Ruiz de Sáez, A; Dolatkhah, R; Chuansumrit, A; Bertrand, M A; Mariani, G

    2016-09-01

    A paucity of data exists on the incidence, diagnosis and treatment of bleeding in women with inherited factor VII (FVII) deficiency. Here we report results of a comprehensive analysis from two international registries of patients with inherited FVII deficiency, depicting the clinical picture of this disorder in women and describing any gender-related differences. A comprehensive analysis of two fully compatible, international registries of patients with inherited FVII deficiency (International Registry of Factor VII deficiency, IRF7; Seven Treatment Evaluation Registry, STER) was performed. In our cohort (N = 449; 215 male, 234 female), the higher prevalence of mucocutaneous bleeds in females strongly predicted ensuing gynaecological bleeding (hazard ratio = 12.8, 95% CI 1.68-97.6, P = 0.014). Menorrhagia was the most prevalent type of bleeding (46.4% of patients), and was the presentation symptom in 12% of cases. Replacement therapies administered were also analysed. For surgical procedures (n = 50), a receiver operator characteristic analysis showed that the minimal first dose of rFVIIa to avoid postsurgical bleeding during the first 24 hours was 22 μg kg(-1) , and no less than two administrations. Prophylaxis was reported in 25 women with excellent or effective outcomes when performed with a total weekly rFVIIa dose of 90 μg kg(-1) (divided as three doses). Women with FVII deficiency have a bleeding disorder mainly characterized by mucocutaneous bleeds, which predicts an increased risk of ensuing gynaecological bleeding. Systematic replacement therapy or long-term prophylaxis with rFVIIa may reduce the impact of menorrhagia on the reproductive system, iron loss and may avoid unnecessary hysterectomies. © 2016 John Wiley & Sons Ltd.

  12. Biological and Phylogenetic Characterization of a Genotype VII Newcastle Disease Virus from Venezuela: Efficacy of Field Vaccination

    PubMed Central

    Perozo, Francisco; Marcano, Rosmar

    2012-01-01

    Here we report the biological and molecular characterization of a virulent genotype VII Newcastle disease virus (NDV) circulating in Venezuela and the assessment of the vaccination efficacy under field conditions compared to controlled rearing conditions. Biological pathotyping showed a mean embryo dead time of 50 h and an intracerebral pathogenicity index of 1.86. Sequence-based phylogenetic analysis demonstrated that the virus belongs to genotype VII in class II (a genotype often found in Asia and Africa), representing the first report of the presence of this genotype in the continent of South America. A vaccine-challenge trial in commercial broilers reared in fields or in a experimental setting included dual (live/killed) priming of 1-day-old chicks plus two live NDV and infectious bursal disease virus (IBDV) field vaccinations at days 7 and 17, followed by a very stringent genotype VII NDV challenge at day 28. Serology for NDV and IBDV, bursal integrity, and protection against NDV lethal challenge were assessed. At 28 days, field vaccinates showed significantly lower NDV (1,356 versus 2,384) and higher IBD (7,295 versus 1,489) enzyme-linked immunosorbent assay (ELISA) antibody titers than the experimentally reared birds. A lower bursal size and bursa-body weight ratio (P < 0.05) and higher bursa lesion score were also detected in the field set. Only 57.1% of field vaccinates survived the lethal challenge, differing (P < 0.05) from 90.5% survival in the experimental farm. Overall, results confirmed the presence of the genotype VII viruses in South America and suggest that field-associated factors such as immunosuppression compromise the efficacy of the vaccination protocols implemented. PMID:22238433

  13. Associations of activated coagulation factor VII and factor VIIa-antithrombin levels with genome-wide polymorphisms and cardiovascular disease risk.

    PubMed

    Olson, N C; Raffield, L M; Lange, L A; Lange, E M; Longstreth, W T; Chauhan, G; Debette, S; Seshadri, S; Reiner, A P; Tracy, R P

    2018-01-01

    Essentials A fraction of coagulation factor VII circulates in blood as an activated protease (FVIIa). We evaluated FVIIa and FVIIa-antithrombin (FVIIa-AT) levels in the Cardiovascular Health Study. Polymorphisms in the F7 and PROCR loci were associated with FVIIa and FVIIa-AT levels. FVIIa may be an ischemic stroke risk factor in older adults and FVIIa-AT may assess mortality risk. Background A fraction of coagulation factor (F) VII circulates as an active protease (FVIIa). FVIIa also circulates as an inactivated complex with antithrombin (FVIIa-AT). Objective Evaluate associations of FVIIa and FVIIa-AT with genome-wide single nucleotide polymorphisms (SNPs) and incident coronary heart disease, ischemic stroke and mortality. Patients/Methods We measured FVIIa and FVIIa-AT in 3486 Cardiovascular Health Study (CHS) participants. We performed a genome-wide association scan for FVIIa and FVIIa-AT in European-Americans (n = 2410) and examined associations of FVII phenotypes with incident cardiovascular disease. Results In European-Americans, the most significant SNP for FVIIa and FVIIa-AT was rs1755685 in the F7 promoter region on chromosome 13 (FVIIa, β = -25.9 mU mL -1 per minor allele; FVIIa-AT, β = -26.6 pm per minor allele). Phenotypes were also associated with rs867186 located in PROCR on chromosome 20 (FVIIa, β = 7.8 mU mL -1 per minor allele; FVIIa-AT, β = 9.9 per minor allele). Adjusted for risk factors, a one standard deviation higher FVIIa was associated with increased risk of ischemic stroke (hazard ratio [HR], 1.12; 95% confidence interval [CI], 1.01, 1.23). Higher FVIIa-AT was associated with mortality from all causes (HR, 1.08; 95% CI, 1.03, 1.12). Among European-American CHS participants the rs1755685 minor allele was associated with lower ischemic stroke (HR, 0.69; 95% CI, 0.54, 0.88), but this association was not replicated in a larger multi-cohort analysis. Conclusions The results support the importance of the F7 and PROCR loci in

  14. Star formation and abundances in the nearby irregular galaxy VII ZW 403

    NASA Astrophysics Data System (ADS)

    Tully, R. B.; Boesgaard, A. M.; Dyck, H. M.; Schempp, W. V.

    1981-05-01

    Photometry in J, H, and K bands reveals that there is an unresolved source of infrared emission associated with the brightest H II region in VII Zw 403, and the colors suggest the presence of a substantial number of K and M supergiants in addition to the hot O stars that must be present to account for the ionized gas. Spectrophotometry of this emission region indicates that reddening is substantial, and that the interpretation of the observed Balmer decrement in terms of reddening is not straightforward. The primary nucleosynthesis products O, S, and Ne are underabundant compared with the sun by a factor of 15; N is underabundant compared with the sun by a factor of 160; and the helium abundance suggests that either there could have been only a small number of star formation episodes or the galaxy is younger than the time scale of the process that deposits N in the interstellar medium.

  15. Congenital Factor VII Deficiency in Children at Tertiary Health Care Facility in Pakistan.

    PubMed

    Alam, Muhammad Matloob; Moiz, Bushra; Rehman, Karim Abdur; Jethwani, Priyanka; Fadoo, Zehra

    2015-10-01

    This study presents the demographics, clinical spectrum, and outcome of patients with congenital factor VII (FVII) deficiency at a tertiary care center over a period of 12 years. Of the 49 patients, 27 (55%) patients were males. Consanguinity was found in 92% of the patients. The median age of symptom onset was 2.4 (interquartile range [IQR]: 1.1-6.5) years with a median age of 5.8 (IQR: 3.1-10) years at diagnosis. Life-threatening complications like intracranial bleeding (ICB) and intra-abdominal bleeding (IAB) were observed in 8 (16.4%) patients. We found that 11 (55%) of the 20 patients with FVII coagulant activity (FVIIc) <1% were either asymptomatic or showed mild phenotype. In contrast, 9 (53%) of the 17 patients with FVIIc >5% were affected by severe symptoms. Age <1 year was the only identified risk factor associated with development of life-threatening bleeding episodes (P = .042; odds ratio 6.46). Overall, 4 (8.2%) died as a consequence of ICB (3 patients) and IAB (1 patient). © The Author(s) 2013.

  16. The preparation and structure of salty ice VII under pressure

    NASA Astrophysics Data System (ADS)

    Klotz, Stefan; Bove, Livia E.; Strässle, Thierry; Hansen, Thomas C.; Saitta, Antonino M.

    2009-05-01

    It is widely accepted that ice, no matter what phase, is unable to incorporate large amounts of salt into its structure. This conclusion is based on the observation that on freezing of salt water, ice expels the salt almost entirely as brine. Here, we show that this behaviour is not an intrinsic physico-chemical property of ice phases. We demonstrate by neutron diffraction that substantial amounts of dissolved LiCl can be built homogeneously into the ice VII structure if it is produced by recrystallization of its glassy (amorphous) state under pressure. Such `alloyed' ice VII has significantly different structural properties compared with pure ice VII, such as an 8% larger unit cell volume, 5 times larger displacement factors, an absence of a transition to an ordered ice VIII structure and plasticity. Our study suggests that there could be a whole new class of `salty' high-pressure ice forms.

  17. The preparation and structure of salty ice VII under pressure.

    PubMed

    Klotz, Stefan; Bove, Livia E; Strässle, Thierry; Hansen, Thomas C; Saitta, Antonino M

    2009-05-01

    It is widely accepted that ice, no matter what phase, is unable to incorporate large amounts of salt into its structure. This conclusion is based on the observation that on freezing of salt water, ice expels the salt almost entirely as brine. Here, we show that this behaviour is not an intrinsic physico-chemical property of ice phases. We demonstrate by neutron diffraction that substantial amounts of dissolved LiCl can be built homogeneously into the ice VII structure if it is produced by recrystallization of its glassy (amorphous) state under pressure. Such 'alloyed' ice VII has significantly different structural properties compared with pure ice VII, such as an 8% larger unit cell volume, 5 times larger displacement factors, an absence of a transition to an ordered ice VIII structure and plasticity. Our study suggests that there could be a whole new class of 'salty' high-pressure ice forms.

  18. Altered lumbar spine structure, biochemistry and biomechanical properties in a canine model of mucopolysaccharidosis type VII

    PubMed Central

    Smith, Lachlan J; Martin, John T; Szczesny, Spencer E; Ponder, Katherine P; Haskins, Mark E; Elliott, Dawn M

    2010-01-01

    Mucopolysaccharidosis VII (MPS VII) is a lysosomal storage disorder characterized by a deficiency in β-glucuronidase activity, leading to systemic accumulation of poorly degraded glycosaminoglycans (GAG). Along with other morbidities, MPS VII is associated with paediatric spinal deformity. The objective of this study was to examine potential associations between abnormal lumbar spine matrix structure and composition in MPS VII, and spine segment and tissue-level mechanical properties, using a naturally occurring canine model with a similar clinical phenotype to the human form of the disorder. Segments from juvenile MPS VII and unaffected dogs were allocated to: radiography, gross morphology, histology, biochemistry, and mechanical testing. MPS VII spines had radiolucent lesions in the vertebral body epiphyses. Histologically, this corresponded to a GAG-rich cartilaginous region in place of bone, and elevated GAG staining was seen in the annulus fibrosus. Biochemically, MPS VII samples had elevated GAG in the outer annulus fibrosus and epiphyses, low calcium in the epiphyses, and high water content in all regions except the nucleus pulposus. MPS VII spine segments had higher range of motion and lower stiffness than controls. Endplate indentation stiffness and failure loads were significantly lower in MPS VII samples, while annulus fibrosus tensile mechanical properties were normal. Vertebral body lesions in MPS VII spines suggest a failure to convert cartilage to bone during development. Low stiffness in these regions likely contributes to mechanical weakness in motion segments and is a potential factor in the progression of spinal deformity. PMID:19918911

  19. 40 CFR Appendix Vii to Part 600 - [Reserved

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 31 2013-07-01 2013-07-01 false [Reserved] VII Appendix VII to Part 600 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) ENERGY POLICY FUEL ECONOMY AND GREENHOUSE GAS EXHAUST EMISSIONS OF MOTOR VEHICLES Appendix VII to Part 600 [Reserved] ...

  20. 40 CFR Appendix Vii to Part 600 - [Reserved

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 31 2012-07-01 2012-07-01 false [Reserved] VII Appendix VII to Part 600 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) ENERGY POLICY FUEL ECONOMY AND GREENHOUSE GAS EXHAUST EMISSIONS OF MOTOR VEHICLES Appendix VII to Part 600 [Reserved] ...

  1. 40 CFR Appendix Vii to Part 600 - [Reserved

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 30 2014-07-01 2014-07-01 false [Reserved] VII Appendix VII to Part 600 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) ENERGY POLICY FUEL ECONOMY AND GREENHOUSE GAS EXHAUST EMISSIONS OF MOTOR VEHICLES Appendix VII to Part 600 [Reserved] ...

  2. Physiological levels of blood coagulation factors IX and X control coagulation kinetics in an in vitro model of circulating tissue factor

    NASA Astrophysics Data System (ADS)

    Tormoen, Garth W.; Khader, Ayesha; Gruber, András; McCarty, Owen J. T.

    2013-06-01

    Thrombosis significantly contributes to cancer morbidity and mortality. The mechanism behind thrombosis in cancer may be circulating tissue factor (TF), as levels of circulating TF are associated with thrombosis. However, circulating TF antigen level alone has failed to predict thrombosis in patients with cancer. We hypothesize that coagulation factor levels regulate the kinetics of circulating TF-induced thrombosis. Coagulation kinetics were measured as a function of individual coagulation factor levels and TF particle concentration. Clotting times increased when pooled plasma was mixed at or above a ratio of 4:6 with PBS. Clotting times increased when pooled plasma was mixed at or above a ratio of 8:2 with factor VII-depleted plasma, 7:3 with factor IX- or factor X-depleted plasmas, or 2:8 with factor II-, V- or VIII-depleted plasmas. Addition of coagulation factors VII, X, IX, V and II to depleted plasmas shortened clotting and enzyme initiation times, and increased enzyme generation rates in a concentration-dependent manner. Only additions of factors IX and X from low-normal to high-normal levels shortened clotting times and increased enzyme generation rates. Our results demonstrate that coagulation kinetics for TF particles are controlled by factor IX and X levels within the normal physiological range. We hypothesize that individual patient factor IX and X levels may be prognostic for susceptibility to circulating TF-induced thrombosis.

  3. Outcomes Following Three-Factor Inactive Prothrombin Complex Concentrate Versus Recombinant Activated Factor VII Administration During Cardiac Surgery.

    PubMed

    Harper, Patrick C; Smith, Mark M; Brinkman, Nathan J; Passe, Melissa A; Schroeder, Darrell R; Said, Sameh M; Nuttall, Gregory A; Oliver, William C; Barbara, David W

    2018-02-01

    To compare outcomes following inactive prothrombin complex concentrate (PCC) or recombinant activated factor VII (rFVIIa) administration during cardiac surgery. Retrospective propensity-matched analysis. Academic tertiary-care center. Patients undergoing cardiac surgery requiring cardiopulmonary bypass who received either rFVIIa or the inactive 3-factor PCC. Outcomes following intraoperative administration of rFVIIa (263) or factor IX complex (72) as rescue therapy to treat bleeding. In the 24 hours after surgery, propensity-matched patients receiving PCC versus rFVIIa had significantly less chest tube outputs (median difference -464 mL, 95% confidence interval [CI] -819 mL to -110 mL), fresh frozen plasma transfusion rates (17% v 38%, p = 0.028), and platelet transfusion rates (26% v 49%, p = 0.027). There were no significant differences between propensity-matched groups in postoperative stroke, deep venous thrombosis, pulmonary embolism, myocardial infarction, or intracardiac thrombus. Postoperative dialysis was significantly less likely in patients administered PCC versus rFVIIa following propensity matching (odds ratio = 0.3, 95% CI 0.1-0.7). No significant difference in 30-day mortality in patients receiving PCC versus rFVIIa was present following propensity matching. Use of rFVIIa versus inactive PCCs was significantly associated with renal failure requiring dialysis and increased postoperative bleeding and transfusions. Copyright © 2018 Elsevier Inc. All rights reserved.

  4. Federal Programs Supporting Educational Change, Vol. VII: Factors Affecting Implementation and Continuation.

    ERIC Educational Resources Information Center

    Berman, Paul; And Others

    This report is one of three volumes that describe the second phase of a study that examined the implementation of four federal change agent programs related to education. Phase 2 of the study focused on what happens to local projects in the two largest change agent programs--ESEA Title III and ESEA Title VII--when federal funding stops. This…

  5. Synergetic Action of Domain II and IV Underlies Persistent Current Generation in Nav1.3 as revealed by a tarantula toxin

    PubMed Central

    Tang, Cheng; Zhou, Xi; Zhang, Yunxiao; xiao, Zhaohua; Hu, Zhaotun; Zhang, Changxin; Huang, Ying; Chen, Bo; Liu, Zhonghua; Liang, Songping

    2015-01-01

    The persistent current (INaP) through voltage-gated sodium channels enhances neuronal excitability by causing prolonged depolarization of membranes. Nav1.3 intrinsically generates a small INaP, although the mechanism underlying its generation remains unclear. In this study, the involvement of the four domains of Nav1.3 in INaP generation was investigated using the tarantula toxin α-hexatoxin-MrVII (RTX-VII). RTX-VII activated Nav1.3 and induced a large INaP. A pre-activated state binding model was proposed to explain the kinetics of toxin-channel interaction. Of the four domains of Nav1.3, both domain II and IV might play important roles in the toxin-induced INaP. Domain IV constructed the binding site for RTX-VII, while domain II might not participate in interacting with RTX-VII but could determine the efficacy of RTX-VII. Our results based on the use of RTX-VII as a probe suggest that domain II and IV cooperatively contribute to the generation of INaP in Nav1.3. PMID:25784299

  6. The Story of Serum Prothrombin Conversion Accelerator, Proconvertin, Stable Factor, Cothromboplastin, Prothrombin Accelerator or Autoprothrombin I, and Their Subsequent Merging into Factor VII.

    PubMed

    Girolami, Antonio; Cosi, Elisabetta; Santarossa, Claudia; Ferrari, Silvia; Luigia Randi, Maria

    2015-06-01

    Factor VII (FVII) deficiency is one of the two congenital coagulation disorders that was not discovered by the description of a new bleeding patient whose clotting pattern did not fit the blood coagulation knowledge of the time (the other is factor XIII deficiency). The existence of an additional factor capable of accelerating the conversion of prothrombin into thrombin was suspected before 1951, the year in which the first family with FVII deficiency was discovered. As several investigators were involved in the discovery of FVII deficiency from both sides of the Atlantic, several different names were tentatively suggested to define this entity, namely stable factor (in contrast with labile factor or FV), cothromboplastin, proconvertin, serum prothrombin conversion accelerator, prothrombin acceleration, and autoprothrombin I. The last term was proposed by those who denied the existence of this new entity, which was instead considered to be a derivate of prothrombin activation, namely autoprothrombin. The description of several families, from all over the world, of the same defect, however clearly demonstrated the singularity of the condition. Factor VII was then proposed to define this protein. In subsequent years, several variants were described with peculiar reactivity toward tissue thromboplastins of different origin. Molecular biology techniques demonstrated several gene mutations, usually missense mutations, often involving exon 8 of the FVII gene. Later studies dealt with the relation of FVII with tissue factor and activated FVII (FVIIa). The evaluation of circulating FVIIa was made possible by the use of a truncated form of tissue factor, which is only sensitive to FVIIa present in the circulation. The development of FVII concentrates, both plasma derived and recombinant, has facilitated therapeutic management of FVII-deficient patients. The use of FVIIa concentrates was noted to be associated with the occasional occurrence of thrombotic events, mainly

  7. 19 CFR Annex Vii to Part 351 - Antidumping Investigations Timeline

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 19 Customs Duties 3 2010-04-01 2010-04-01 false Antidumping Investigations Timeline VII Annex VII to Part 351 Customs Duties INTERNATIONAL TRADE ADMINISTRATION, DEPARTMENT OF COMMERCE ANTIDUMPING AND COUNTERVAILING DUTIES Pt. 351, Annex VII Annex VII to Part 351—Antidumping Investigations Timeline ER19MY97.001 ...

  8. 19 CFR Annex Vii to Part 351 - Antidumping Investigations Timeline

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 19 Customs Duties 3 2014-04-01 2014-04-01 false Antidumping Investigations Timeline VII Annex VII to Part 351 Customs Duties INTERNATIONAL TRADE ADMINISTRATION, DEPARTMENT OF COMMERCE ANTIDUMPING AND COUNTERVAILING DUTIES Pt. 351, Annex VII Annex VII to Part 351—Antidumping Investigations Timeline ER19MY97.001 ...

  9. 19 CFR Annex Vii to Part 351 - Antidumping Investigations Timeline

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 19 Customs Duties 3 2011-04-01 2011-04-01 false Antidumping Investigations Timeline VII Annex VII to Part 351 Customs Duties INTERNATIONAL TRADE ADMINISTRATION, DEPARTMENT OF COMMERCE ANTIDUMPING AND COUNTERVAILING DUTIES Pt. 351, Annex VII Annex VII to Part 351—Antidumping Investigations Timeline ER19MY97.001 ...

  10. 19 CFR Annex Vii to Part 351 - Antidumping Investigations Timeline

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 19 Customs Duties 3 2013-04-01 2013-04-01 false Antidumping Investigations Timeline VII Annex VII to Part 351 Customs Duties INTERNATIONAL TRADE ADMINISTRATION, DEPARTMENT OF COMMERCE ANTIDUMPING AND COUNTERVAILING DUTIES Pt. 351, Annex VII Annex VII to Part 351—Antidumping Investigations Timeline ER19MY97.001 ...

  11. 19 CFR Annex Vii to Part 351 - Antidumping Investigations Timeline

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 19 Customs Duties 3 2012-04-01 2012-04-01 false Antidumping Investigations Timeline VII Annex VII to Part 351 Customs Duties INTERNATIONAL TRADE ADMINISTRATION, DEPARTMENT OF COMMERCE ANTIDUMPING AND COUNTERVAILING DUTIES Pt. 351, Annex VII Annex VII to Part 351—Antidumping Investigations Timeline ER19MY97.001 ...

  12. Recombinant activated factor VII: its mechanism of action and role in the control of hemorrhage.

    PubMed

    Allen, Geoffrey A; Hoffman, Maureane; Roberts, Harold R; Monroe, Dougald M

    2002-12-01

    Recombinant activated factor VII (rFVIIa) has proven both safe and efficacious in the treatment of bleeding episodes in patients with hemophilia A or B who have developed inhibitors. More recently, a growing number of reports suggests that rFVIIa may also have indications for the treatment of bleeding in patients with other hemostatic disorders, including qualitative and quantitative platelet defects, factor deficiencies other than hemophilia, and in otherwise healthy patients with uncontrollable hemorrhage following surgery or trauma. We have attempted to reconcile the various proposed mechanisms of action of rFVIIa with its apparent efficacy in such diverse clinical settings. A review of the literature was performed to determine those clinical scenarios in which rFVIIa appears to have been effective in controlling associated hemorrhage. Findings from our group and others have demonstrated that rFVIIa is able to directly activate factor X and increase thrombin production on the surface of activated platelets in the absence of factor VIII or IX, as well as to improve thrombin generation in thrombocytopenia, and to yield a fibrin dot more resistant to fibrinolysis in vitro. Through these primary mechanisms, we believe that rFVIIa may be able to compensate for a variety of defects in hemostasis and merits further investigation as a general therapeutic for uncontrollable hemorrhage.

  13. Title VII and the Male/Female Earnings Gap: An Economic Analysis.

    ERIC Educational Resources Information Center

    Beller, Andrea

    1978-01-01

    After controlling statistically for the effects of other factors that affect earnings, it was found that enforcement of sex discrimination charges under Title VII increased the relative demand for women and thus decreased the male/female earnings differential between 1967 and 1974. (Author)

  14. A product Pearson-type VII density distribution

    NASA Astrophysics Data System (ADS)

    Nadarajah, Saralees; Kotz, Samuel

    2008-01-01

    The Pearson-type VII distributions (containing the Student's t distributions) are becoming increasing prominent and are being considered as competitors to the normal distribution. Motivated by real examples in decision sciences, Bayesian statistics, probability theory and Physics, a new Pearson-type VII distribution is introduced by taking the product of two Pearson-type VII pdfs. Various structural properties of this distribution are derived, including its cdf, moments, mean deviation about the mean, mean deviation about the median, entropy, asymptotic distribution of the extreme order statistics, maximum likelihood estimates and the Fisher information matrix. Finally, an application to a Bayesian testing problem is illustrated.

  15. Factor II assay

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/003674.htm Factor II assay To use the sharing features on ... M. is also a founding member of Hi-Ethics and subscribes to the principles of the Health ...

  16. 40 CFR Table II-1 to Subpart II of... - Emission Factors

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 21 2014-07-01 2014-07-01 false Emission Factors II Table II-1 to Subpart II of Part 98 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) MANDATORY GREENHOUSE GAS REPORTING Industrial Wastewater Treatment Pt. 98, Subpt. II, Table II-1...

  17. 40 CFR Table II-1 to Subpart II of... - Emission Factors

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 22 2013-07-01 2013-07-01 false Emission Factors II Table II-1 to Subpart II of Part 98 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) MANDATORY GREENHOUSE GAS REPORTING Industrial Wastewater Treatment Pt. 98, Subpt. II, Table II-1...

  18. What Are Rare Clotting Factor Deficiencies?

    MedlinePlus

    ... Deficiency Factor V Deficiency Combined FV & FVIII Deficiencies Factor VII Deficiency Factor X Deficiency Factor XI Deficiency Factor ... Deficiency Factor V Deficiency Combined FV & FVIII Deficiencies Factor VII Deficiency Factor X Deficiency Factor XI Deficiency Factor ...

  19. [The role of recombinant activated factor VII in neuro- surgical and neurocritical patients].

    PubMed

    Rama-Maceiras, P; Ingelmo-Ingelmo, I; Fábregas-Juliá, N; Hernández-Palazón, J

    2011-06-01

    Central nervous system haemorrhage is a severe pathology, as a small amount of bleeding inside the brain can result in devastating consequences. Haemostatic agents might decrease the consequences of intra- cranial bleeding, whichever spontaneous, traumatic, or anticoagulation treatment etiology. Proacogulant recombinant activated factor VII (rFVIIa) has been given after central nervous system bleeding, with an off-label indication. In this update, we go over the drug mechanism of action, its role in the treatment of central nervous system haemorrhage and the published evidences regarding this subject. We carried out a literature review concerning the treatment with rFVIIa in central nervous system haemorrhage, neurocritical pathologies and neurosurgical procedures, searching in MEDLINE and in clinical trials registry: http://clinicaltrials.gov (last review September 2010), as well as performing a manual analysis of collected articles, looking for aditional references. The results of randomized clinical trials do not support the systematic administration of rFVIIa for spontaneous intracranial cerebral haemorrhage. In other central nervous system related haemorrhages, the current available data consist on retrospective studies, expert opinion or isolated case reports.

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

    PubMed

    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.

  1. LEA Title VII Program Evaluations. Panel Presentations.

    ERIC Educational Resources Information Center

    Balu, Raj

    These panel presentations focus on LEA Title VII Program Evaluations. Raj Balu, an administrator of bilingual programs in Chicago presents information regarding the bilingual education program in the Chicago public schools, as well as information on Title VII programs and what kind of evaluation is being done. Jesus Salazar, who is currently…

  2. Management of Labour and Delivery in a Patient With Acquired Factor VII Deficiency With Inhibitor: A Case Report.

    PubMed

    Matei, Anca; Dolan, Sean; Andrews, James; Rivard, Georges-Étienne

    2016-02-01

    Acquired factor VII (FVII) deficiency with inhibitor increases the risk of hemorrhage during pregnancy. However, there are no published reports guiding its management in the peripartum period. A 24-year-old woman with inhibitory antibodies to FVII delivered at 34 weeks of gestation. The patient was administered recombinant factor VIIa (rFVIIa) and tranexamic acid. There were no bleeding-related complications; however, the FVII level was supratherapeutic. The patient returned during a second pregnancy. A reduced dose of rFVIIa was administered. The delivery was complicated by postpartum hemorrhage, which resolved with the addition of uterotonic agents. Recombinant FVIIa and tranexamic acid offer an effective peripartum treatment in women with inhibitory antibody to FVII. Further research should delineate the optimal time of administration. Copyright © 2016 Society of Obstetricians and Gynaecologists of Canada. Published by Elsevier Inc. All rights reserved.

  3. Venom Concentrations and Clotting Factor Levels in a Prospective Cohort of Russell's Viper Bites with Coagulopathy.

    PubMed

    Isbister, Geoffrey K; Maduwage, Kalana; Scorgie, Fiona E; Shahmy, Seyed; Mohamed, Fahim; Abeysinghe, Chandana; Karunathilake, Harendra; O'Leary, Margaret A; Gnanathasan, Christeine A; Lincz, Lisa F

    2015-01-01

    Russell's viper envenoming is a major problem in South Asia and causes venom induced consumption coagulopathy. This study aimed to investigate the kinetics and dynamics of venom and clotting function in Russell's viper envenoming. In a prospective cohort of 146 patients with Russell's viper envenoming, we measured venom concentrations, international normalised ratio [INR], prothrombin time (PT), activated partial thromboplastin time (aPTT), coagulation factors I, II, V, VII, VIII, IX and X, and von Willebrand factor antigen. The median age was 39 y (16-82 y) and 111 were male. The median peak INR was 6.8 (interquartile range [IQR]: 3.7 to >13), associated with low fibrinogen [median,<0.01 g/L; IQR: <0.01-0.9 g/L), low factor V levels [median,<5%; IQR: <5-4%], low factor VIII levels [median,40%; IQR: 12-79%] and low factor X levels [median, 48%; IQR: 29-67%]. There were smaller reductions in factors II, IX and VII over time. All factors recovered over 48 h post-antivenom. The median INR remained >3 at 6 h post-antivenom but had reduced to <2, by 24 h. The aPTT had also returned to close to normal (<50 sec) at 24 h. Factor VII, VIII and IX levels were unusually high pre-antivenom, median peak concentrations of 393%, 307% and 468% respectively. Pre-antivenom venom concentrations and the INR (r = 0.20, p = 0.02) and aPTT (r = 0.19, p = 0.03) were correlated (non-parametric Spearman analysis). Russell's viper coagulopathy results in prolonged aPTT, INR, low fibrinogen, factors V, VIII and X which recover over 48 h. Severity of clotting abnormalities was associated with venom concentrations.

  4. Congenital factor XI and factor VII deficiencies assure an apparent opposite protection against arterial or venous thrombosis: An intriguing observation.

    PubMed

    Girolami, A; Peroni, E; Girolami, B; Ferrari, S; Lombardi, A M

    2016-09-01

    To investigate the prevalence and type of thrombotic events reported in patients with congenital factor XI (FXI) or factor VII (FVII) deficiency. Data on all patients with congenital FXI or FVII deficiency and a thrombotic event were gathered by means of a time unlimited PubMed search carried out in June 2014 and in February 2015. Appropriate keywords including the medical subject headings were used in both instances. Side tables were also consulted and cross-checking of the references was carried out to avoid omissions. The thrombosis event had to be proven by objective methods. Forty-three patients with FXI deficiency had arterial thrombosis and only eight had venous thrombosis. On the contrary, only five patients with FVII deficiency had arterial thrombosis whereas 31 patients had venous thrombosis. The arterial/venous ratios were 5.37 and 0.17 for FXI or FVII, respectively. Arterial thrombosis is frequent in FXI deficiency whereas venous thrombosis is rare. The reverse is true for FVII deficiency. The significance of these findings is discussed especially in view of the recent use of synthetic anti-FXI compounds in the prophylaxis of post-orthopedic surgery of venous thrombosis complications.

  5. Pseudane-VII Isolated from Pseudoalteromonas sp. M2 Ameliorates LPS-Induced Inflammatory Response In Vitro and In Vivo

    PubMed Central

    Kim, Mi Eun; Jung, Inae; Na, Ju Yong; Kim, Woo Jung; Kim, Young-Ok; Park, Yong-Duk; Lee, Jun Sik

    2017-01-01

    The ocean is a rich resource of flora, fauna, food, and biological products. We found a wild-type bacterial strain, Pseudoalteromonas sp. M2, from marine water and isolated various secondary metabolites. Pseudane-VII is a compound isolated from the Pseudoalteromonas sp. M2 metabolite that possesses anti-melanogenic activity. Inflammation is a response of the innate immune system to microbial infections. Macrophages have a critical role in fighting microbial infections and inflammation. Recent studies reported that various compounds derived from natural products can regulate immune responses including inflammation. However, the anti-inflammatory effects and mechanism of pseudane-VII in macrophages are still unknown. In this study, we investigated the anti-inflammatory effects of pseudane-VII. In present study, lipopolysaccharide (LPS)-induced nitric oxide (NO) production was significantly decreased by pseudane-VII treatment at 6 μM. Moreover, pseudane-VII treatment dose-dependently reduced mRNA levels of pro-inflammatory cytokines including inos, cox-2, il-1β, tnf-α, and il-6 in LPS-stimulated macrophages. Pseudane-VII also diminished iNOS protein levels and IL-1β secretion. In addition, Pseudane-VII elicited anti-inflammatory effects by inhibiting ERK, JNK, p38, and nuclear factor (NF)-κB-p65 phosphorylation. Consistently, pseudane-VII was also shown to inhibit the LPS-stimulated release of IL-1β and expression of iNOS in mice. These results suggest that pseudane-VII exerted anti-inflammatory effects on LPS-stimulated macrophage activation via inhibition of ERK, JNK, p38 MAPK phosphorylation, and pro-inflammatory gene expression. These findings may provide new approaches in the effort to develop anti-inflammatory therapeutics. PMID:29104209

  6. Pseudane-VII Isolated from Pseudoalteromonas sp. M2 Ameliorates LPS-Induced Inflammatory Response In Vitro and In Vivo.

    PubMed

    Kim, Mi Eun; Jung, Inae; Lee, Jong Suk; Na, Ju Yong; Kim, Woo Jung; Kim, Young-Ok; Park, Yong-Duk; Lee, Jun Sik

    2017-11-01

    The ocean is a rich resource of flora, fauna, food, and biological products. We found a wild-type bacterial strain, Pseudoalteromonas sp. M2, from marine water and isolated various secondary metabolites. Pseudane-VII is a compound isolated from the Pseudoalteromonas sp. M2 metabolite that possesses anti-melanogenic activity. Inflammation is a response of the innate immune system to microbial infections. Macrophages have a critical role in fighting microbial infections and inflammation. Recent studies reported that various compounds derived from natural products can regulate immune responses including inflammation. However, the anti-inflammatory effects and mechanism of pseudane-VII in macrophages are still unknown. In this study, we investigated the anti-inflammatory effects of pseudane-VII. In present study, lipopolysaccharide (LPS)-induced nitric oxide (NO) production was significantly decreased by pseudane-VII treatment at 6 μM. Moreover, pseudane-VII treatment dose-dependently reduced mRNA levels of pro-inflammatory cytokines including inos , cox-2 , il-1β , tnf-α , and il-6 in LPS-stimulated macrophages. Pseudane-VII also diminished iNOS protein levels and IL-1β secretion. In addition, Pseudane-VII elicited anti-inflammatory effects by inhibiting ERK, JNK, p38, and nuclear factor (NF)-κB-p65 phosphorylation. Consistently, pseudane-VII was also shown to inhibit the LPS-stimulated release of IL-1β and expression of iNOS in mice. These results suggest that pseudane-VII exerted anti-inflammatory effects on LPS-stimulated macrophage activation via inhibition of ERK, JNK, p38 MAPK phosphorylation, and pro-inflammatory gene expression. These findings may provide new approaches in the effort to develop anti-inflammatory therapeutics.

  7. Pathogenesis of mitral valve disease in mucopolysaccharidosis VII dogs.

    PubMed

    Bigg, Paul W; Baldo, Guilherme; Sleeper, Meg M; O'Donnell, Patricia A; Bai, Hanqing; Rokkam, Venkata R P; Liu, Yuli; Wu, Susan; Giugliani, Roberto; Casal, Margret L; Haskins, Mark E; Ponder, Katherine P

    2013-11-01

    Mucopolysaccharidosis VII (MPS VII) is due to the deficient activity of β-glucuronidase (GUSB) and results in the accumulation of glycosaminoglycans (GAGs) in lysosomes and multisystemic disease with cardiovascular manifestations. The goal here was to determine the pathogenesis of mitral valve (MV) disease in MPS VII dogs. Untreated MPS VII dogs had a marked reduction in the histochemical signal for structurally-intact collagen in the MV at 6 months of age, when mitral regurgitation had developed. Electron microscopy demonstrated that collagen fibrils were of normal diameter, but failed to align into large parallel arrays. mRNA analysis demonstrated a modest reduction in the expression of genes that encode collagen or collagen-associated proteins such as the proteoglycan decorin which helps collagen fibrils assemble, and a marked increase for genes that encode proteases such as cathepsins. Indeed, enzyme activity for cathepsin B (CtsB) was 19-fold normal. MPS VII dogs that received neonatal intravenous injection of a gamma retroviral vector had an improved signal for structurally-intact collagen, and reduced CtsB activity relative to that seen in untreated MPS VII dogs. We conclude that MR in untreated MPS VII dogs was likely due to abnormalities in MV collagen structure. This could be due to upregulation of enzymes that degrade collagen or collagen-associated proteins, to the accumulation of GAGs that compete with proteoglycans such as decorin for binding to collagen, or to other causes. Further delineation of the etiology of abnormal collagen structure may lead to treatments that improve biomechanical properties of the MV and other tissues. © 2013.

  8. Pathogenesis of Mitral Valve Disease in Mucopolysaccharidosis VII Dogs

    PubMed Central

    Bigg, Paul W.; Baldo, Guilherme; Sleeper, Meg M.; O'Donnell, Patricia A.; Bai, Hanqing; Rokkam, Venkata R.P.; Liu, Yuli; Wu, Susan; Giugliani, Roberto; Casal, Margret L.; Haskins, Mark E.; Ponder, Katherine P.

    2013-01-01

    Mucopolysaccharidosis VII (MPS VII) is due to deficient activity of β-glucuronidase (GUSB) and results in the accumulation of glycosaminoglycans (GAGs) in lysosomes and multisystemic disease with cardiavascular manifestations. The goal here was to determine the pathogenesis of mitral valve (MV) disease in MPS VII dogs. Untreated MPS VII dogs had a marked reduction in the histochemical signal for structurally-intact collagen in the MV at 6 months of age, when mitral regurgitation had developed. Electron microscopy demonstrated that collagen fibrils were of normal diameter, but failed to align into large parallel arrays. mRNA analysis demonstrated a modest reduction in the expression of genes that encode collagen or collagen-associated proteins such as the proteoglycan decorin which helps collagen fibrils assemble, and a marked increase for genes that encode proteases such as cathepsins. Indeed, enzyme activity for cathepsin B (CtsB) was 19-fold normal. MPS VII dogs that received neonatal intravenous injection of a gamma retroviral vector had an improved signal for structurally-intact collagen, and reduced CtsB activity relative to that seen in untreated MPS VII dogs. We conclude that MR in untreated MPS VII dogs was likely due to abnormalities in MV collagen structure. This could be due to upregulation of enzymes that degrade collagen or collagen-associated proteins, to the accumulation of GAGs that compete with proteoglycans such as decorin for binding to collagen, or to other causes. Further delineation of the etiology of abnormal collagen structure may lead to treatments that improve biomechanical properties of the MV and other tissues. PMID:23856419

  9. The role of recombinant activated factor VII in neurosurgery: hope or hype?

    PubMed

    Hawryluk, Gregory W J; Cusimano, Michael D

    2006-12-01

    Recombinant activated factor VII (rFVIIa) is a relatively new pharmaceutical agent developed for use in patients with hemophilia in whom inhibitors to clotting factors VIII or IX have developed. Use of this drug has become common in recent years because of its efficacy and safety in patients with coagulation disorders as well as in patients who are at high risk for thromboembolism, even when other means of establishing hemostasis have failed. The use of rFVIIa in neurosurgery has lagged behind its use in other fields, although there is a growing body of literature on such uses. In this article the authors review the history and science of rFVIIa as well as dosing and safety information. Various uses pertinent to the neurosurgeon are reviewed, including the treatment of patients with coagulation disorders, those suffering trauma, and those with perioperative hemorrhage, intracerebral hemorrhage, or subarachnoid hemorrhage. Based on their review of the uses of rFVIIa, the authors conclude that rFVIIa is a safe and effective agent with the potential to revolutionize the treatment of neurosurgical patients with hemorrhage. Cost is a major impediment to the widespread use of rFVIIa, and there is some evidence that its use in the neurosurgical population may be subject to higher risk than in other populations studied thus far. Although further study is needed to better delineate the safety and efficacy of the drug in many nonlicensed uses, it is clear that rFVIIa is an agent with tremendous promise.

  10. Replacement therapy for bleeding episodes in factor VII deficiency. A prospective evaluation.

    PubMed

    Mariani, Guglielmo; Napolitano, Mariasanta; Dolce, Alberto; Pérez Garrido, Rosario; Batorova, Angelika; Karimi, Mehran; Platokouki, Helen; Auerswald, Günter; Bertrand, Anne-Marie; Di Minno, Giovanni; Schved, Jean F; Bjerre, Jens; Ingerslev, Jorgen; Sørensen, Benny; Ruiz-Saez, Arlette

    2013-02-01

    Patients with inherited factor VII (FVII) deficiency display different clinical phenotypes requiring ad hoc management. This study evaluated treatments for spontaneous and traumatic bleeding using data from the Seven Treatment Evaluation Registry (STER). One-hundred one bleeds were analysed in 75 patients (41 females; FVII coagulant activity <1-20%). Bleeds were grouped as haemarthroses (n=30), muscle/subcutaneous haematomas (n=16), epistaxis (n=12), gum bleeding (n=13), menorrhagia (n=16), central nervous system (CNS; n=9), gastrointestinal (GI; n=2) and other (n=3). Of 93 evaluable episodes, 76 were treated with recombinant, activated FVII (rFVIIa), eight with fresh frozen plasma (FFP), seven with plasma-derived FVII (pdFVII) and two with prothrombin-complex concentrates. One-day replacement therapy resulted in very favourable outcomes in haemarthroses, and was successful in muscle/subcutaneous haematomas, epistaxis and gum bleeding. For menorrhagia, single- or multiple-dose schedules led to favourable outcomes. No thrombosis occurred; two inhibitors were detected in two repeatedly treated patients (one post-rFVIIa, one post-pdFVII). In FVII deficiency, most bleeds were successfully treated with single 'intermediate' doses (median 60 µg/kg) of rFVIIa. For the most severe bleeds (CNS, GI) short- or long-term prophylaxis may be optimal.

  11. Factor VII deficiency

    MedlinePlus

    ... disorders: coagulation factor deficiencies. In: Goldman L, Schafer AI, eds. Goldman-Cecil Medicine . 25th ed. ... Florida Cancer Specialists & Research Institute, Wellington, FL. Review provided by ...

  12. [Prophylactic use of a recombinant activated factor VII in delivery haemorrhage by caesarean in a woman with major factor VII deficiency: a case report].

    PubMed

    Comes, Jean-François; Devignes, Jean; Thiebaugeorges, Olivier; Briquel, Marie-Elisabeth; Lecompte, Thomas

    2011-01-01

    Taking in charge the delivery of pregnant women with inherited major deficiency of factor VII (FVII) is poorly reported in literature. We report here the haemorrhagic prophylaxis of delivery by recombinant activated FVII (rFVIIa) in a 27-year-old women, gravida 1, para 0, with major deficiency FVII by missense mutation (p.Arg337Cys). Her parents, first germen, presented a FVII deficiency. She has four brothers and three sisters, of which only one brother has major FVII deficiency with hemorrhagic diathesis in childhood (hematochezia). At her birth, because of dystocia, a right sterno-cleido-mastoid muscle hematoma and left clavicle fracture occurred. The FVII concentration was 0.08 U/mL. At the age of fifteen, a surgery of appendicitis was performed with substitution by FVII from plasma donors without any haemorrhagic complication. Because of anatomic specificity (bifid uterus and vagina), caesarean was planned. After reviewing of the literature, caesarean was performed at 38th week of gestation with haemorrhagic prophylaxis consisting in administration of rFVIIa (eptacog alfa) at a dose of 20 μg/kg, 30 min before surgery, then every 3 h during 48 h. No haemorrhagic complication occurred. Thrombosis prophylaxis was ensured by enoxaparin (4000 UI a day subcutaneously started 6 h after surgery for 5 days). Clinical examination of the newborn was normal. In future, modalities of taking in charge have to be evaluated by prospective studies involving a sufficiently numerous group of woman with FVII major deficiency, or by retrospective studies with the means of national or European registers.

  13. The Impact of Potassium Manganate (VII) on the Effectiveness of Coagulation in the Removal of Iron and Manganese from Groundwater with an Increased Content of Organic Substances

    NASA Astrophysics Data System (ADS)

    Krupińska, Izabela

    2017-12-01

    The article presents the results of studies concerning the impact of the method of Fe(II) ion oxidisation (dissolved oxygen and potassium manganate (VII)) on the effectiveness of coagulation in the removal of iron and manganese from groundwater with an increased content of organic substances. The efficiencies of two coagulants were compared: aluminium sulphate (VI) and polyaluminium chloride (Flokor 1.2A). Among the used methods of iron (II) oxidisation, the best effects have been achieved by potassium manganate (VII) because one of the oxidation products was manganese oxide (IV) precipitating from water. Better results in purifying the water were obtained with the use of a prehydrolysed coagulant Flokor 1.2 A than aluminium sulphate (VI).

  14. 32 CFR 2003.7 - Support Staff (Article VII).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 32 National Defense 6 2014-07-01 2014-07-01 false Support Staff (Article VII). 2003.7 Section 2003... (ISCAP) BYLAWS, RULES, AND APPEAL PROCEDURES Bylaws § 2003.7 Support Staff (Article VII). The staff of..., provides program and administrative support for the Panel. The Executive Secretary supervises the staff in...

  15. 32 CFR 2003.7 - Support Staff (Article VII).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 32 National Defense 6 2013-07-01 2013-07-01 false Support Staff (Article VII). 2003.7 Section 2003... (ISCAP) BYLAWS, RULES, AND APPEAL PROCEDURES Bylaws § 2003.7 Support Staff (Article VII). The staff of..., provides program and administrative support for the Panel. The Executive Secretary supervises the staff in...

  16. Mutational analysis of a patient with mucopolysaccharidosis type VII, and identification of pseudogenes

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Shipley, J.M.; Klinkenberg, M.; Wu, B.M.

    1993-03-01

    PCR of cDNA produced from patient fibroblasts allowed the authors to determine the paternal mutation in the first patient reported with [beta]-glucuronidase-deficiency mucopolysaccharidosis type VII (MPS VII). The G[r arrow]T transversion 1,881 bp downstream of the ATG translation initiation codon destroys an MboII restriction site and converts Trp627 to Cys (W627C). Digestion of genomic DNA PCR fragments with MboII indicated that the patient and the father were heterozygous for this missense mutation in exon 12. Failure to find cDNAs from patient RNA which did not contain this mutation suggested that the maternal mutation leads to greatly reduced synthesis or reducedmore » stability of mRNA from the mutant allele. In order to identify the maternal mutation, it was necessary to analyze genomic sequences. This approach was complicated by the finding of multiple unprocessed pseudogenes and/or closely related genes. Using PCR with a panel of human/rodent hybrid cell lines, the authors found that these pseudogenes were present over chromosomes 5-7, 20, and 22 and the Y chromosome. Conditions were defined which allowed them to amplify and characterize genomic sequences for the true [beta]-glucuronidase gene despite this background of related sequences. The patient proved to be heterozygous for a second mutation, in which a C[r arrow]T transition introduces a termination codon (R356STOP) in exon 7. The mother was also heterozygous for this mutation. Expression of a cDNA containing the maternal mutation produced no enzyme activity, as expected. Expression of the paternal mutation in COS-7 cells produced a surprisingly high (65% of control) level of activity. However, activity was 13% of control in transiently transfected murine MPS VII cells. The level of activity of this mutant allele appears to correlate with the level of overexpression. 39 refs., 5 figs., 1 tab.« less

  17. Gene therapy ameliorates cardiovascular disease in dogs with mucopolysaccharidosis VII.

    PubMed

    Sleeper, M M; Fornasari, B; Ellinwood, N M; Weil, M A; Melniczek, J; O'Malley, T M; Sammarco, C D; Xu, L; Ponder, K P; Haskins, M E

    2004-08-17

    Mucopolysaccharidosis VII (MPS VII) is a lysosomal storage disease caused by deficient beta-glucuronidase (GUSB) activity resulting in defective catabolism of glycosaminoglycans (GAGs). Cardiac disease is a major cause of death in MPS VII because of accumulation of GAGs in cardiovascular cells. Manifestations include cardiomyopathy, mitral and aortic valve thickening, and aortic root dilation and may cause death in the early months of life or may be compatible with a fairly normal lifespan. We previously reported that neonatal administration of a retroviral vector (RV) resulted in transduction of hepatocytes, which secreted GUSB into the blood and could be taken up by cells throughout the body. The goal of this study was to evaluate the effect on cardiac disease. Six MPS VII dogs were treated intravenously with an RV-expressing canine GUSB. Echocardiographic parameters, cardiovascular lesions, and biochemical parameters of these dogs were compared with those of normal and untreated MPS VII dogs. RV-treated dogs were markedly improved compared with untreated MPS VII dogs. Most RV-treated MPS VII dogs had mild or moderate mitral regurgitation at 4 to 5 months after birth, which improved or disappeared when evaluated at 9 to 11 and at 24 months. Similarly, mitral valve thickening present early in some animals disappeared over time, whereas aortic dilation and aortic valve thickening were absent at all times. Both myocardium and aorta had significant levels of GUSB and reduction in GAGs.

  18. An engineered tale-transcription factor rescues transcription of factor VII impaired by promoter mutations and enhances its endogenous expression in hepatocytes.

    PubMed

    Barbon, Elena; Pignani, Silvia; Branchini, Alessio; Bernardi, Francesco; Pinotti, Mirko; Bovolenta, Matteo

    2016-06-24

    Tailored approaches to restore defective transcription responsible for severe diseases have been poorly explored. We tested transcription activator-like effectors fused to an activation domain (TALE-TFs) in a coagulation factor VII (FVII) deficiency model. In this model, the deficiency is caused by the -94C > G or -61T > G mutation, which abrogate the binding of Sp1 or HNF-4 transcription factors. Reporter assays in hepatoma HepG2 cells naturally expressing FVII identified a single TALE-TF (TF4) that, by targeting the region between mutations, specifically trans-activated both the variant (>100-fold) and wild-type (20-40-fold) F7 promoters. Importantly, in the genomic context of transfected HepG2 and transduced primary hepatocytes, TF4 increased F7 mRNA and protein levels (2- to 3-fold) without detectable off-target effects, even for the homologous F10 gene. The ectopic F7 expression in renal HEK293 cells was modestly affected by TF4 or by TALE-TF combinations. These results provide experimental evidence for TALE-TFs as gene-specific tools useful to counteract disease-causing promoter mutations.

  19. Fat high in stearic acid favorably affects blood lipids and factor VII coagulant activity in comparison with fats high in palmitic acid or high in myristic and lauric acids.

    PubMed

    Tholstrup, T; Marckmann, P; Jespersen, J; Sandström, B

    1994-02-01

    The effect of fats high in individual, prevalent saturated dietary fatty acids on lipoproteins and hemostatic variables in young healthy subjects was evaluated in a randomized strictly controlled metabolic feeding study. Three experimental diets: shea butter (S; 42% stearic acid), palm oil (P; 43% palmitic palmitic acid), and palm-kernel oil with high-oleic sunflower oil (ML; 10% myristic acid, 30% lauric acid) were served to 15 men for 3 wk each, separated by washout periods. Diet S compared with diet P resulted in significant reduction in plasma cholesterol (22%) LDL cholesterol (26%), apolipoprotein B (18%), HDL cholesterol (12%), apolipoprotein A-I (13%), and a 13% lower factor VII coagulant activity (P = 0.001). Similar differences were observed between diets S and ML. In conclusion, intake of shea butter high in stearic acid favorably affects blood lipids and factor VII coagulant activity in young men, compared with fats high in saturated fatty acids with 12-16 carbons.

  20. Rhenium(VII) Catalysis of Prins Cyclization Reactions

    PubMed Central

    Tadpetch, Kwanruthai; Rychnovsky, Scott D.

    2009-01-01

    The rhenium(VII) complex O3ReOSiPh3 are particularly effective catalyst for Prins cyclizations using aromatic and α,β-unsaturated aldehydes. The reaction conditions are mild and the highly substituted 4-hydroxy tetrahydropyran products are formed stereoselectively. Rhenium(VII) complexes appear to spontaneously form esters with alcohols and to directly activate electron rich alcohols for solvolysis. Re2O7 and perrhenic acid were equally effective in catalyzing these cyclizations. PMID:18816133

  1. The Back Pay Remedy in Title VII Class Actions: Problems of Procedure

    ERIC Educational Resources Information Center

    Edwards, Charles A.

    1974-01-01

    The class action for back pay has developed as a significant factor in employment discrimination litigation under Title VII of the Civil Rights Act of 1964. Problems of demonstrating each class member's entitlement are examined and a bifurcated trial procedure is proposed as a method for handling such cases. (JT)

  2. 40 CFR Appendixes I-Vii to Part 85 - [Reserved

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 18 2011-07-01 2011-07-01 false [Reserved] I Appendixes I-VII to Part 85 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) CONTROL OF AIR POLLUTION FROM MOBILE SOURCES Appendixes I-VII to Part 85 [Reserved] ...

  3. 40 CFR Appendixes I-Vii to Part 85 - [Reserved

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 18 2010-07-01 2010-07-01 false [Reserved] I Appendixes I-VII to Part 85 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) CONTROL OF AIR POLLUTION FROM MOBILE SOURCES Appendixes I-VII to Part 85 [Reserved] ...

  4. 40 CFR Appendixes I-Vii to Part 85 - [Reserved

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 19 2012-07-01 2012-07-01 false [Reserved] I Appendixes I-VII to Part 85 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) CONTROL OF AIR POLLUTION FROM MOBILE SOURCES Appendixes I-VII to Part 85 [Reserved] ...

  5. 40 CFR Appendixes I-Vii to Part 85 - [Reserved

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 19 2013-07-01 2013-07-01 false [Reserved] I Appendixes I-VII to Part 85 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) CONTROL OF AIR POLLUTION FROM MOBILE SOURCES Appendixes I-VII to Part 85 [Reserved] ...

  6. 40 CFR Appendixes I-Vii to Part 85 - [Reserved

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 19 2014-07-01 2014-07-01 false [Reserved] I Appendixes I-VII to Part 85 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) CONTROL OF AIR POLLUTION FROM MOBILE SOURCES Appendixes I-VII to Part 85 [Reserved] ...

  7. SUPPORT FOR BEIR VII

    EPA Science Inventory

    The office is supporting the continued funding of National Academy of Sciences Study to update our understanding of the effects of low-level radiation. In particular, this study, entitled the Biological Effects of Ionizing Radiation VII, will draw upon the most recent data avail...

  8. 40 CFR Appendixes Vi-Vii to Part 600 - [Reserved

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 29 2010-07-01 2010-07-01 false [Reserved] VI Appendixes VI-VII to Part 600 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) ENERGY POLICY FUEL ECONOMY AND CARBON-RELATED EXHAUST EMISSIONS OF MOTOR VEHICLES Appendixes VI-VII to Part 600 [Reserved] ...

  9. 40 CFR Appendixes Vi-Vii to Part 600 - [Reserved

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 30 2011-07-01 2011-07-01 false [Reserved] VI Appendixes VI-VII to Part 600 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) ENERGY POLICY FUEL ECONOMY AND CARBON-RELATED EXHAUST EMISSIONS OF MOTOR VEHICLES Appendixes VI-VII to Part 600 [Reserved] ...

  10. Experimental evidence for competitive growth advantage of genotype VII over VI: implications for foot-and-mouth disease virus serotype A genotype turnover in nature.

    PubMed

    Mohapatra, J K; Subramaniam, S; Singh, N K; Sanyal, A; Pattnaik, B

    2012-04-01

    In India, systematic genotype replacement has been observed for serotype A foot-and-mouth disease virus. After a decade of co-circulation of genotypes VI and VII, genotype VII emerged as the single dominant genotype since 2001. To derive possible explanations for such epochal evolution dynamics, in vitro intergenotype growth competition experiments involving both co- and superinfection regimes were conducted. Coinfection of BHK-21 cells demonstrated abrupt loss in the genotype VI viral load with commensurate increase in the load of genotype VII as measured by the genotype differentiating ELISA, RT-PCR and real-time RT-PCR. The superinfection dynamics was shaped by temporal spacing of infection, where the invading genotype VII took more number of passages than coinfection to eventually overtake the resident genotype VI. It was speculated that such superior replicative fitness of genotype VII could have been a possible factor for the ultimate dominance of genotype VII in nature. Copyright © 2011 Elsevier Ltd. All rights reserved.

  11. Anatomic Variability of the Upper Mediastinal Lymph Node Level VII.

    PubMed

    Hartl, Dana M; Breuskin, Ingrid; Mirghani, Haïtham; Berdelou, Amandine; Déandréis, Désirée; Pottier, Edwige; Borget, Isabelle; Schlumberger, Martin; Leboulleux, Sophie

    2016-08-01

    Lymph node level VII, between the sternal notch and the innominate artery, is a frequent site of lymph node metastases in thyroid cancer. The objective of this study was to determine the cranial-caudal dimensions of level VII in patients undergoing central neck dissection for thyroid cancer and its accessibility through a neck incision only. Consecutive patients undergoing central neck dissection for thyroid cancer, with no previous neck dissection, mediastinal or thoracic surgery. The innominate artery was identified and the distance between the sternal notch and the upper border of the artery was measured to the nearest .5 mm. The sizes of level VII were compared with respect to age, sex, height, body mass index, type of neck dissection (therapeutic or prophylactic), and the incidence of previous thyroidectomy. One-hundred-one consecutive patients (65 women, 36 men, mean age 44 years (range 15-87) underwent prophylactic (n = 55) or therapeutic (n = 46) bilateral central compartment neck dissection. Level VII was accessible via the horizontal neck incision in all cases. Sizes of level VII ranged from 6 cm above the sternal notch to 35 mm below the sternal notch, with a mean distance of 3.5 mm below the sternal notch. The innominate artery was at the level of the sternal notch in 29 patients, and cranial to the sternal notch in 20 cases. No statistical relationship with age, sex, therapeutic/prophylactic neck dissection, previous surgery, body mass index or height was found. The maximal distance below the sternal notch was 35 mm. Level VII did not exist in 49 % of patients, and was less than 25 mm caudal to the sternal notch in 95 % of cases. Distinguishing level VII from level VI in thyroid cancer surgery may not be pertinent, due to the ease of access via a classic horizontal neck incision and the small sizes of level VII in the majority of patients.

  12. Learning from history: the legacy of Title VII in academic family medicine.

    PubMed

    Newton, Warren; Arndt, Jane E

    2008-11-01

    The current renaissance of interest in primary care could benefit from reviewing the history of federal investment in academic family medicine. The authors review 30 years of experience with the Title VII, Section 747 Training in Primary Care Medicine and Dentistry (Title VII) grant program, addressing three questions: (1) What Title VII grant programs were available to family medicine, and what were their goals? (2) How did Title VII change the discipline? and (3) What impact did Title VII family medicine programs have outside the discipline?Title VII grant programs evolved from broad support for the new discipline of family medicine to a sharper focus on specific national workforce objectives such as improving care for underserved and vulnerable populations and increasing diversity in the health professions. Grant programs were instrumental in establishing family medicine in nearly all medical schools and in supporting the educational underpinnings of the field. Title VII grants helped enhance the social capital of the discipline. Outside family medicine, Title VII fostered the development of innovative ambulatory education, institutional initiatives focusing on underserved and vulnerable populations, and primary care research capacity. Adverse effects include relative inattention to clinical and research missions in family medicine academic units and, institutionally, the development of medical education initiatives without core institutional support, which has put innovation and extension of education to communities at risk as grant funding has decreased. Reinvestment in academic family medicine can yield substantial benefits for family medicine and help reorient academic health centers. This article is part of a theme issue of Academic Medicine on the Title VII health professions training programs.

  13. What Is Combined Deficiency of Vitamin K-Dependent Clotting Factors?

    MedlinePlus

    ... Deficiency Factor V Deficiency Combined FV & FVIII Deficiencies Factor VII Deficiency Factor X Deficiency Factor XI Deficiency Factor ... Deficiency Factor V Deficiency Combined FV & FVIII Deficiencies Factor VII Deficiency Factor X Deficiency Factor XI Deficiency Factor ...

  14. Severe coagulation factor VII deficiency caused by a novel homozygous mutation (p. Trp284Gly) in loop 140s.

    PubMed

    Hao, Xiuping; Cheng, XiaoLi; Ye, Jiajia; Wang, Yingyu; Yang, LiHong; Wang, Mingshan; Jin, Yanhui

    2016-06-01

    Congenital coagulation factor VII (FVII) deficiency is a rare disorder caused by mutation in F7 gene. Herein, we reported a patient who had unexplained hematuria and vertigo with consanguineous parents. He has been diagnosed as having FVII deficiency based on the results of reduced FVII activity (2.0%) and antigen (12.8%). The thrombin generation tests verified that the proband has obstacles in producing thrombin. Direct sequencing analysis revealed a novel homozygous missense mutation p.Trp284Gly. Also noteworthy is the fact that the mutational residue belongs to structurally conserved loop 140s, which majorly undergo rearrangement after FVII activation. Model analysis indicated that the substitution disrupts these native hydrophobic interactions, which are of great importance to the conformation in the activation domain of FVIIa.

  15. Gentamicin induces functional type VII collagen in recessive dystrophic epidermolysis bullosa patients

    PubMed Central

    Woodley, David T.; Cogan, Jon; Hou, Yingping; Lyu, Chao; Marinkovich, M. Peter; Keene, Douglas

    2017-01-01

    BACKGROUND. Recessive dystrophic epidermolysis bullosa (RDEB) is an incurable disease caused by mutations in the gene encoding type VII collagen, the major component of anchoring fibrils (AF). We previously demonstrated that gentamicin produced functional type VII collagen in RDEB cells harboring nonsense mutations. Herein, we determined whether topical or intradermal gentamicin administration induces type VII collagen and AFs in RDEB patients. METHODS. A double-blind, placebo-controlled pilot trial assessed safety and efficacy of topical and intradermal gentamicin in 5 RDEB patients with nonsense mutations. The topical arm tested 0.1% gentamicin ointment or placebo application 3 times daily at 2 open erosion sites for 2 weeks. The intradermal arm tested daily intradermal injection of gentamicin solution (8 mg) or placebo into 2 intact skin sites for 2 days in 4 of 5 patients. Primary outcomes were induction of type VII collagen and AFs at the test sites and safety assessment. A secondary outcome assessed wound closure of topically treated erosions. RESULTS. Both topical and intradermal gentamicin administration induced type VII collagen and AFs at the dermal-epidermal junction of treatment sites. Newly created type VII collagen varied from 20% to 165% of that expressed in normal human skin and persisted for 3 months. Topical gentamicin corrected dermal-epidermal separation, improved wound closure, and reduced blister formation. There were no untoward side effects from gentamicin treatments. Type VII collagen induction did not generate anti–type VII collagen autoantibodies in patients’ blood or skin. CONCLUSION. Topical and intradermal gentamicin suppresses nonsense mutations and induces type VII collagen and AFs in RDEB patients. Gentamicin therapy may provide a readily available treatment for RDEB patients with nonsense mutations. TRIAL REGISTRATION. ClinicalTrials.gov NCT02698735. FUNDING. Epidermolysis Bullosa Research Partnership, Epidermolysis Bullosa

  16. Structural incorporation of MgCl2 into ice VII at room temperature

    NASA Astrophysics Data System (ADS)

    Watanabe, Mao; Komatsu, Kazuki; Noritake, Fumiya; Kagi, Hiroyuki

    2017-05-01

    Raman spectra and X-ray diffraction patterns were obtained from 1:100 and 1:200 \\text{MgCl}2:\\text{H}2\\text{O} solutions (in molar ratio) at pressures up to 6 GPa using diamond anvil cells (DACs) and compared with those of pure water. The O-H stretching band from ice VII crystallized from the 1:200 solution was approximately 10 cm-1 higher than that of pure ice VII. The phase boundaries between ice VII and VIII crystallized from the MgCl2 solutions at 4 GPa were 2 K lower than those of pure ice VII and VIII. These observations indicate that ice VII incorporates MgCl2 into its structure. The unit cell volumes of ice VII crystallized from pure water and the two solutions coincided with each other within the experimental error, and salt incorporation was not detectable from the cell volume. Possible configurations of ion substitution and excess volume of ice VIII were simulated on the basis of density functional theory (DFT) calculations.

  17. Recombinant activated factor VII use in critically ill infants with active hemorrhage.

    PubMed

    Jen, Howard; Shew, Stephen

    2008-12-01

    Recombinant activated factor VII (rFVIIa) is infrequently used off-label in infants despite a paucity of data in this population. We report a retrospective review of rFVIIa use in infants focusing on safety and efficacy. Between 2002 and 2007, 32 critically ill nonhemophiliac infants less than 1 year old received rFVIIa at our institution. Indications of rFVIIa and post-rFVIIa venous thrombosis were reviewed. Transfusion requirements were calculated 8 hours before and after rFVIIa administration. Infants received on average 2 doses of rFVIIa at a mean dosage of 90 microg/kg. Active hemorrhage was the indication for rFVIIa in 24 infants, which included postoperative bleeding in 16 and nonsurgical bleeding in 8. The remaining 8 infants had preoperative coagulopathy. Thrombosis was noted in 4 infants (13%) and was not related to transfusion requirements, the number of doses, or dosage of rFVIIa. For infants who had active hemorrhage, rFVIIa was able to significantly reduce the requirements of packed red blood cells by 36.17 mL/kg (P < .005), platelets by 10.31 mL/kg (P < .01), and cryoprecipitates by 2.19 mL/kg (P < .05). This is the first large case series demonstrating the efficacy of rFVIIa in critically ill infants with active hemorrhage by reducing their transfusion requirements. Furthermore, venous thrombosis was not associated with increase in either the number of doses or dosage of rFVIIa.

  18. Absence of in vitro Procoagulant Activity in Immunoglobulin Preparations due to Activated Coagulation Factors

    PubMed Central

    Oviedo, Adriana E.; Bernardi, María E.; Guglielmone, Hugo A.; Vitali, María S.

    2015-01-01

    Summary Background Immunoglobulin (IG) products, including intravenous (IVIG) or subcutaneous (SCIG) immunoglobulins are considered safe and effective for medical therapy; however, a sudden and unexpected increase in thromboembolic events (TE) after administration of certain batches of IVIG products has been attributed to the presence of activated coagulation factors, mainly factor XIa. Our aims were to examine the presence of enduring procoagulant activity during the manufacturing process of IGs, with special focus on monitoring factor XIa, and to evaluate the presence of in vitro procoagulant activity attributed to coagulation factors in different lots of IVIG and SCIG. Methods Samples of different steps of IG purification, 19 lots of IVIG and 9 of SCIG were analyzed and compared with 1 commercial preparation of IVIG and 2 of SCIG, respectively. Factors II, VII, IX, XI and XIa and non-activated partial thromboplastin time (NAPTT) were assayed. Results The levels of factors II, VII, IX, X and XI were non-quantifiable once fraction II had been re-dissolved and in all analyzed lots of IVIG and SCIG. The level of factor XIa at that point was under the detection limits of the assay, and NAPTT yielded values greater than the control during the purification process. In SCIG, we detected higher concentrations of factor XIa in the commercial products, which reached values up to 5 times higher than the average amounts found in the 9 batches produced by UNC-Hemoderivados. Factor XIa in commercial IVIG reached levels slightly higher than those of the 19 batches produced by UNC-Hemoderivados. Conclusion IVIG and SCIG manufactured by UNC-Hemoderivados showed a lack of thrombogenic potential, as demonstrated not only by the laboratory data obtained in this study but also by the absence of any reports of TE registered by the post marketing pharmacovigilance department. PMID:26733772

  19. Blister-inducing antibodies target multiple epitopes on collagen VII in mice

    PubMed Central

    Csorba, Kinga; Chiriac, Mircea Teodor; Florea, Florina; Ghinia, Miruna Georgiana; Licarete, Emilia; Rados, Andreea; Sas, Alexandra; Vuta, Vlad; Sitaru, Cassian

    2014-01-01

    Epidermolysis bullosa acquisita (EBA) is an autoimmune subepidermal blistering disease of mucous membranes and the skin caused by autoantibodies against collagen VII. In silico and wet laboratory epitope mapping studies revealed numerous distinct epitopes recognized by EBA patients' autoantibodies within the non-collagenous (NC)1 and NC2 domains of collagen VII. However, the distribution of pathogenic epitopes on collagen VII has not yet been described. In this study, we therefore performed an in vivo functional epitope mapping of pathogenic autoantibodies in experimental EBA. Animals (n = 10/group) immunized against fragments of the NC1 and NC2 domains of collagen VII or injected with antibodies generated against the same fragments developed to different extent experimental EBA. Our results demonstrate that antibodies targeting multiple, distinct epitopes distributed over the entire NC1, but not NC2 domain of collagen VII induce blistering skin disease in vivo. Our present findings have crucial implications for the development of antigen-specific B- and T cell-targeted therapies in EBA. PMID:25091020

  20. Health economic review of recombinant activated factor VII for treatment of bleeding episodes in hemophilia patients with inhibitors.

    PubMed

    Stephens, Jennifer M; Joshi, Ashish V; Sumner, Michael; Botteman, Marc F

    2007-06-01

    Severe hemophilia with inhibitors is a rare disease with substantial clinical, humanistic and economic consequences. This review provides an overview of the role of recombinant activated factor VII (rFVIIa) versus plasma-derived bypassing agents for hemophilia with inhibitors and summarizes the 13 formal economic analyses (6 burden of illness and 7 comparative studies) that have been published in this indication. The findings suggest that the economic impact of rFVIIa has occurred primarily during hospitalization to manage major bleeding episodes and to allow for elective orthopedic surgeries that would not have been attempted prior to rFVIIa. Comparative analyses for on-demand treatment suggest that the total cost of treating a bleeding episode with rFVIIa may be lower than with plasma-based agents due to faster bleeding resolution, higher initial efficacy rates and avoidance of second and third lines of treatment.

  1. Pathogenesis of aortic dilatation in mucopolysaccharidosis VII mice may involve complement activation

    PubMed Central

    Baldo, Guilherme; Wu, Susan; Howe, Ruth A.; Ramamoothy, Meera; Knutsen, Russell H.; Fang, Jiali; Mecham, Robert P.; Liu, Yuli; Wu, Xiaobo; Atkinson, John P.; Ponder, Katherine P.

    2012-01-01

    Mucopolysaccharidosis VII (MPS VII) is due to mutations within the gene encoding the lysosomal enzyme β-glucuronidase, and results in the accumulation of glycosaminoglycans. MPS VII causes aortic dilatation and elastin fragmentation, which is associated with upregulation of the elastases cathepsin S (CtsS) and matrix metalloproteinase 12 (MMP12). To test the role of these enzymes, MPS VII mice were crossed with mice deficient in CtsS or MMP12, and the effect upon aortic dilatation was determined. CtsS deficiency did not protect against aortic dilatation in MPS VII mice, but also failed to prevent an upregulation of cathepsin enzyme activity. Further analysis with substrates and inhibitors specific for particular cathepsins suggests that this enzyme activity was due to CtsB, which could contribute to elastin fragmentation. Similarly, MMP12 deficiency and deficiency of both MMP12 and CtsS could not prevent aortic dilatation in MPS VII mice. Microarray and reverse-transcriptase real-time PCR were performed to look for upregulation of other elastases. This demonstrated that mRNA for complement component D was elevated in MPS VII mice, while immunostaining demonstrated high levels of complement component C3 on surfaces within the aortic media. Finally, we demonstrate that neonatal intravenous injection of a retroviral vector encoding β-glucuronidase reduced aortic dilatation. We conclude that neither CtsS nor MMP12 are necessary for elastin fragmentation in MPS VII mouse aorta, and propose that CtsB and/or complement component D may be involved. Complement may be activated by the GAGs that accumulate, and may play a role in signal transduction pathways that upregulate elastases. PMID:21944884

  2. Compression Freezing Kinetics of Water to Ice VII

    DOE PAGES

    Gleason, A. E.; Bolme, C. A.; Galtier, E.; ...

    2017-07-11

    Time-resolved x-ray diffraction (XRD) of compressed liquid water shows transformation to ice VII in 6 nsec, revealing crystallization rather than amorphous solidification during compression freezing. Application of classical nucleation theory indicates heterogeneous nucleation and one-dimensional (e.g., needlelike) growth. In conclusion, these first XRD data demonstrate rapid growth kinetics of ice VII with implications for fundamental physics of diffusion-mediated crystallization and thermodynamic modeling of collision or impact events on ice-rich planetary bodies.

  3. Compression Freezing Kinetics of Water to Ice VII

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Gleason, A. E.; Bolme, C. A.; Galtier, E.

    Time-resolved x-ray diffraction (XRD) of compressed liquid water shows transformation to ice VII in 6 nsec, revealing crystallization rather than amorphous solidification during compression freezing. Application of classical nucleation theory indicates heterogeneous nucleation and one-dimensional (e.g., needlelike) growth. In conclusion, these first XRD data demonstrate rapid growth kinetics of ice VII with implications for fundamental physics of diffusion-mediated crystallization and thermodynamic modeling of collision or impact events on ice-rich planetary bodies.

  4. Monitoring of treatment with vitamin K antagonists: recombinant thromboplastins are more sensitive to factor VII than tissue-extract thromboplastins.

    PubMed

    Biedermann, J S; van den Besselaar, A M H P; de Maat, M P M; Leebeek, F W G; Kruip, M J H A

    2017-03-01

    Essentials Differences in sensitivity to factor VII (FVII) have been suggested between thromboplastins. FVII-induced International Normalized Ratio (INR) changes differ between commercial reagents. Recombinant human thromboplastins are more sensitive to FVII than tissue-extract thromboplastins. Thromboplastin choice may affect FVII-mediated INR stability. Background Differences regarding sensitivity to factor VII have been suggested for recombinant human and tissue-extract thromboplastins used for International Normalized Ratio (INR) measurement, but the evidence is scarce. Differences in FVII sensitivity are clinically relevant, as they can affect INR stability during treatment with vitamin K antagonists (VKAs). Objectives To determine whether commercial thromboplastins react differently to changes in FVII. Methods We studied the effect of addition of FVII on the INR in plasma by using three tissue-extract (Neoplastin C1+, Hepato Quick, and Thromborel S) and three recombinant human (Recombiplastin 2G, Innovin, and CoaguChek XS) thromboplastins. Three different concentrations of purified human FVII (0.006, 0.012 and 0.062 μg mL -1 plasma), or buffer, were added to five certified pooled plasmas of patients using VKAs (INR of 1.5-3.5). Changes in FVII activity were measured with two bioassays (Neoplastin and Recombiplastin), and relative INR changes were compared between reagents. Results After addition of 0.062 μg mL -1 FVII, FVII activity in the pooled plasmas increased by approximately 20% (Neoplastin) or 32% (Recombiplastin) relative to the activity in pooled normal plasma. All thromboplastins showed dose-dependent INR decreases. The relative INR change in the pooled plasmas significantly differed between the six thromboplastins. No differences were observed among recombinant or tissue-extract thromboplastins. Pooled results indicated that the FVII-induced INR change was greater for recombinant than for tissue-extract thromboplastins. Conclusions Differences

  5. Discovery of the type VII ESX-1 secretion needle?

    PubMed

    Ates, Louis S; Brosch, Roland

    2017-01-01

    Mycobacterium tuberculosis, the etiological agent of human tuberculosis, harbours five ESAT-6/type VII secretion (ESX/T7S) systems. The first esx gene clusters were identified during the genome-sequencing project of M. tuberculosis H37Rv. Follow-up studies revealed additional genes playing important roles in ESX/T7S systems. Among the latter genes, one can find those that encode Pro-Glu (PE) and Pro-Pro-Glu (PPE) proteins as well as a gene cluster that is encoded >260 kb upstream of the esx-1 locus and encodes ESX-1 secretion-associated proteins EspA (Rv3616c), EspC (Rv3615c) and EspD (Rv3614c). The espACD cluster has been suggested to have an important function in ESX-1 secretion since EspA-EspC and EsxA-EsxB are mutually co-dependent on each other for secretion. However, the molecular mechanism of this co-dependence and interaction between the substrates remained unknown. In this issue of Molecular Microbiology, Lou and colleagues show that EspC forms high-molecular weight polymerization complexes that resemble selected components of type II, III and/or IV secretion systems of Gram-negative bacteria. Indeed, EspC-multimeric complexes form filamentous structures that could well represent a secretion needle of ESX-1 type VII secretion systems. This exciting observation opens new avenues for research to discover and characterize ESX/T7S components and elucidates the co-dependence of EsxA/B secretion with EspA/C. © 2016 John Wiley & Sons Ltd.

  6. The effect of recombinant activated factor VII in the treatment of intracerebral hemorrhage on health plan budgets.

    PubMed

    Earnshaw, Stephanie R; Wilson, Michele R; Joshi, Ashish V

    2006-11-01

    Treating patients with intracerebral hemorrhage (ICH) using recombinant activated factor VII (rFVIla) has been found to improve survival and functional outcome. To examine how the introduction of rFVIla 80 microg/kg as a treatment for ICH affects the budget of a health plan, a decision-analysis model was developed which considered both short-term hospitalization costs and long-term management of disability. Assuming a health plan enrollment of 1 million members and initial rFVIla uptake of 50% in appropriate patients, the annual health plan cost may be expected to increase by dollar 64,781 (dollar 0.005 per-member per-month). With a 5% increase in uptake each year, the annual health plan's cost may decrease compared with the current budget within three years. The implications for this sample health plan's budget are modest in the first year, and a reduction in costs is expected within three years owing to improved functional outcomes of patients.

  7. Polymorphisms of the factor VII gene associated with the low activities of vitamin K-dependent coagulation factors in one-month-old infants.

    PubMed

    Ito, Koichi; Goto, Kenji; Sugiura, Tokio; Muramatsu, Kanji; Ando, Toshihiro; Maniwa, Hiroko; Yokoyama, Takao; Sugiyama, Kohachiro; Togari, Hajime

    2007-01-01

    Despite administration of vitamin K (VK), some infants show lower activity of VK-dependent coagulation factors and they could develop intracranial hemorrhage. For preventing VK deficiency bleeding (VKDB) in infants, oral administration of VK and a screening test for VK deficiency are carried out in Japan. For the screening, the total activity of VK-dependent coagulation factors is measured using a commercial product, Normotest. This study was undertaken to clarify the importance of the following genetic and environmental factors on the coagulation status in one-month-old infants: two polymorphisms in the factor VII gene, -323P0/10 (a 10-bp insertion in the promoter region at position -323) and R353Q (the replacement of arginine [R] with glutamine [Q] at residue 353) and sex, age, gestational age, birth weight, and feeding regimen. Two hundred Japanese infants (34.6 +/- 4.0 days old) were screened for VK-dependent coagulation activity with Normotest and were genotyped for the two polymorphisms. Among the subjects screened, 18 infants (9%) carried the P10 allele and 26 (13%) carried the R353Q allele. Multiple regression analysis showed that the 10-bp inserted (P10) allele or the Q allele was associated with the lower coagulation activities. The coagulation activities for the R/Q genotype were significantly lower than those for the R/R genotype and those for the P0/P10 genotype were significantly lower than those for the P0/P0 genotype. Therefore, infants who carry the P10 allele or the Q allele show lower activity of VK-dependent coagulation factors. These infants may have a higher risk of VKDB manifestation.

  8. Comparison of student's learning achievement through realistic mathematics education (RME) approach and problem solving approach on grade VII

    NASA Astrophysics Data System (ADS)

    Ilyas, Muhammad; Salwah

    2017-02-01

    The type of this research was experiment. The purpose of this study was to determine the difference and the quality of student's learning achievement between students who obtained learning through Realistic Mathematics Education (RME) approach and students who obtained learning through problem solving approach. This study was a quasi-experimental research with non-equivalent experiment group design. The population of this study was all students of grade VII in one of junior high school in Palopo, in the second semester of academic year 2015/2016. Two classes were selected purposively as sample of research that was: year VII-5 as many as 28 students were selected as experiment group I and VII-6 as many as 23 students were selected as experiment group II. Treatment that used in the experiment group I was learning by RME Approach, whereas in the experiment group II by problem solving approach. Technique of data collection in this study gave pretest and posttest to students. The analysis used in this research was an analysis of descriptive statistics and analysis of inferential statistics using t-test. Based on the analysis of descriptive statistics, it can be concluded that the average score of students' mathematics learning after taught using problem solving approach was similar to the average results of students' mathematics learning after taught using realistic mathematics education (RME) approach, which are both at the high category. In addition, It can also be concluded that; (1) there was no difference in the results of students' mathematics learning taught using realistic mathematics education (RME) approach and students who taught using problem solving approach, (2) quality of learning achievement of students who received RME approach and problem solving approach learning was same, which was at the high category.

  9. The effects of recombinant activated factor VII dose on the incidence of thromboembolic events in patients with coagulopathic bleeding.

    PubMed

    Bucklin, Mason H; Acquisto, Nicole M; Nelson, Catherine

    2014-05-01

    Previous studies have suggested the used of off-label recombinant factor VII (rFVIIa) increases the risk of thromboembolic events, but the effect of the dose of rFVIIa is not well described in the literature. All adult patients that received off-label rFVIIa from 2005-2012 were included in this single-center, retrospective cohort study. The primary endpoint was the incidence of a thromboembolic event in the low dose (<50 mcg/kg) compared to the high dose (≥50 mcg/kg) cohort. Secondary endpoints compared time to thromboembolic event, incidence of arterial compared to venous events, and mortality. There were 152 patients that received rFVIIa during the study period with 66 in the low dose cohort and 86 in the high dose cohort. Mean total dose of rFVIIa was 30.2 mcg/kg (SD ± 9.5 mcg/kg) in the low dose and 99.8 mcg/kg (SD ± 64.7 mcg/kg) in the high dose cohort (p=0.0001). The overall incidence of thromboembolic events was 12.5%. There were 12 (14%) events in the low dose cohort and seven (10.6%) in the high dose cohort, RR=0.76 (95% CI 0.31-1.82). There were no differences in any of the secondary outcomes. A higher incidence of thromboembolic events in cardiothoracic surgery (20.8%) and penetrating trauma patients (21.4%) was seen compared to the remaining cohort (6.7%). No significant difference in the incidence of thromboembolic events was seen between low dose versus high dose rFVIIa over a seven year period at our institution. However, due to the relatively low overall incidence and a small sample size, type II error may be present. Copyright © 2014 Elsevier Ltd. All rights reserved.

  10. Plasmodium falciparum ookinete expression of plasmepsin VII and plasmepsin X.

    PubMed

    Li, Fengwu; Bounkeua, Viengngeun; Pettersen, Kenneth; Vinetz, Joseph M

    2016-02-24

    Plasmodium invasion of the mosquito midgut is a population bottleneck in the parasite lifecycle. Interference with molecular mechanisms by which the ookinete invades the mosquito midgut is one potential approach to developing malaria transmission-blocking strategies. Plasmodium aspartic proteases are one such class of potential targets: plasmepsin IV (known to be present in the asexual stage food vacuole) was previously shown to be involved in Plasmodium gallinaceum infection of the mosquito midgut, and plasmepsins VII and plasmepsin X (not known to be present in the asexual stage food vacuole) are upregulated in Plasmodium falciparum mosquito stages. These (and other) parasite-derived enzymes that play essential roles during ookinete midgut invasion are prime candidates for transmission-blocking vaccines. Reverse transcriptase PCR (RT-PCR) was used to determine timing of P. falciparum plasmepsin VII (PfPM VII) and plasmepsin X (PfPM X) mRNA transcripts in parasite mosquito midgut stages. Protein expression was confirmed by western immunoblot and immunofluorescence assays (IFA) using anti-peptide monoclonal antibodies (mAbs) against immunogenic regions of PfPM VII and PfPM X. These antibodies were also used in standard membrane feeding assays (SMFA) to determine whether inhibition of these proteases would affect parasite transmission to mosquitoes. The Mann-Whitney U test was used to analyse mosquito transmission assay results. RT-PCR, western immunoblot and immunofluorescence assay confirmed expression of PfPM VII and PfPM X in mosquito stages. Whereas PfPM VII was expressed in zygotes and ookinetes, PfPM X was expressed in gametes, zygotes, and ookinetes. Antibodies against PfPM VII and PfPM X decreased P. falciparum invasion of the mosquito midgut when used at high concentrations, indicating that these proteases play a role in Plasmodium mosquito midgut invasion. Failure to generate genetic knockouts of these genes limited determination of the precise role of

  11. Protein Replacement Therapy and Gene Transfer in Canine Models of Hemophilia A, Hemophilia B, von Willebrand Disease, and Factor VII Deficiency

    PubMed Central

    Nichols, Timothy C.; Dillow, Aaron M.; Franck, Helen W.G.; Merricks, Elizabeth P.; Raymer, Robin A.; Bellinger, Dwight A.; Arruda, Valder R.; High, Katherine A.

    2011-01-01

    Dogs with hemophilia A, hemophilia B, von Willebrand disease (VWD), and factor VII deficiency faithfully recapitulate the severe bleeding phenotype that occurs in humans with these disorders. The first rational approach to diagnosing these bleeding disorders became possible with the development of reliable assays in the 1940s through research that used these dogs. For the next 60 years, treatment consisted of replacement of the associated missing or dysfunctional protein, first with plasma-derived products and subsequently with recombinant products. Research has consistently shown that replacement products that are safe and efficacious in these dogs prove to be safe and efficacious in humans. But these highly effective products require repeated administration and are limited in supply and expensive; in addition, plasma-derived products have transmitted bloodborne pathogens. Recombinant proteins have all but eliminated inadvertent transmission of bloodborne pathogens, but the other limitations persist. Thus, gene therapy is an attractive alternative strategy in these monogenic disorders and has been actively pursued since the early 1990s. To date, several modalities of gene transfer in canine hemophilia have proven to be safe, produced easily detectable levels of transgene products in plasma that have persisted for years in association with reduced bleeding, and correctly predicted the vector dose required in a human hemophilia B liver-based trial. Very recently, however, researchers have identified an immune response to adeno-associated viral gene transfer vector capsid proteins in a human liver-based trial that was not present in preclinical testing in rodents, dogs, or nonhuman primates. This article provides a review of the strengths and limitations of canine hemophilia, VWD, and factor VII deficiency models and of their historical and current role in the development of improved therapy for humans with these inherited bleeding disorders. PMID:19293459

  12. Type VII Collagen Expression in the Human Vitreoretinal Interface, Corpora Amylacea and Inner Retinal Layers

    PubMed Central

    Wullink, Bart; Pas, Hendri H.; Van der Worp, Roelofje J.; Kuijer, Roel; Los, Leonoor I.

    2015-01-01

    Type VII collagen, as a major component of anchoring fibrils found at basement membrane zones, is crucial in anchoring epithelial tissue layers to their underlying stroma. Recently, type VII collagen was discovered in the inner human retina by means of immunohistochemistry, while proteomic investigations demonstrated type VII collagen at the vitreoretinal interface of chicken. Because of its potential anchoring function at the vitreoretinal interface, we further assessed the presence of type VII collagen at this site. We evaluated the vitreoretinal interface of human donor eyes by means of immunohistochemistry, confocal microscopy, immunoelectron microscopy, and Western blotting. Firstly, type VII collagen was detected alongside vitreous fibers6 at the vitreoretinal interface. Because of its known anchoring function, it is likely that type VII collagen is involved in vitreoretinal attachment. Secondly, type VII collagen was found within cytoplasmic vesicles of inner retinal cells. These cells resided most frequently in the ganglion cell layer and inner plexiform layer. Thirdly, type VII collagen was found in astrocytic cytoplasmic inclusions, known as corpora amylacea. The intraretinal presence of type VII collagen was confirmed by Western blotting of homogenized retinal preparations. These data add to the understanding of vitreoretinal attachment, which is important for a better comprehension of common vitreoretinal attachment pathologies. PMID:26709927

  13. The role of recombinant activated factor VII in the haematological management of elective orthopaedic surgery in haemophilia A patients with inhibitors

    PubMed Central

    Castaman, Giancarlo

    2017-01-01

    The clinical profile and expectations of haemophilic patients with inhibitors have changed over the last three decades, mainly because of the prolongation of life-expectancy, often resulting in an increase of the orthopaedic burden. Recombinant activated factor VII (rFVIIa) is the most frequently used bypassing agent in haemophilia patients with inhibitors during elective orthopaedic surgery. For nearly 30 years, rFVIIa has been successfully used to control haemostasis in several major and minor surgical procedures. Clinical trials, case series, reports and surveys were progressively aimed at optimising rFVIIa usage in very demanding conditions managed in highly specialised centres. Recommendations from consensus opinions and guidelines have been provided on the basis of this clinical experience. PMID:28686157

  14. The Trigeminal (V) and Facial (VII) Cranial Nerves

    PubMed Central

    Sanders, Richard D.

    2010-01-01

    There are close functional and anatomical relationships between cranial nerves V and VII in both their sensory and motor divisions. Sensation on the face is innervated by the trigeminal nerves (V) as are the muscles of mastication, but the muscles of facial expression are innervated mainly by the facial nerve (VII) as is the sensation of taste. This article briefly reviews the anatomy of these cranial nerves, disorders of these nerves that are of particular importance to psychiatry, and some considerations for differential diagnosis. PMID:20386632

  15. Large deletions play a minor but essential role in congenital coagulation factor VII and X deficiencies.

    PubMed

    Rath, M; Najm, J; Sirb, H; Kentouche, K; Dufke, A; Pauli, S; Hackmann, K; Liehr, T; Hübner, C A; Felbor, U

    2015-01-01

    Congenital factor VII (FVII) and factor X (FX) deficiencies belong to the group of rare bleeding disorders which may occur in separate or combined forms since both the F7 and F10 genes are located in close proximity on the distal long arm of chromosome 13 (13q34). We here present data of 192 consecutive index cases with FVII and/or FX deficiency. 10 novel and 53 recurrent sequence alterations were identified in the F7 gene and 5 novel as well as 11 recurrent in the F10 gene including one homozygous 4.35 kb deletion within F7 (c.64+430_131-6delinsTCGTAA) and three large heterozygous deletions involving both the F7 and F10 genes. One of the latter proved to be cytogenetically visible as a chromosome 13q34 deletion and associated with agenesis of the corpus callosum and psychomotor retardation. Large deletions play a minor but essential role in the mutational spectrum of the F7 and F10 genes. Copy number analyses (e. g. MLPA) should be considered if sequencing cannot clarify the underlying reason of an observed coagulopathy. Of note, in cases of combined FVII/FX deficiency, a deletion of the two contiguous genes might be part of a larger chromosomal rearrangement.

  16. 76 FR 31892 - Recordkeeping and Reporting Requirements Under Title VII, the ADA, and GINA

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-06-02

    ... Requirements Under Title VII, the ADA, and GINA AGENCY: Equal Employment Opportunity Commission. ACTION: Notice...'' or ``Commission'') proposes to extend its existing recordkeeping requirements under title VII of the Civil Rights Act of 1964 (Title VII) and the Americans with Disabilities Act (ADA) to entities covered...

  17. Effect of neonatal gene therapy on lumbar spine disease in mucopolysaccharidosis VII dogs

    PubMed Central

    Smith, Lachlan J; Martin, John T; O'Donnell, Patricia; Wang, Ping; Elliott, Dawn M; Haskins, Mark E; Ponder, Katherine P

    2012-01-01

    Mucopolysaccharidosis VII (MPS VII) is due to deficient β-glucuronidase (GUSB) activity, which leads to accumulation of chondroitin, heparan, and dermatan sulfate glycosaminoglycans in various tissues including those of the spine. Associated spine disease can be due to abnormalities in the vertebrae, the intervertebral discs, or other spine tissues. The goal of this study was to determine if neonatal gene therapy could prevent lumbar spine disease in MPS VII dogs. MPS VII dogs were injected intravenously with a retroviral vector (RV) expressing canine GUSB at 2 to 3 days after birth, which resulted in transduction of hepatocytes that secreted GUSB into blood. Expression was stable for up to 11 years, and mean survival was increased from 0.4 years in untreated dogs to 6.1 years in treated dogs. Despite a profound positive clinical effect, 6-month-old RV-treated MPS VII dogs still had hypoplastic ventral epiphyses with reduced calcification in the lumbar spine, which resulted in a reduced stiffness and increased range of motion that was not improved relative to untreated MPS VII dogs. At six to 11 years of age, ventral vertebrae remained hypoplastic in RV-treated MPS VII dogs, and there was desiccation of the nucleus pulposus in some discs. Histochemical staining demonstrated that discs did not have detectable GUSB activity despite high serum GUSB activity, which is likely due to poor diffusion into this relatively avascular structure. Thus, neonatal gene therapy cannot prevent lumbar spine disease in MPS VII dogs, which predicts that enzyme replacement therapy (ERT) will similarly be relatively ineffective even if started at birth. PMID:22510705

  18. Effect of neonatal gene therapy on lumbar spine disease in mucopolysaccharidosis VII dogs.

    PubMed

    Smith, Lachlan J; Martin, John T; O'Donnell, Patricia; Wang, Ping; Elliott, Dawn M; Haskins, Mark E; Ponder, Katherine P

    2012-09-01

    Mucopolysaccharidosis VII (MPS VII) is due to deficient β-glucuronidase (GUSB) activity, which leads to accumulation of chondroitin, heparan, and dermatan sulfate glycosaminoglycans in various tissues including those of the spine. Associated spine disease can be due to abnormalities in the vertebrae, the intervertebral disks, or other spine tissues. The goal of this study was to determine if neonatal gene therapy could prevent lumbar spine disease in MPS VII dogs. MPS VII dogs were injected intravenously with a retroviral vector (RV) expressing canine GUSB at 2 to 3 days after birth, which resulted in transduction of hepatocytes that secreted GUSB into blood. Expression was stable for up to 11 years, and mean survival was increased from 0.4 years in untreated dogs to 6.1 years in treated dogs. Despite a profound positive clinical effect, 6-month-old RV-treated MPS VII dogs still had hypoplastic ventral epiphyses with reduced calcification in the lumbar spine, which resulted in a reduced stiffness and increased range of motion that were not improved relative to untreated MPS VII dogs. At six to 11 years of age, ventral vertebrae remained hypoplastic in RV-treated MPS VII dogs, and there was desiccation of the nucleus pulposus in some disks. Histochemical staining demonstrated that disks did not have detectable GUSB activity despite high serum GUSB activity, which is likely due to poor diffusion into this relatively avascular structure. Thus, neonatal gene therapy cannot prevent lumbar spine disease in MPS VII dogs, which predicts that enzyme replacement therapy (ERT) will similarly be relatively ineffective even if started at birth. Copyright © 2012 Elsevier Inc. All rights reserved.

  19. Forces necessary for the disruption of the cisternal segments of cranial nerves II through XII.

    PubMed

    Tubbs, R Shane; Wellons, John C; Blount, Jeffrey P; Salter, E George; Oakes, W Jerry

    2007-04-01

    Manipulation of the cisternal segment of cranial nerves is often performed by the neurosurgeon. To date, attempts at quantifying the forces necessary to disrupt these nerves in situ, to our knowledge, has not been performed. The present study seeks to further elucidate the forces necessary to disrupt the cranial nerves while within the subarachnoid space. The cisternal segments of cranial nerves II through XII were exposed in six unfixed cadavers, all less than 6 hr postmortem. Forces to failure were then measured. Mean forces necessary to disrupt nerves for left sides in increasing order were found for cranial nerves IX, VII, IV, X, XII, III, VIII, XI, VI, V, and II, respectively. Mean forces for right-sided cranial nerves in increasing order were found for cranial nerves IX, VII, IV, X, XII, VIII, V, VI, XI, III, and II, respectively. Overall, cranial nerves requiring the least amount of force prior to failure included cranial nerves IV, VII, and IX. Those requiring the highest amount of force included cranial nerves II, V, VI, and XI. There was an approximately ten-fold difference between the least and greatest forces required to failure. Cranial nerve III was found to require significantly (P < 0.05) greater forces to failure for right versus left sides. To date, the neurosurgeon has had no experimentally derived data from humans for the in situ forces necessary to disrupt the cisternal segment of cranial nerves II through XII. We found that cranial nerve IX consistently took the least amount of force until its failure and cranial nerve II took the greatest. Other cranial nerves that took relatively small amount of force prior to failure included cranial nerves IV and VII. Although in vivo damage can occur prior to failure of a cranial nerve, our data may serve to provide a rough estimation for the maximal amount of tension that can be applied to a cranial nerve that is manipulated while within its cistern.

  20. 76 FR 79065 - Recordkeeping and Reporting Requirements Under Title VII, the ADA and GINA

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-21

    ... DEPARTMENT OF LABOR Equal Employment Opportunity Commission 29 CFR Part 1602 Recordkeeping and Reporting Requirements Under Title VII, the ADA and GINA CFR Correction In Title 29 of the Code of Federal... title VII or section 107 of the ADA'' and add in their place the words ``section 709(c) of title VII...

  1. The production of coagulation factor VII by adipocytes is enhanced by tumor necrosis factor-α or isoproterenol.

    PubMed

    Takahashi, N; Yoshizaki, T; Hiranaka, N; Kumano, O; Suzuki, T; Akanuma, M; Yui, T; Kanazawa, K; Yoshida, M; Naito, S; Fujiya, M; Kohgo, Y; Ieko, M

    2015-05-01

    A relationship has been reported between blood concentrations of coagulation factor VII (FVII) and obesity. In addition to its role in coagulation, FVII has been shown to inhibit insulin signals in adipocytes. However, the production of FVII by adipocytes remains unclear. We herein investigated the production and secretion of FVII by adipocytes, especially in relation to obesity-related conditions including adipose inflammation and sympathetic nerve activation. C57Bl/6J mice were fed a low- or high-fat diet and the expression of FVII messenger RNA (mRNA) was then examined in adipose tissue. 3T3-L1 cells were used as an adipocyte model for in vitro experiments in which these cells were treated with tumor necrosis factor-α (TNF-α) or isoproterenol. The expression and secretion of FVII were assessed by quantitative real-time PCR, Western blotting and enzyme-linked immunosorbent assays. The expression of FVII mRNA in the adipose tissue of mice fed with high-fat diet was significantly higher than that in mice fed with low-fat diet. Expression of the FVII gene and protein was induced during adipogenesis and maintained in mature adipocytes. The expression and secretion of FVII mRNA were increased in the culture medium of 3T3-L1 adipocytes treated with TNF-α, and these effects were blocked when these cells were exposed to inhibitors of mitogen-activated kinases or NF-κB activation. The β-adrenoceptor agonist isoproterenol stimulated the secretion of FVII from mature adipocytes via the cyclic AMP/protein kinase A pathway. Blockade of secreted FVII with the anti-FVII antibody did not affect the phosphorylation of Akt in the isoproterenol-stimulated adipocytes. Obese adipose tissue produced FVII. The production and secretion of FVII by adipocytes was enhanced by TNF-α or isoproterenol via different mechanisms. These results indicate that FVII is an adipokine that plays an important role in the pathogenesis of obesity.

  2. Photosynthetic pigments of oceanic Chlorophyta belonging to prasinophytes clade VII.

    PubMed

    Lopes Dos Santos, Adriana; Gourvil, Priscillia; Rodríguez, Francisco; Garrido, José Luis; Vaulot, Daniel

    2016-02-01

    The ecological importance and diversity of pico/nanoplanktonic algae remains poorly studied in marine waters, in part because many are tiny and without distinctive morphological features. Amongst green algae, Mamiellophyceae such as Micromonas or Bathycoccus are dominant in coastal waters while prasinophytes clade VII, yet not formerly described, appear to be major players in open oceanic waters. The pigment composition of 14 strains representative of different subclades of clade VII was analyzed using a method that improves the separation of loroxanthin and neoxanthin. All the prasinophytes clade VII analyzed here showed a pigment composition similar to that previously reported for RCC287 corresponding to pigment group prasino-2A. However, we detected in addition astaxanthin for which it is the first report in prasinophytes. Among the strains analyzed, the pigment signature is qualitatively similar within subclades A and B. By contrast, RCC3402 from subclade C (Picocystis) lacks loroxanthin, astaxanthin, and antheraxanthin but contains alloxanthin, diatoxanthin, and monadoxanthin that are usually found in diatoms or cryptophytes. For subclades A and B, loroxanthin was lowest at highest light irradiance suggesting a light-harvesting role of this pigment in clade VII as in Tetraselmis. © 2015 Phycological Society of America.

  3. Title VII Evaluation, 1987-88.

    ERIC Educational Resources Information Center

    Baenen, Nancy R.; Yonan, Barbara

    Title VII federal funds have been used in the Austin (Texas) Independent School District (AISD) since 1985-86 to enhance the regular secondary bilingual and English-as-a-second-language programs for Hispanic limited English proficient (LEP) students. The four secondary campuses involved were those with the highest concentrations of Hispanic LEP…

  4. Onset of ice VII phase during ps laser pulse propagation through liquid water

    NASA Astrophysics Data System (ADS)

    Kumar, V. Rakesh; Kiran, P. Prem

    2017-01-01

    Water dominantly present in liquid state on earth gets transformed to crystalline polymorphs under different dynamic loading conditions. Out of different crystalline phases discovered till date, ice VII is observed to be stable over wide pressure (2-63 GPa) and temperature (>273 K) ranges. The formation of ice VII crystalline structure has been vastly reported during high pressure static compression using diamond anvil cell and propagation of high energy (>50 mJ/pulse) nanosecond laser pulse induced dynamic high pressures through liquid water. We present the onset of ice VII phase at low threshold of 2 mJ/pulse during 30 ps (532 nm, 10 Hz) laser pulse induced shock propagating through liquid water. Role of input pulse energy on the evolution of Stoke's and anti-Stoke's Raman shift of the dominant A1g mode of ice VII, filamentation, free-electrons, plasma shielding is presented. The H-bond network rearrangement, electron ion energy transfer time coinciding with the excitation pulse duration supported by the filamentation and plasma shielding of the ps laser pulses reduced the threshold of ice VII structure formation. Filamentation and the plasma shielding have shown the localized creation and sustenance of ice VII structure in liquid water over 3 mm length and 50 μm area of cross-section.

  5. Compound heterozygous mutations (p.Leu13Pro and p.Tyr294*) associated with factor VII deficiency cause impaired secretion through ineffective translocation and extensive intracellular degradation of factor VII.

    PubMed

    Suzuki, Keijiro; Sugawara, Takeshi; Ishida, Yoji; Suwabe, Akira

    2013-02-01

    Congenital coagulation factor VII (FVII) deficiency is a rare coagulation disease. We investigated the molecular mechanisms of this FVII deficiency in a patient with compound heterozygous mutations. A 22-year-old Japanese female was diagnosed with asymptomatic FVII deficiency. The FVII activity and antigen were greatly reduced (activity, 13.0%; antigen, 10.8%). We analyzed the F7 gene of this patient and characterized mutant FVII proteins using in vitro expression studies. Sequence analysis revealed that the patient was compound heterozygous with a point mutation (p.Leu13Pro) in the central hydrophobic core of the signal peptides and a novel non-sense mutation (p.Tyr294*) in the catalytic domain. Expression studies revealed that mutant FVII with p.Leu13Pro (FVII13P) showed less accumulation in the cells (17.5%) and less secretion into the medium (64.8%) than wild type showed. Truncated FVII resulting from p.Tyr294* (FVII294X) was also decreased in the cells (32.0%), but was not secreted into the medium. Pulse-chase experiments revealed that both mutants were extensively degraded intracellularly compared to wild type. The majority of FVII13P cannot translocate into endoplasmic reticulum (ER). However, a small amount of FVII13P was processed normally with post-translational modifications and was secreted into the medium. The fact that FVII294X was observed only in ER suggests that it is retained in ER. Proteasome apparently plays a central role in these degradations. These findings demonstrate that both mutant FVIIs impaired secretion through ineffective translocation to and retention in ER with extensive intracellular degradation, resulting in an insufficient phenotype. Copyright © 2012 Elsevier Ltd. All rights reserved.

  6. Adenovirus Core Protein VII Downregulates the DNA Damage Response on the Host Genome

    PubMed Central

    Avgousti, Daphne C.; Della Fera, Ashley N.; Otter, Clayton J.; Herrmann, Christin; Pancholi, Neha J.

    2017-01-01

    ABSTRACT Viral manipulation of cellular proteins allows viruses to suppress host defenses and generate infectious progeny. Due to the linear double-stranded DNA nature of the adenovirus genome, the cellular DNA damage response (DDR) is considered a barrier to successful infection. The adenovirus genome is packaged with protein VII, a virally encoded histone-like core protein that is suggested to protect incoming viral genomes from detection by the cellular DNA damage machinery. We showed that protein VII localizes to host chromatin during infection, leading us to hypothesize that protein VII may affect DNA damage responses on the cellular genome. Here we show that protein VII at cellular chromatin results in a significant decrease in accumulation of phosphorylated H2AX (γH2AX) following irradiation, indicating that protein VII inhibits DDR signaling. The oncoprotein SET was recently suggested to modulate the DDR by affecting access of repair proteins to chromatin. Since protein VII binds SET, we investigated a role for SET in DDR inhibition by protein VII. We show that knockdown of SET partially rescues the protein VII-induced decrease in γH2AX accumulation on the host genome, suggesting that SET is required for inhibition. Finally, we show that knockdown of SET also allows ATM to localize to incoming viral genomes bound by protein VII during infection with a mutant lacking early region E4. Together, our data suggest that the protein VII-SET interaction contributes to DDR evasion by adenovirus. Our results provide an additional example of a strategy used by adenovirus to abrogate the host DDR and show how viruses can modify cellular processes through manipulation of host chromatin. IMPORTANCE The DNA damage response (DDR) is a cellular network that is crucial for maintaining genome integrity. DNA viruses replicating in the nucleus challenge the resident genome and must overcome cellular responses, including the DDR. Adenoviruses are prevalent human pathogens that

  7. 40 CFR 82.24 - Recordkeeping and reporting requirements for class II controlled substances.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... transformation; (v) The date on which the class II controlled substances were imported; (vi) The port of entry.... Customs entry form; (xiv) Dated records documenting the sale or transfer of class II controlled substances... source facility; (vii) The U.S. port of entry for the import, the expected date of shipment and the...

  8. 40 CFR 82.24 - Recordkeeping and reporting requirements for class II controlled substances.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... transformation; (v) The date on which the class II controlled substances were imported; (vi) The port of entry.... Customs entry form; (xiv) Dated records documenting the sale or transfer of class II controlled substances... source facility; (vii) The U.S. port of entry for the import, the expected date of shipment and the...

  9. 11p15 duplication and 13q34 deletion with Beckwith-Wiedemann syndrome and factor VII deficiency.

    PubMed

    Jurkiewicz, Dorota; Kugaudo, Monika; Tańska, Anna; Wawrzkiewicz-Witkowska, Angelika; Tomaszewska, Agnieszka; Kucharczyk, Marzena; Cieślikowska, Agata; Ciara, Elżbieta; Krajewska-Walasek, Małgorzata

    2015-06-01

    Here we report a patient with 11p15.4p15.5 duplication and 13q34 deletion presenting with Beckwith-Wiedemann syndrome (BWS) and moderate deficiency of factor VII (FVII). The duplication was initially diagnosed on methylation-sensitive multiplex ligation-dependent probe amplification. Array comparative genome hybridization confirmed its presence and indicated a 13q34 distal deletion. The patient's clinical symptoms, including developmental delay and facial dysmorphism, were typical of BWS with paternal 11p15 trisomy. Partial 13q monosomy in this patient is associated with moderate deficiency of FVII and may also overlap with a few symptoms of paternal 11p15 trisomy such as developmental delay and some facial features. To our knowledge this is the first report of 11p15.4p15.5 duplication associated with deletion of 13q34 and FVII deficiency. Moreover, this report emphasizes the importance of detailed clinical as well as molecular examinations in patients with BWS features and developmental delay. © 2015 Japan Pediatric Society.

  10. 40 CFR Appendix Vii to Part 86 - Standard Bench Cycle (SBC)

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    .... VII Appendix VII to Part 86—Standard Bench Cycle (SBC) 1. The standard bench aging durability procedures [Ref. § 86.1823-08(d)] consist of aging a catalyst-oxygen-sensor system on an aging bench which follows the standard bench cycle (SBC) described in this appendix. 2. The SBC requires use of an aging...

  11. 40 CFR Appendix Vii to Part 86 - Standard Bench Cycle (SBC)

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    .... VII Appendix VII to Part 86—Standard Bench Cycle (SBC) 1. The standard bench aging durability procedures [Ref. § 86.1823-08(d)] consist of aging a catalyst-oxygen-sensor system on an aging bench which follows the standard bench cycle (SBC) described in this appendix. 2. The SBC requires use of an aging...

  12. Opposite Smad and chicken ovalbumin upstream promoter transcription factor inputs in the regulation of the collagen VII gene promoter by transforming growth factor-beta.

    PubMed

    Calonge, María Julia; Seoane, Joan; Massagué, Joan

    2004-05-28

    A critical component of the epidermal basement membrane, collagen type VII, is produced by keratinocytes and fibroblasts, and its production is stimulated by the cytokine transforming growth factor-beta (TGF-beta). The gene, COL7A1, is activated by TGF-beta via Smad transcription factors in cooperation with AP1. Here we report a previously unsuspected level of complexity in this regulatory process. We provide evidence that TGF-beta may activate the COL7A1 promoter by two distinct inputs operating through a common region of the promoter. One input is provided by TGF-beta-induced Smad complexes via two Smad binding elements that function redundantly depending on the cell type. The second input is provided by relieving the COL7A1 promoter from chicken ovalbumin upstream promoter transcription factor (COUP-TF)-mediated transcriptional repression. We identified COUP-TFI and -TFII as factors that bind to the TGF-beta-responsive region of the COL7A1 promoter in an expression library screening. COUP-TFs bind to a site between the two Smad binding elements independently of Smad or AP1 and repress the basal and TGF-beta-stimulated activities of this promoter. We provide evidence that endogenous COUP-TF activity represses the COL7A1 promoter. Furthermore, we show that TGF-beta addition causes a rapid and profound down-regulation of COUP-TF expression in keratinocytes and fibroblasts. The results suggest that TGF-beta signaling may exert tight control over COL7A1 by offsetting the balance between opposing Smad and COUP-TFs.

  13. Delayed hypertrophic differentiation of epiphyseal chondrocytes contributes to failed secondary ossification in mucopolysaccharidosis VII dogs

    PubMed Central

    Peck, Sun H.; O'Donnell, Philip J.M.; Kang, Jennifer L.; Malhotra, Neil R.; Dodge, George R.; Pacifici, Maurizio; Shore, Eileen M.; Haskins, Mark E.; Smith, Lachlan J.

    2015-01-01

    Mucopolysaccharidosis (MPS) VII is a lysosomal storage disorder characterized by deficient β-glucuronidase activity, which leads to the accumulation of incompletely degraded glycosaminoglycans (GAGs). MPS VII patients present with severe skeletal abnormalities, which are particularly prevalent in the spine. Incomplete cartilage-to-bone conversion in MPS VII vertebrae during postnatal development is associated with progressive spinal deformity and spinal cord compression. The objectives of this study were to determine the earliest postnatal developmental stage at which vertebral bone disease manifests in MPS VII and to identify the underlying cellular basis of impaired cartilage-to-bone conversion, using the naturally-occurring canine model. Control and MPS VII dogs were euthanized at 9 and 14 days-of-age, and vertebral secondary ossification centers analyzed using micro-computed tomography, histology, qPCR, and protein immunoblotting. Imaging studies and mRNA analysis of bone formation markers established that secondary ossification commences between 9 and 14 days in control animals, but not in MPS VII animals. mRNA analysis of differentiation markers revealed that MPS VII epiphyseal chondrocytes are unable to successfully transition from proliferation to hypertrophy during this critical developmental window. Immunoblotting demonstrated abnormal persistence of Sox9 protein in MPS VII cells between 9 and 14 days-of-age, and biochemical assays revealed abnormally high intra and extracellular GAG content in MPS VII epiphyseal cartilage at as early as 9 days-of-age. In contrast, assessment of vertebral growth plates and primary ossification centers revealed no significant abnormalities at either age. The results of this study establish that failed vertebral bone formation in MPS VII can be traced to the failure of epiphyseal chondrocytes to undergo hypertrophic differentiation at the appropriate developmental stage, and suggest that aberrant processing of Sox9 protein

  14. Use of recombinant activated factor VII for reduction of perioperative blood loss during elective surgical correction of spine deformity in a Jehovah's Witness. Case report.

    PubMed

    Kącka, Katarzyna; Kącki, Wojciech; Merak, Joanna; Błęka, Adam

    2010-01-01

    Planned surgical procedures at patients who refuse allogenic blood transfusion because of religious convictions are important problem, not only medical but also ethical and juristical. At the study authors report the successful use of activated recombinant factor VII (rFVIIa) for the reduction of perioperative blood loss in four years old child - Jehovah's Witness, who had planned Torode kyphectomy. Applied perioperative management together with preparing to surgery with erythropoietin allowed for reduction of blood loss and avoiding of blood transfusion. Authors state, that appropriate perioperative proceeding makes a possibility of safe surgical procedures also at patients who refuse the transfusion.

  15. 29 CFR 1604.8 - Relationship of title VII to the Equal Pay Act.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... GUIDELINES ON DISCRIMINATION BECAUSE OF SEX § 1604.8 Relationship of title VII to the Equal Pay Act. (a) The employee coverage of the prohibitions against discrimination based on sex contained in title VII is...

  16. New isochromophilones VII and VIII produced by Penicillium sp. FO-4164.

    PubMed

    Yang, D J; Tomoda, H; Tabata, N; Masuma, R; Omura, S

    1996-03-01

    New isochromophilones VII and VIII were isolated from the culture broth of Penicillium sp. FO-4164. The structures were elucidated as 6H-2-benzopyran-6,8(7H)-dione, 5-chloro-3-(3',5'-dimethyl-1',3'-heptadienyl)-1,7,8a-trihydro-7, 8a-dihydroxy-7-methyl-7-acetate for isochromophilone VII and 6H-2-benzopyran-6-one,5-chloro-3-(3',5'-dimethyl-1', 3'-heptadienyl)-1,7,8,8a-tetrahydro-7,8-dihydroxy-7-methyl-8-acetate for isochromophilone VIII. Isochromophilones VII and VIII inhibited diacylglycerol acyltransferase activity with IC50 values of 20.0 and 127 microM and acyl-CoA: cholesterol acyltransferase activity with IC50 values of 24.5 and 47.0 microM, respectively.

  17. The Factor Structure of the Beck Depression Inventory-II: An Evaluation

    ERIC Educational Resources Information Center

    Vanheule, Stijn; Desmet, Mattias; Groenvynck, Hans; Rosseel, Yves; Fontaine, Johnny

    2008-01-01

    The Beck Depression Inventory-II (BDI-II) is a frequently used scale for measuring depressive severity. BDI-II data (404 clinical; 695 nonclinical adults) were analyzed by means of confirmatory factor analysis to test whether the factor structure model with a somatic-affective and cognitive component of depression, formulated by Beck and…

  18. Onset of ice VII phase during ps laser pulse propagation through liquid water

    NASA Astrophysics Data System (ADS)

    Paturi, Prem Kiran; Vaddapally, Rakesh Kumar; Acrhem Team

    2015-06-01

    Water dominantly present in liquid state on earth gets transformed to crystalline polymorphs under different dynamic loading conditions. Out of 15 different crystalline phases discovered till date, ice VII is observed to be stable over wide pressure (2-63 GPa) and temperature (>273 K) ranges. We present the onset of ice VII phase at low threshold of 2 mJ/pulse during 30 ps (532 nm, 10 Hz) laser pulse induced shock propagating through liquid water. Role of input pulse energy on the evolution of Stoke's and anti-Stoke's Raman shift of the dominant A1g mode of ice VII, filamentation, free-electrons, plasma shielding is presented. The H-bond network rearrangement, electron ion energy transfer time coinciding with the excitation pulse duration supported by the filamentation and plasma shielding of the ps laser pulses reduced the threshold of ice VII structure formation. Filamentation and the plasma shielding have shown the localized creation and sustenance of ice VII structure in liquid water over 3 mm length and 50 μm area of cross-section. The work is supported by Defence Research and Developement Organization, India through Grants-in-Aid Program.

  19. Correction of murine mucopolysaccharidosis VII by a human. beta. -glucuronidase transgene

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kyle, J.W.; Vogler, C.; Hoffmann, J.W.

    1990-05-01

    The authors recently described a murine model for mucopolysaccharidosis VII in mice that have an inherited deficiency of {beta}-glucuronidase. Affected mice, of genotype gus{sup mps}/gus{sup mps}, present clinical manifestations similar to those of humans with mucopolysaccharidosis VII (Sly syndrome) and are shown here to have secondary elevations of other lysosomal enzymes. The mucopolysaccharidosis VII phenotype in both species includes dwarfism, skeletal deformities, and premature death. Lysosome storage is visualized within enlarged vesicles and correlates biochemically with accumulation of undegraded and partially degraded glycosaminoglycans. In this report they describe the consequences of introducing the human {beta}-glucuronidase gene, GUSB, into gus{sup mps}/gus{supmore » mps} mice that produce virtually no murine {beta}-glucuronidase. Transgenic mice homozygous for the mucopolysaccharidosis VII mutation expressed high levels of human {beta}-glucuronidase activity in all tissues examined and were phenotypically normal. Biochemically, both the intralysosomal storage of glycosaminoglycans and the secondary elevation of other acid hydrolases were corrected. These findings demonstrate that the GUSB transgene is expressed in gus{sup mps}/gus{sup mps} mice and that human {beta}-glucuronidase corrects the murine mucopolysaccharidosis storage disease.« less

  20. Collagen VII deficient mice show morphologic and histologic corneal changes that phenotypically mimic human dystrophic epidermolysis bullosa of the eye.

    PubMed

    Chen, Vicki M; Shelke, Rajani; Nyström, Alexander; Laver, Nora; Sampson, James F; Zhiyi, Cao; Bhat, Najma; Panjwani, Noorjahan

    2018-06-16

    Absence of collagen VII causes blistering of the skin, eyes and many other tissues. This disease is termed dystrophic epidermolysis bullosa (DEB). Corneal fibrosis occurs in up to 41% and vision loss in up to 64% of patients. Standard treatments are supportive and there is no cure. The immune-histologic and morphologic changes in the corneas of the mouse model for this disease have not been described in the literature. Our purpose is to characterize the eyes of these mice to determine if this is an appropriate model for study of human therapeutics. Western blot analysis (WB) and immunohistochemistry (IHC) were performed to assess the relative collagen VII protein levels and its location within the cornea. Additional IHC for inflammatory and fibrotic biomarkers alpha-smooth muscle actin (α-SMA), transforming growth factor-beta (TGF-β), connective tissue growth factor (CTGF), proteinase 3, tenascin C and collagen III were performed. Clinical photographs documenting opacification of the corneas of animals of differing ages were assessed and scored independently by 2 examiners. Histology was then used to investigate morphologic changes. IHC and WB confirmed that these mice are deficient in collagen VII production at the level of the basement membrane when compared with wild-types. IHC showed anomalous deposition of collagen III throughout the stroma. Of the 5 biomarkers tested, TGF-β showed the strongest and most consistently staining. Photographs documented corneal opacities only in mice older than 10 weeks, opacities were not seen in younger animals. Histology showed multiple abnormalities, including epithelial hyperplasia, ulceration, fibrosis, edema, dysplasia, neovascularization and bullae formation. The collagen VII hypomorphic mouse shows reduced collagen VII production at the level of the corneal basement membrane. Corneal changes are similar to pathology seen in humans with this disease. The presence of anomalous stromal collagen III and TGF-β appear to be

  1. MIZEX: A Program for Mesoscale Air-Ice-Ocean Interaction Experiments in Arctic Marginal Ice Zones. MIZEX Bulletin VII.

    DTIC Science & Technology

    1986-03-01

    8217 ILI L2.2363 31-25 UICRQCCW p O TEST C4ART’OPSMa, -f AoA IV 4 86 9 ’ 5 MIZEX BULLETIN SERIES: INFORMATION FOR CONTRIBUTORS The main purpose of the...Ice-Ocean Interaction Experiments in Arctic Marginal Ice Zones MIZEX BULLETIN VII LEC T E SEP 2 9 1986 ’Jl P March 1986 J A ’QOzltnal OontsSn$ ooLoP...studies in both the northern and southern hemispheres. W.D. HIBLER Ill March 1986 ii CONTENTS* Page P reface

  2. 77 FR 47116 - Manufacturer of Controlled Substances; Notice of Registration; Penick Corporation

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-08-07

    ... Ecgonine (9180) II Hydrocodone (9193) VII Morphine (9300) II Oripavine (9330) II Thebaine (9333) II... has considered the factors in 21 U.S.C. 823(a) and determined that the registration of Penick...

  3. Gene disruption reveals a dispensable role for plasmepsin VII in the Plasmodium berghei life cycle.

    PubMed

    Mastan, Babu S; Kumari, Anchala; Gupta, Dinesh; Mishra, Satish; Kumar, Kota Arun

    2014-06-01

    Plasmepsins (PM), aspartic proteases of Plasmodium, comprises a family of ten proteins that perform critical functions in Plasmodium life cycle. Except VII and VIII, functions of the remaining plasmepsin members have been well characterized. Here, we have generated a mutant parasite lacking PM VII in Plasmodium berghei using reverse genetics approach. Systematic comparison of growth kinetics and infection in both mosquito and vertebrate host revealed that PM VII depleted mutants exhibited no defects in development and progressed normally throughout the parasite life cycle. These studies suggest a dispensable role for PM VII in Plasmodium berghei life cycle. Copyright © 2014 Elsevier B.V. All rights reserved.

  4. Title VII funding and physician practice in rural or low-income areas.

    PubMed

    Krist, Alex H; Johnson, Robert E; Callahan, David; Woolf, Steven H; Marsland, David

    2005-01-01

    Whether Title VII funding enhances physician supply in underserved areas has not clearly been established. To determine the relation between Title VII funding in medical school, residency, or both, and the number of family physicians practicing in rural or low-income communities. A retrospective cross sectional analysis was carried out using the 2000 American Academy of Family Physicians physician database, Title VII funding records, and 1990 U.S. Census data. Included were 9,107 family physicians practicing in 9 nationally representative states in the year 2000. Physicians exposed to Title VII funding through medical school and residency were more likely to have their current practice in low-income communities (11.9% vs 9.9%, P< or =.02) and rural areas (24.5% vs 21.8%, P< or =.02). Physicians were more likely to practice in rural communities if they attended medical schools (24.2% vs 21.4%; P =.009) and residencies (24.0% vs 20.3%; P =.011) after the school or program had at least 5 years of Title VII funding vs before. Similar increases were not observed for practice in low-income communities. In a multivariate analysis, exposure to funding and attending an institution with more years of funding independently increased the odds of practicing in rural or low-income communities. Title VII funding is associated with an increase in the family physician workforce in rural and low-income communities. This effect is temporally related to initiation of funding and independently associated with effect in a multivariate analysis, suggesting a potential causal relationship. Whereas the absolute 2% increase in family physicians in these underserved communities may seem modest, it can represent a substantial increase in access to health care for community members.

  5. Managing Information Technology: Facing the Issues. Track VII: Applications and Technology Issues.

    ERIC Educational Resources Information Center

    CAUSE, Boulder, CO.

    Eight papers making up Track VII of the 1989 conference of the Professional Association for the Management of Information Technology in Higher Education (known as CAUSE, an acronym of the association's former name) are presented in this document. The focus of Track VII is on applications and technology issues, and the papers include: "The…

  6. Using a minigene approach to characterize a novel splice site mutation in human F7 gene causing inherited factor VII deficiency in a Chinese pedigree.

    PubMed

    Yu, T; Wang, X; Ding, Q; Fu, Q; Dai, J; Lu, Y; Xi, X; Wang, H

    2009-11-01

    Factor VII deficiency which transmitted as an autosomal recessive disorder is a rare haemorrhagic condition. The aim of this study was to identify the molecular genetic defect and determine its functional consequences in a Chinese pedigree with FVII deficiency. The proband was diagnosed as inherited coagulation FVII deficiency by reduced plasma levels of FVII activity (4.4%) and antigen (38.5%). All nine exons and their flanking sequence of F7 gene were amplified by polymerase chain reaction (PCR) for the proband and the PCR products were directly sequenced. The compound heterozygous mutations of F7 (NM_000131.3) c.572-1G>A and F7 (NM_000131.3) c.1165T>G; p.Cys389Gly were identified in the proband's F7 gene. To investigate the splicing patterns associated with F7 c.572-1G>A, ectopic transcripts in leucocytes of the proband were analyzed. F7 minigenes, spanning from intron 4 to intron 7 and carrying either an A or a G at position -1 of intron 5, were constructed and transiently transfected into human embryonic kidney (HEK) 293T cells, followed by RT-PCR analysis. The aberrant transcripts from the F7 c.572-1G>A mutant allele were not detected by ectopic transcription study. Sequencing of the RT-PCR products from the mutant transfectant demonstrated the production of an erroneously spliced mRNA with exon 6 skipping, whereas a normal splicing occurred in the wide type transfectant. The aberrant mRNA produced from the F7 c.572-1G>A mutant allele is responsible for the factor VII deficiency in this pedigree.

  7. THE SPLASH SURVEY: INTERNAL KINEMATICS, CHEMICAL ABUNDANCES, AND MASSES OF THE ANDROMEDA I, II, III, VII, X, AND XIV DWARF SPHEROIDAL GALAXIES {sup ,}

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kalirai, Jason S.; Beaton, Rachael L.; Majewski, Steven R.

    2010-03-10

    We present new Keck/DEIMOS spectroscopic observations of hundreds of individual stars along the sightline to the first three of the Andromeda (M31) dwarf spheroidal (dSph) galaxies to be discovered, And I, II, and III, and combine them with recent spectroscopic studies by our team of three additional M31 dSphs, And VII, X, and XIV, as a part of the SPLASH Survey (Spectroscopic and Photometric Landscape of Andromeda's Stellar Halo). Member stars of each dSph are isolated from foreground Milky Way dwarf stars and M31 field contamination using a variety of photometric and spectroscopic diagnostics. Our final spectroscopic sample of membermore » stars in each dSph, for which we measure accurate radial velocities with a median uncertainty (random plus systematic errors) of 4-5 km s{sup -1}, includes 80 red giants in And I, 95 in And II, 43 in And III, 18 in And VII, 22 in And X, and 38 in And XIV. The sample of confirmed members in the six dSphs is used to derive each system's mean radial velocity, intrinsic central velocity dispersion, mean abundance, abundance spread, and dynamical mass. This combined data set presents us with a unique opportunity to perform the first systematic comparison of the global properties (e.g., metallicities, sizes, and dark matter masses) of one-third of Andromeda's total known dSph population with Milky Way counterparts of the same luminosity. Our overall comparisons indicate that the family of dSphs in these two hosts have both similarities and differences. For example, we find that the luminosity-metallicity relation is very similar between L {approx} 10{sup 5} and 10{sup 7} L{sub sun}, suggesting that the chemical evolution histories of each group of dSphs are similar. The lowest luminosity M31 dSphs appear to deviate from the relation, possibly suggesting tidal stripping. Previous observations have noted that the sizes of M31's brightest dSphs are systematically larger than Milky Way satellites of similar luminosity. At lower

  8. Analysis of functional xylanases in xylan degradation by Aspergillus niger E-1 and characterization of the GH family 10 xylanase XynVII.

    PubMed

    Takahashi, Yui; Kawabata, Hiroaki; Murakami, Shuichiro

    2013-01-01

    Xylanases produced by Aspergillus niger are industrially important and many types of xylanases have been reported. Individual xylanases have been well studied for their enzymatic properties, gene cloning, and heterologous expression. However, less attention has been paid to the relationship between xylanase genes carried on the A. niger genome and xylanases produced by A. niger strains. Therefore, we examined xylanase genes encoded on the genome of A. niger E-1 and xylanases produced in culture. Seven putative xylanase genes, xynI-VII (named in ascending order of the molecular masses of the deduced amino acid sequences), were amplified from the strain E-1 genome using primers designed from the genome sequence of A. niger CBS 513.88 by PCR and phylogenetically classified into three clusters. Additionally, culture supernatant analysis by DE52 anion-exchange column chromatography revealed that this strain produced three xylanases, XynII, XynIII, and XynVII, which were identified by N-terminal amino acid sequencing and MALDI-TOF-MS analyses, in culture when gown in 0.5% xylan medium supplemented with 50 mM succinate. Furthermore, XynVII, the only GH family 10 xylanase in A. niger E-1, was purified and characterized. The purified enzyme showed a single band with a molecular mass of 35 kDa by SDS-PAGE. The highest activity of purified XynVII was observed at 55°C and pH 5.5. The enzyme was stable in the broad pH range of 3-10 and up to 60°C and was resistant to most metal ions and modifying regents. XynVII showed high specificity against beechwood xylan with K m and V max values of 2.8 mg mL(-1) and 127 μmol min(-1)mg(-1), respectively. TLC and MALDI-TOF-MS analyses showed that the final hydrolyzed products of the enzyme from beechwood xylan were xylose, xylobiose, and xylotriose substituted with a 4-o-metylglucuronic acid residue.

  9. 76 FR 52656 - Lock+Hydro Friends Fund VII; Notice of Preliminary Permit Application Accepted for Filing and...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-23

    ... Friends Fund VII; Notice of Preliminary Permit Application Accepted for Filing and Soliciting Comments, Motions To Intervene, and Competing Applications On August 4, 2011, Lock+Hydro Friends Fund VII, filed an... Friends Fund VII, 5090 Richmond Avenue 390, Houston, TX 77056; phone (877) 556- 6566 x709. FERC Contact...

  10. Type I and II Endometrial Cancers: Have They Different Risk Factors?

    PubMed Central

    Setiawan, Veronica Wendy; Yang, Hannah P.; Pike, Malcolm C.; McCann, Susan E.; Yu, Herbert; Xiang, Yong-Bing; Wolk, Alicja; Wentzensen, Nicolas; Weiss, Noel S.; Webb, Penelope M.; van den Brandt, Piet A.; van de Vijver, Koen; Thompson, Pamela J.; Strom, Brian L.; Spurdle, Amanda B.; Soslow, Robert A.; Shu, Xiao-ou; Schairer, Catherine; Sacerdote, Carlotta; Rohan, Thomas E.; Robien, Kim; Risch, Harvey A.; Ricceri, Fulvio; Rebbeck, Timothy R.; Rastogi, Radhai; Prescott, Jennifer; Polidoro, Silvia; Park, Yikyung; Olson, Sara H.; Moysich, Kirsten B.; Miller, Anthony B.; McCullough, Marjorie L.; Matsuno, Rayna K.; Magliocco, Anthony M.; Lurie, Galina; Lu, Lingeng; Lissowska, Jolanta; Liang, Xiaolin; Lacey, James V.; Kolonel, Laurence N.; Henderson, Brian E.; Hankinson, Susan E.; Håkansson, Niclas; Goodman, Marc T.; Gaudet, Mia M.; Garcia-Closas, Montserrat; Friedenreich, Christine M.; Freudenheim, Jo L.; Doherty, Jennifer; De Vivo, Immaculata; Courneya, Kerry S.; Cook, Linda S.; Chen, Chu; Cerhan, James R.; Cai, Hui; Brinton, Louise A.; Bernstein, Leslie; Anderson, Kristin E.; Anton-Culver, Hoda; Schouten, Leo J.; Horn-Ross, Pamela L.

    2013-01-01

    Purpose Endometrial cancers have long been divided into estrogen-dependent type I and the less common clinically aggressive estrogen-independent type II. Little is known about risk factors for type II tumors because most studies lack sufficient cases to study these much less common tumors separately. We examined whether so-called classical endometrial cancer risk factors also influence the risk of type II tumors. Patients and Methods Individual-level data from 10 cohort and 14 case-control studies from the Epidemiology of Endometrial Cancer Consortium were pooled. A total of 14,069 endometrial cancer cases and 35,312 controls were included. We classified endometrioid (n = 7,246), adenocarcinoma not otherwise specified (n = 4,830), and adenocarcinoma with squamous differentiation (n = 777) as type I tumors and serous (n = 508) and mixed cell (n = 346) as type II tumors. Results Parity, oral contraceptive use, cigarette smoking, age at menarche, and diabetes were associated with type I and type II tumors to similar extents. Body mass index, however, had a greater effect on type I tumors than on type II tumors: odds ratio (OR) per 2 kg/m2 increase was 1.20 (95% CI, 1.19 to 1.21) for type I and 1.12 (95% CI, 1.09 to 1.14) for type II tumors (Pheterogeneity < .0001). Risk factor patterns for high-grade endometrioid tumors and type II tumors were similar. Conclusion The results of this pooled analysis suggest that the two endometrial cancer types share many common etiologic factors. The etiology of type II tumors may, therefore, not be completely estrogen independent, as previously believed. PMID:23733771

  11. Intraoperative Use of Low-Dose Recombinant Activated Factor VII During Thoracic Aortic Operations

    PubMed Central

    Andersen, Nicholas D.; Bhattacharya, Syamal D.; Williams, Judson B.; Fosbol, Emil L.; Lockhart, Evelyn L.; Patel, Mayur B.; Gaca, Jeffrey G.; Welsby, Ian J.; Hughes, G. Chad

    2013-01-01

    Background Numerous studies have supported the effectiveness of recombinant activated factor VII (rFVIIa) for the control of bleeding after cardiac procedures; however safety concerns persist. Here we report the novel use of intraoperative low-dose rFVIIa in thoracic aortic operations, a strategy intended to improve safety by minimizing rFVIIa exposure. Methods Between July 2005 and December 2010, 425 consecutive patients at a single referral center underwent thoracic aortic operations with cardiopulmonary bypass (CPB); 77 of these patients received intraoperative low-dose rFVIIa (≤60 μg/kg) for severe coagulopathy after CPB. Propensity matching produced a cohort of 88 patients (44 received intraoperative low-dose rFVIIa and 44 controls) for comparison. Results Matched patients receiving intraoperative low-dose rFVIIa got an initial median dose of 32 μg/kg (interquartile range [IQR], 16–43 μg/kg) rFVIIa given 51 minutes (42–67 minutes) after separation from CPB. Patients receiving intraoperative low-dose rFVIIa demonstrated improved postoperative coagulation measurements (partial thromboplastin time 28.6 versus 31.5 seconds; p = 0.05; international normalized ratio, 0.8 versus 1.2; p < 0.0001) and received 50% fewer postoperative blood product transfusions (2.5 versus 5.0 units; p = 0.05) compared with control patients. No patient receiving intraoperative low-dose rFVIIa required postoperative rFVIIa administration or reexploration for bleeding. Rates of stroke, thromboembolism, myocardial infarction, and other adverse events were equivalent between groups. Conclusions Intraoperative low-dose rFVIIa led to improved postoperative hemostasis with no apparent increase in adverse events. Intraoperative rFVIIa administration in appropriately selected patients may correct coagulopathy early in the course of refractory blood loss and lead to improved safety through the use of smaller rFVIIa doses. Appropriately powered randomized studies are necessary to confirm

  12. Cost-effectiveness of recombinant activated factor VII in the treatment of intracerebral hemorrhage.

    PubMed

    Earnshaw, Stephanie R; Joshi, Ashish V; Wilson, Michele R; Rosand, Jonathan

    2006-11-01

    Intracerebral hemorrhage (ICH) is among the most costly and debilitating forms of stroke. Results from a recent Phase IIb clinical trial demonstrate that administration of recombinant activated factor VII (rFVIIa) reduces ICH mortality and improves functional outcome. In the current analysis, we examine the cost-effectiveness of early treatment with rFVIIa for ICH in the United States. A decision-analytic model was developed to estimate the lifetime costs and outcomes associated with rFVIIa treatment at doses of 40, 80 and 160 microg/kg compared with current standard of care in treating ICH, from a US third-party payer perspective. The patient population was similar to that of the Phase IIb clinical trial. Model structure and inputs were obtained from published literature, clinical trial data, claims databases, and expert opinion. All costs are presented in 2005 US dollars. Outcomes included incremental cost per life-year (LY) saved and incremental cost per quality-adjusted life-year (QALY) gained. Costs and outcomes were discounted at 3% annually. Univariate and multivariate sensitivity analyses were conducted to assess model robustness. Compared with standard care, treatment with rFVIIa 40 microg/kg, and 160 microg/kg results in total lifetime cost-effectiveness ratios of 6308 dollars/QALY and 3152 dollars/QALY, respectively. Treatment with rFVIIa 80 microg/kg was found to be cost saving and a gain of 1.67 QALYs is achieved over a patient's lifetime. These results are robust to changes in input parameters. Treatment of ICH with rFVIIa 40 microg/kg and 160 microg/kg appears to be cost-effective (

  13. Underuse of Title VII Funding for Indian Education in Arizona, Nevada, and Utah

    ERIC Educational Resources Information Center

    West Comprehensive Center at WestEd, 2015

    2015-01-01

    Title VII provides funding for the education of American Indian/Alaska Native students based on a formula grant available to school districts, charter schools, and local education agencies (LEAs). This report explores why some eligible schools and districts do not apply for federal Title VII, potentially resulting in American Indian/Alaska Native…

  14. Remarks on KERMA Factors in ACE files

    NASA Astrophysics Data System (ADS)

    Konno, C.; Ochiai, K.; Takakura, K.; Sato, S.

    2014-04-01

    Some neutron KERMA factors in ACE files are negative and extremely large if nuclear data libraries do not keep energy-balance. The status of neutron KERMA factors in the official ACE file of ENDF/B-VII.1 is examined. As a result, it is found out that neutron KERMA factors of nuclei more than 200 in ENDF/B-VII.1 have some problems. Effects of the inadequate KERMA factor are also investigated, which are large for neutron heat while those are small for total (neutron + gamma) heat. Users who use only neutron KERMA factors should check if the factors are adequate or not before they use the factors.

  15. Leveraging Information Technology. Track VII: Outstanding Applications.

    ERIC Educational Resources Information Center

    CAUSE, Boulder, CO.

    Eight papers from the 1987 CAUSE conference's Track VII, Outstanding Applications, are presented. They include: "Image Databases in the University" (Reid Kaplan and Gordon Mathieson); "Using Information Technology for Travel Management at the University of Michigan" (Robert E. Russell and John C. Hufziger); "On-Line Access…

  16. The Effect of Neonatal Gene Therapy on Skeletal Manifestations in Mucopolysaccharidosis VII Dogs after a Decade

    PubMed Central

    Xing, Elizabeth M.; Knox, Van W.; O'Donnell, Patricia A.; Sikura, Tracey; Liu, Yuli; Wu, Susan; Casal, Margret L.; Haskins, Mark E.; Ponder, Katherine P.

    2013-01-01

    Mucopolysaccharidosis (MPS) VII is a lysosomal storage disease due to deficient activity of β-glucuronidase (GUSB), and results in glycosaminoglycan accumulation. Skeletal manifestations include bone dysplasia, degenerative joint disease, and growth retardation. One gene therapy approach for MPS VII involves neonatal intravenous injection of a gamma retroviral vector expressing GUSB, which results in stable expression in liver and secretion of enzyme into blood at levels predicted to be similar or higher to enzyme replacement therapy. The goal of this study was to evaluate the long-term effect of neonatal gene therapy on skeletal manifestations in MPS VII dogs. Treated MPS VII dogs could walk throughout their lives, while untreated MPS VII dogs could not stand beyond 6 months and were dead by 2 years. Luxation of the coxofemoral joint and the patella, dysplasia of the acetabulum and supracondylar ridge, deep erosions of the distal femur, and synovial hyperplasia were reduced, and the quality of articular bone was improved in treated dogs at 6 to 11 years of age compared with untreated MPS VII dogs at 2 years or less. However, treated dogs continued to have osteophyte formation, cartilage abnormalities, and an abnormal gait. Enzyme activity was found near synovial blood vessels, and there was 2% as much GUSB activity in synovial fluid as in serum. We conclude that neonatal gene therapy reduces skeletal abnormalities in MPS VII dogs, but clinically-relevant abnormalities remain. Enzyme replacement therapy will probably have similar limitations long-term. PMID:23628461

  17. PREFACE: VII Mexican School on Gravitation and Mathematical Physics

    NASA Astrophysics Data System (ADS)

    Alcubierre Moya, Miguel; García Compeán, Héctor Hugo; Ureña López, Luis Arturo

    2007-07-01

    The present collection of papers was presented during the VII Mexican School on Gravitation and Mathematical Physics, which was held in Playa del Carmen, Quintana Roo, México, from 26 November to 2 December 2006. The Mexican School on Gravitation and Mathematical Physics, sponsored by the Mexican Physical Society, started in 1994 with the purpose of discussing and exchanging current ideas in gravitational physics. Each school has been devoted to a particular subject, and on previous occasions these subjects have covered topics such as supergravity, branes, black holes, the early Universe, observational cosmology, and quantum gravity. At the dawn of the XXI Century, General Relativity has finally become a standard tool in our understanding of numerous astrophysical phenomena. At the same time, the new generation of large interferometric gravitational wave detectors that are just beginning operation holds the promise of finally allowing the detection of gravitational waves and opening a new window on the Universe. However, because of the complexity of the Einstein field equations, the modelling of realistic astrophysical systems and gravitational wave sources can only be done using numerical simulations. Because of this, we have dedicated our VII School to the topic of relativistic astrophysics and numerical relativity. As in all our previous Schools, international leaders in the field were invited to give courses and plenary lectures. The school was complemented with more specialized talks presented in parallel sessions, some of which are included in these proceedings. All the contributions in this volume have been refereed, and they represent a sample of the courses, invited talks and contributed talks presented during our VII School. Our deep gratitude goes to all those who contributed to these proceedings, and to making our VII Mexican School a great success. Miguel Alcubierre Moya, Héctor Hugo García Compeán and Luis Arturo Ureña López Editors

  18. 29 CFR 1604.8 - Relationship of title VII to the Equal Pay Act.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 29 Labor 4 2010-07-01 2010-07-01 false Relationship of title VII to the Equal Pay Act. 1604.8 Section 1604.8 Labor Regulations Relating to Labor (Continued) EQUAL EMPLOYMENT OPPORTUNITY COMMISSION GUIDELINES ON DISCRIMINATION BECAUSE OF SEX § 1604.8 Relationship of title VII to the Equal Pay Act. (a) The...

  19. 29 CFR 1604.8 - Relationship of title VII to the Equal Pay Act.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 29 Labor 4 2012-07-01 2012-07-01 false Relationship of title VII to the Equal Pay Act. 1604.8 Section 1604.8 Labor Regulations Relating to Labor (Continued) EQUAL EMPLOYMENT OPPORTUNITY COMMISSION GUIDELINES ON DISCRIMINATION BECAUSE OF SEX § 1604.8 Relationship of title VII to the Equal Pay Act. (a) The...

  20. 29 CFR 1604.8 - Relationship of title VII to the Equal Pay Act.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 29 Labor 4 2013-07-01 2013-07-01 false Relationship of title VII to the Equal Pay Act. 1604.8 Section 1604.8 Labor Regulations Relating to Labor (Continued) EQUAL EMPLOYMENT OPPORTUNITY COMMISSION GUIDELINES ON DISCRIMINATION BECAUSE OF SEX § 1604.8 Relationship of title VII to the Equal Pay Act. (a) The...

  1. 29 CFR 1604.8 - Relationship of title VII to the Equal Pay Act.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 29 Labor 4 2011-07-01 2011-07-01 false Relationship of title VII to the Equal Pay Act. 1604.8 Section 1604.8 Labor Regulations Relating to Labor (Continued) EQUAL EMPLOYMENT OPPORTUNITY COMMISSION GUIDELINES ON DISCRIMINATION BECAUSE OF SEX § 1604.8 Relationship of title VII to the Equal Pay Act. (a) The...

  2. Factor VII and incidence of myocardial infarction in a Japanese population: The Jichi Medical School Cohort Study.

    PubMed

    Shiraishi, Takuya; Ishikawa, Shizukiyo; Kario, Kazuomi; Kayaba, Kazunori; Kajii, Eiji

    2017-11-01

    The role of factor VII (FVII) as a risk factor in myocardial infarction (MI) has been the subject of numerous studies. However, it remains uncertain whether the FVII levels are associated with development of MI. The subjects were 4142 men and women whose activated FVII (FVIIa) and FVII coagulant (FVIIc) levels were measured in the Jichi Medical School Cohort Study. Subjects were divided into tertiles by FVIIa and FVIIc levels, and Cox's proportional hazard model was used to calculate hazard ratios (HRs) for MI. The multivariate-adjusted HRs (95% confidential interval [CI]) for FVIIa in men were 0.67 (0.67-1.78) in tertile 2 (T2), and 0.52 (0.17-1.60) in T3. In women, the multivariate-adjusted HRs (95% CI) were 0.18 (0.02-1.60) in T2, and 0.39 (0.07-2.20) in T3. The multivariate-adjusted HRs (95% CI) for FVIIc in men were 0.54 (0.21-1.36) in T2, and 0.20 (0.04-0.91) in T3. In women, the multivariate-adjusted HRs (95% CI) were 0.44 (0.07-2.85) in T2, and 0.35 (0.06-2.22) in T3. We used T1 as a reference for all measures. Our findings revealed a significant association between low FVIIc level and incidence of MI in men. The FVIIa and FVIIc levels were inversely related to increased MI risk, but did not reach statistical significance. Future studies are needed to confirm this association. © 2017 Wiley Periodicals, Inc.

  3. Insulin-like growth factor-II regulates bone sialoprotein gene transcription.

    PubMed

    Choe, Jin; Sasaki, Yoko; Zhou, Liming; Takai, Hideki; Nakayama, Yohei; Ogata, Yorimasa

    2016-09-01

    Insulin-like growth factor-I and -II (IGF-I and IGF-II) have been found in bone extracts of several different species, and IGF-II is the most abundant growth factor stored in bone. Bone sialoprotein (BSP) is a noncollagenous extracellular matrix glycoprotein associated with mineralized connective tissues. In this study, we have investigated the regulation of BSP transcription by IGF-II in rat osteoblast-like ROS17/2.8 cells. IGF-II (50 ng/ml) increased BSP mRNA and protein levels after 6-h stimulation, and enhanced luciferase activities of the constructs pLUC3 (-116 to +60), pLUC4 (-425 to +60), pLUC5 (-801 to +60) and pLUC6 (-938 to +60). Effects of IGF-II were inhibited by tyrosine kinase, extracellular signal-regulated kinase1/2 and phosphatidylinositol 3-kinase inhibitors, and abrogated by 2-bp mutations in cAMP response element (CRE), FGF2 response element (FRE) and homeodomain protein-binding site (HOX). The results of gel shift assays showed that nuclear proteins binding to CRE, FRE and HOX sites were increased by IGF-II (50 ng/ml) at 3 and 6 h. CREB1, phospho-CREB1, c-Fos and c-Jun antibodies disrupted the formation of the CRE-protein complexes. Dlx5 and Runx2 antibodies disrupted the FRE- and HOX-protein complex formations. These studies therefore demonstrated that IGF-II increased BSP transcription by targeting CRE, FRE and HOX elements in the proximal promoter of the rat BSP gene. Moreover, phospho-CREB1, c-Fos, c-Jun, Dlx5 and Runx2 transcription factors appear to be key regulators of IGF-II effects on BSP transcription.

  4. Weather applications and products enabled through vehicle infrastructure integration (VII) : feasibility and concept development study

    DOT National Transportation Integrated Search

    2007-01-01

    Vehicle Infrastructure Integration (VII) involves the two-way wireless transmission of data from vehicle-to-vehicle and vehicle-to-infrastructure utilizing Dedicated Short Range Communications (DSRC). VII will enable the development of weather-relate...

  5. The Fokker "Trimotor F VII" commercial transport monoplane

    NASA Technical Reports Server (NTRS)

    1928-01-01

    Directly developed from the single engined type F VII ten passenger monoplanes, The Fokker Trimotor closely follows the commercial aircraft that preceded it. It has three Wright Whirlwind air-cooled engines, rated at 200 HP each.

  6. Production of coagulation factor VII in human cell lines Sk-Hep-1 and HKB-11.

    PubMed

    Corrêa de Freitas, Marcela Cristina; Bomfim, Aline de Sousa; Mizukami, Amanda; Picanço-Castro, Virgínia; Swiech, Kamilla; Covas, Dimas Tadeu

    2017-09-01

    Recombinant factor VII (rFVII) is the main therapeutic choice for hemophilia patients who have developed inhibitory antibodies against conventional treatments (FVIII and FIX). Because of the post-translational modifications, rFVII needs to be produced in mammalian cell lines. In this study, for the first time, we have shown efficient rFVII production in HepG2, Sk-Hep-1, and HKB-11 cell lines. Experiments in static conditions for a period of 96 h showed that HepG2-FVII produced the highest amounts of rhFVII, with an average of 1843 ng/mL. Sk-hep-1-FVII cells reached a maximum protein production of 1432 ng/mL and HKB-11-FVII cells reached 1468 ng/mL. Sk-Hep-1-rFVII and HKB-11-rFVII were selected for the first step of scale-up. Over 10 days of spinner flask culture, HKB-11 and SK-Hep-1 cells showed a cumulative production of rFVII of 152 μg and 202.6 μg in 50 mL, respectively. Thus, these human cell lines can be used for an efficient production of recombinant FVII. With more investment in basic research, human cell lines can be optimized for the commercial production of different bio therapeutic proteins. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Examination of the Beck Depression Inventory-II Factor Structure Among Bariatric Surgery Candidates.

    PubMed

    Hayes, Sharon; Stoeckel, Nina; Napolitano, Melissa A; Collins, Charlotte; Wood, G Craig; Seiler, Jamie; Grunwald, Heidi E; Foster, Gary D; Still, Christopher D

    2015-07-01

    The Beck Depression Inventory-II (BDI-II) is frequently used to evaluate bariatric patients in clinical and research settings; yet, there are limited data regarding the factor structure of the BDI-II with a bariatric surgery population. Exploratory factor analysis (EFA) using principal axis factoring with oblimin rotation was employed with data from 1228 consecutive presurgical bariatric candidates. Independent t tests were used to examine potential differences between sexes. Confirmatory factor analysis (CFA) was conducted with the next 383 consecutive presurgical patients to evaluate the proposed model based on EFA results. EFA revealed three factors: negative perceptions, diminished vigor, and cognitive dysregulation, each with adequate internal consistency. Six BDI-II items did not load significantly on any of the three factors. CFA results largely supported the proposed model. Results suggest that dimensions of depression for presurgical bariatric candidates vary from other populations and raise important caveats regarding the utility of the BDI-II in bariatric research.

  8. Treatment of lysosomal storage disease in MPS VII mice using a recombinant adeno-associated virus.

    PubMed

    Watson, G L; Sayles, J N; Chen, C; Elliger, S S; Elliger, C A; Raju, N R; Kurtzman, G J; Podsakoff, G M

    1998-12-01

    Mucopolysaccharidosis type VII (MPS VII) is a lysosomal storage disease caused by a genetic deficiency of beta-glucuronidase (GUS). We used a recombinant adeno-associated virus vector (AAV-GUS) to deliver GUS cDNA to MPS VII mice. The route of vector administration had a dramatic effect on the extent and distribution of GUS activity. Intramuscular injection of AAV-GUS resulted in high, localized production of GUS, while intravenous administration produced low GUS activity in several tissues. This latter treatment of MPS VII mice reduced glycosaminoglycan levels in the liver to normal and reduced storage granules dramatically. We show that a single administration of AAV-GUS can provide sustained expression of GUS in a variety of cell types and is sufficient to reverse the disease phenotype at least in the liver.

  9. The ice VII-ice X phase transition with implications for planetary interiors

    NASA Astrophysics Data System (ADS)

    Aarestad, B.; Frank, M. R.; Scott, H.; Bricker, M.; Prakapenka, V.

    2008-12-01

    A significant amount of research on the high pressure polymorphs of H2O have detailed the lattice structure and density of these phases, namely ice VI, ice VII, and ice X. These high pressure ices are noteworthy as they may comprise a considerable part of the interior of large icy planets and satellites. However, there is a dearth of data on how the incorporation of an impurity, charged or non-charged, affects the ice VII-ice X transition. This study examined the ice VII-ice X transition that occurs at approximately 62 GPa with a pure system and two select impure systems. Solutions of pure H2O, 1.6 mole percent NaCl in H2O, and 1.60 mole percent CH3OH in H2O were compressed in a diamond anvil cell (DAC). The experiments were performed at the GSECARS 13-BM-D beam line at the Advanced Photon Source at Argonne National Laboratory. Powder diffraction data of the ice samples were collected using monochromatic X-ray radiation, 0.2755 Å, and a MAR 345 online imaging system at intervals of approximately 2 GPa up to ~71.5, ~74.5, and ~68 GPa, respectively. Analyses of the data provided volume-pressure relations (at 298 K) which were used to detail the ice VII-ice X phase transition. The pressure of the phase transition, based upon an interpretation of the X-ray diffraction data, was found to vary as a function of the impurity type. Thus, the depth of the ice VII-ice X phase transition within an ice-rich planetary body can be influenced by trace-level impurities.

  10. The effect of neonatal gene therapy on skeletal manifestations in mucopolysaccharidosis VII dogs after a decade.

    PubMed

    Xing, Elizabeth M; Knox, Van W; O'Donnell, Patricia A; Sikura, Tracey; Liu, Yuli; Wu, Susan; Casal, Margret L; Haskins, Mark E; Ponder, Katherine P

    2013-06-01

    Mucopolysaccharidosis (MPS) VII is a lysosomal storage disease due to deficient activity of β-glucuronidase (GUSB), and results in glycosaminoglycan accumulation. Skeletal manifestations include bone dysplasia, degenerative joint disease, and growth retardation. One gene therapy approach for MPS VII involves neonatal intravenous injection of a gamma retroviral vector expressing GUSB, which results in stable expression in liver and secretion of enzyme into blood at levels predicted to be similar or higher to enzyme replacement therapy. The goal of this study was to evaluate the long-term effect of neonatal gene therapy on skeletal manifestations in MPS VII dogs. Treated MPS VII dogs could walk throughout their lives, while untreated MPS VII dogs could not stand beyond 6 months and were dead by 2 years. Luxation of the coxofemoral joint and the patella, dysplasia of the acetabulum and supracondylar ridge, deep erosions of the distal femur, and synovial hyperplasia were reduced, and the quality of articular bone was improved in treated dogs at 6 to 11 years of age compared with untreated MPS VII dogs at 2 years or less. However, treated dogs continued to have osteophyte formation, cartilage abnormalities, and an abnormal gait. Enzyme activity was found near synovial blood vessels, and there was 2% as much GUSB activity in synovial fluid as in serum. We conclude that neonatal gene therapy reduces skeletal abnormalities in MPS VII dogs, but clinically-relevant abnormalities remain. Enzyme replacement therapy will probably have similar limitations long-term. Copyright © 2013 Elsevier Inc. All rights reserved.

  11. Radiographic evaluation of bones and joints in mucopolysaccharidosis I and VII dogs after neonatal gene therapy.

    PubMed

    Herati, Ramin Sedaghat; Knox, Van W; O'Donnell, Patricia; D'Angelo, Marina; Haskins, Mark E; Ponder, Katherine P

    2008-11-01

    Mucopolysaccharidosis I (MPS I) and MPS VII are due to deficient activity of the glycosaminoglycan-degrading lysosomal enzymes alpha-L-iduronidase and beta-glucuronidase, respectively, and result in abnormal bones and joints. Here, the severity of skeletal disease in MPS I and MPS VII dogs and the effects of neonatal gene therapy were evaluated. For untreated MPS VII dogs, the lengths of the second cervical vertebrae (C2) and the femur were only 56% and 84% of normal, respectively, and bone dysplasia and articular erosions, and joint subluxation were severe. Previously, we reported that neonatal intravenous injection of a retroviral vector (RV) with the appropriate gene resulted in expression in liver and blood cells, and high serum enzyme activity. In this study, we demonstrate that C2 and femurs of RV-treated MPS VII dogs were longer at 82% and 101% of normal, respectively, and there were partial improvements of qualitative abnormalities. For untreated MPS I dogs, the lengths of C2 and femurs (91% and 96% of normal, respectively) were not significantly different from normal dogs. Qualitative changes in MPS I bones and joints were generally modest and were partially improved with RV treatment, although cervical spine disease was severe and was difficult to correct with gene therapy in both models. The greater severity of skeletal disease in MPS VII than in MPS I dogs may reflect accumulation of chondroitin sulfate in cartilage in MPS VII, or could relate to the specific mutations. Neonatal RV-mediated gene therapy ameliorates, but does not prevent, skeletal disease in MPS I and MPS VII dogs.

  12. 76 FR 57013 - Recordkeeping and Reporting Requirements Under Title VII, the ADA, and GINA

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-15

    ... EQUAL EMPLOYMENT OPPORTUNITY COMMISSION 29 CFR Part 1602 RIN 3046-AA89 Recordkeeping and Reporting Requirements Under Title VII, the ADA, and GINA AGENCY: Equal Employment Opportunity Commission. ACTION... under title VII, the ADA, and GINA. (76 FR 31892, June 2, 2011). No requests to present oral testimony...

  13. [Significance of vitamin K (VK) administration in patients under chemotherapy during postoperative fasting period].

    PubMed

    Ojiro, M; Takenoshita, M; Toshinaga, T; Shimazu, H

    1992-01-01

    Recently coagulopathy caused by vitamin K (VK) deficiency following antibiotic therapy in malnourished patients has been reported. We studied on the same problem particularly in patients under chemotherapy during postoperative fasting period. For this purpose, prothrombin time (PT), vitamin K-dependent coagulation factors (Factor II (F-II), VII (F-VII) and protein C), PIVKA-II (PK-II) and plasma level of VK in two groups of patients with or without VK administration were measured in esophageal cancer patients. In the group with VK, VK2 were given intravenously everyday. In the group without VK, PT prolonged and F-II decreased from the seventh postoperative day, especially on the 14th day significantly. Although F-VII and protein C decreased on the first day and returned subsequently on the seventh day, no significance was observed between two groups. PK-II increased clearly in the group without VK from the seventh day, whereas no significant changes were observed in the group with VK. The plasma level of VK1 decreased in both groups, but VK2, especially MK-4, was high in the group with VK.

  14. 1990 Clean Air Act Amendment Summary: Title VII

    EPA Pesticide Factsheets

    This page provides an overview of the 1990 amendments to Title VII of the Clean Air Act, which were enacted to curb acid rain, urban air pollution and toxic air emissions. The edits to this title deal with enforcement provisions.

  15. Ice-VII inclusions in diamonds: Evidence for aqueous fluid in Earth’s deep mantle

    NASA Astrophysics Data System (ADS)

    Tschauner, O.; Huang, S.; Greenberg, E.; Prakapenka, V. B.; Ma, C.; Rossman, G. R.; Shen, A. H.; Zhang, D.; Newville, M.; Lanzirotti, A.; Tait, K.

    2018-03-01

    Water-rich regions in Earth’s deeper mantle are suspected to play a key role in the global water budget and the mobility of heat-generating elements. We show that ice-VII occurs as inclusions in natural diamond and serves as an indicator for such water-rich regions. Ice-VII, the residue of aqueous fluid present during growth of diamond, crystallizes upon ascent of the host diamonds but remains at pressures as high as 24 gigapascals; it is now recognized as a mineral by the International Mineralogical Association. In particular, ice-VII in diamonds points toward fluid-rich locations in the upper transition zone and around the 660-kilometer boundary.

  16. 20 CFR Appendix Vii to Subpart C... - “Old-Law” Contribution and Benefit Base

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... Appendix VII to Subpart C of Part 404 Employees' Benefits SOCIAL SECURITY ADMINISTRATION FEDERAL OLD-AGE, SURVIVORS AND DISABILITY INSURANCE (1950- ) Computing Primary Insurance Amounts Pt. 404, Subpt. C, App. VII... Security Act without the enactment of the 1977 amendments. Year Amount 1979 $18,900 1980 20,400 1981 22,200...

  17. 40 CFR 86.1806-04 - On-board diagnostics.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 2002). (vii) As an alternative to the above standards, heavy-duty vehicles may conform to the... standards shall utilize multiplicative factors from the California vehicle type (i.e. LEV II, ULEV II... standards shall utilize the Tier 2 Bin 4 emission standards and the CARB ULEV II multiplicative factors to...

  18. Specific DNA binding of a potential transcriptional regulator, inosine 5'-monophosphate dehydrogenase-related protein VII, to the promoter region of a methyl coenzyme m reductase I-encoding operon retrieved from Methanothermobacter thermautotrophicus strain DeltaH.

    PubMed

    Shinzato, Naoya; Enoki, Miho; Sato, Hiroaki; Nakamura, Kohei; Matsui, Toru; Kamagata, Yoichi

    2008-10-01

    Two methyl coenzyme M reductases (MCRs) encoded by the mcr and mrt operons of the hydrogenotrophic methanogen Methanothermobacter thermautotrophicus DeltaH are expressed in response to H(2) availability. In the present study, cis elements and trans-acting factors responsible for the gene expression of MCRs were investigated by using electrophoretic mobility shift assay (EMSA) and affinity particle purification. A survey of their operator regions by EMSA with protein extracts from mrt-expressing cultures restricted them to 46- and 41-bp-long mcr and mrt upstream regions, respectively. Affinity particle purification of DNA-binding proteins conjugated with putative operator regions resulted in the retrieval of a protein attributed to IMP dehydrogenase-related protein VII (IMPDH VII). IMPDH VII is predicted to have a winged helix-turn-helix DNA-binding motif and two cystathionine beta-synthase domains, and it has been suspected to be an energy-sensing module. EMSA with oligonucleotide probes with unusual sequences showed that the binding site of IMPDH VII mostly overlaps the factor B-responsible element-TATA box of the mcr operon. The results presented here suggest that IMPDH VII encoded by MTH126 is a plausible candidate for the transcriptional regulator of the mcr operon in this methanogen.

  19. Radiographic Evaluation of Bones and Joints in Mucopolysaccharidosis I and VII Dogs After Neonatal Gene Therapy

    PubMed Central

    Herati, Ramin Sedaghat; Knox, Van W.; O’Donnell, Patricia; D’Angelo, Marina; Haskins, Mark E.; Ponder, Katherine P.

    2009-01-01

    Mucopolysaccharidosis I (MPS I) and MPS VII are due to deficient activity of the glycosaminoglycan-degrading lysosomal enzymes α-L-iduronidase and β-glucuronidase, respectively, and result in abnormal bones and joints. Here, the severity of skeletal disease in MPS I and MPS VII dogs and the effects of neonatal gene therapy were evaluated. For untreated MPS VII dogs, the lengths of the second cervical vertebrae (C2) and the femur were only 56% and 84% of normal, respectively, and bone dysplasia and articular erosions, and joint subluxation were severe. Previously, we reported that neonatal intravenous injection of a retroviral vector (RV) with the appropriate gene resulted in expression in liver and blood cells, and high serum enzyme activity. In this study, we demonstrate that C2 and femurs of RV-treated MPS VII dogs were longer at 82% and 101% of normal, respectively, and there were partial improvements of qualitative abnormalities. For untreated MPS I dogs, the lengths of C2 and femurs (91% and 96% of normal, respectively) were not significantly different from normal dogs. Qualitative changes in MPS I bones and joints were generally modest and were partially improved with RV treatment, although cervical spine disease was severe and was difficult to correct with gene therapy in both models. The greater severity of skeletal disease in MPS VII than in MPS I dogs may reflect accumulation of chondroitin sulfate in cartilage in MPS VII, or could relate to the specific mutations. Neonatal RV-mediated gene therapy ameliorates, but does not prevent, skeletal disease in MPS I and MPS VII dogs. PMID:18707908

  20. Anti-Type VII Collagen Antibodies Are Identified in a Subpopulation of Bullous Pemphigoid Patients With Relapse

    PubMed Central

    Giusti, Delphine; Gatouillat, Grégory; Le Jan, Sébastien; Plée, Julie; Bernard, Philippe; Antonicelli, Frank; Pham, Bach-Nga

    2018-01-01

    Bullous pemphigoid (BP) is an autoimmune bullous skin disease characterized by anti-BP180 and anti-BP230 autoantibodies (AAbs). Mucous membrane involvement is an uncommon clinical feature of BP which may evoke epidermolysis bullosa acquisita, another skin autoimmune disease characterized by anti-type VII collagen AAbs. We therefore evaluated the presence of anti-type VII collagen AAbs in the serum of BP patients with and without mucosal lesions at time of diagnosis and under therapy. Anti-BP180, anti-BP230, and anti-type VII collagen AAbs were measured by ELISA in the serum of unselected patients fulfilling clinical and histo/immunopathological BP criteria at baseline (n = 71) and at time of relapse (n = 24). At baseline, anti-type VII collagen AAbs were detected in 2 out of 24 patients with BP presenting with mucosal involvement, but not in patients without mucosal lesions (n = 47). At the time of relapse, 10 out of 24 BP patients either displayed a significant induction or increase of concentrations of anti-type VII collagen AAbs (P < 0.01), independently of mucosal involvement. Those 10 relapsing BP patients were also characterized by a sustained high concentration of anti-BP180 AAb, whereas the serum anti-BP230 AAb concentrations did not vary in BP patients with relapse according to the presence of anti-type VII collagen AAbs. Thus, our study showed that anti-type VII collagen along with anti-BP180 AAbs detection stratified BP patients at time of relapse, illustrating a still dysregulated immune response that could reflect a potential epitope spreading mechanism in those BP patients. PMID:29619029

  1. A presomite human embryo of Horizon VII.

    PubMed Central

    Rewell, R E; Harrison, R G

    1976-01-01

    A presomite embryo of Horizon VII aged approximately 18 days is described and illustrated. It is compared with some other embryos of a similar age, and a considerable variation of histological characteristics within the same Horizon is noted. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 PMID:1254532

  2. Employment Discrimination: Alternative Remedies to Title VII

    ERIC Educational Resources Information Center

    Whittier, Ann M.; Whittier, Gary L.

    1975-01-01

    This article is intended to familiarize Missouri lawyers with the advantages, limitations, and important procedural aspects of four remedies that can supplement or offer alternatives to Title VII litigation in appropriate situations: The Equal Pay Act; section 1983 of the Civil Rights Act of 1871, Executive Order No. 11,246, and the Missouri Fair…

  3. The hemostatic profile of recombinant activated factor VII. Can low concentrations stop bleeding in off-label indications?

    PubMed Central

    2010-01-01

    Background High concentrations of recombinant activated factor VII (rFVIIa) can stop bleeding in hemophilic patients. However the rFVIIa dose needed for stopping haemhorrage in off-label indications is unknown. Since thrombin is the main hemostatic agent, this study investigated the effect of rFVIIa and tissue factor (TF) on thrombin generation (TG) in vitro. Methods Lag time (LT), time to peak (TTP), peak TG (PTG), and area under the curve after 35 min (AUCo-35 min) with the calibrated automated thrombography was used to evaluate TG. TG was assayed in platelet-rich plasma (PRP) samples from 29 healthy volunteers under basal conditions and after platelet stimulation with 5.0 μg/ml, 2.6 μg/ml, 0.5 μg/ml, 0.25 μg/ml, and 0.125 μg/ml rFVIIa alone and in normal platelet-poor plasma (PPP) samples from 22 healthy volunteers, rFVIIa in combination with various concentrations of TF (5.0, 2.5, 1.25 and 0.5 pM). Results In PRP activated by rFVIIa, there was a statistically significant increase in TG compared to basal values. A significant TF dose-dependent shortening of LT and increased PTG and AUCo→35 min were obtained in PPP. The addition of rFVIIa increased the effect of TF in shorting the LT and increasing the AUCo→35 min with no effect on PTG but were independent of rFVIIa concentration. Conclusion Low concentrations of rFVIIa were sufficient to form enough thrombin in normal PRP or in PPP when combined with TF, and suggest low concentrations for normalizing hemostasis in off-label indications. PMID:20444280

  4. Monthly haemostatic factor variability in women and men.

    PubMed

    Hill, Alison M; Stewart, Paul W; Fung, Mark K; Kris-Etherton, Penny M; Ginsberg, Henry N; Tracy, Russell P; Pearson, Thomas A; Lefevre, Michael; Reed, Roberta G; Elmer, Patricia J; Holleran, Stephen; Ershow, Abby G

    2014-01-01

    Hormonal status influences haemostatic factors including fibrinogen, factor VII and plasminogen activator inhibitor (PAI-1), and concentrations differ among men, premenopausal and postmenopausal women. This study examines how phases of the menstrual cycle influence variability of fibrinogen, factor VII and PAI-1. We studied 103 subjects (39 premenopausal women, 18 postmenopausal women and 46 men) during three, randomized, 8-week energy- and nutrient-controlled experimental diets in the Dietary Effects on Lipids and Thrombogenic Activity (DELTA) Study. Fasting blood samples were collected weekly during the last 4 weeks of each diet period, and haemostatic factors were quantified. Two linear mixed-effects models were used for fibrinogen, factor VII and PAI-1: one to estimate and compare group-specific components of variance, and the other to estimate additional fixed effects representing cyclical functions of day of menstrual cycle in premenopausal women. Systematic cyclical variation with day of menstrual cycle was observed for fibrinogen (P < 0.0001), factor VII (P = 0.0012) and PAI-1 (P = 0.0024) in premenopausal women. However, the amplitude of cycling was small relative to the total magnitude of intra-individual variability. In addition, the intra-individual variance and corresponding coefficient of variation observed in premenopausal women did not differ from postmenopausal women and men. The variability in haemostatic factors in premenopausal women is no greater than for postmenopausal women or men. Consequently, premenopausal women can be included in studies investigating haemostatic factor responses without controlling for stage of menstrual cycle. © 2014 Stichting European Society for Clinical Investigation Journal Foundation.

  5. Ice-VII inclusions in diamonds: Evidence for aqueous fluid in Earth's deep mantle.

    PubMed

    Tschauner, O; Huang, S; Greenberg, E; Prakapenka, V B; Ma, C; Rossman, G R; Shen, A H; Zhang, D; Newville, M; Lanzirotti, A; Tait, K

    2018-03-09

    Water-rich regions in Earth's deeper mantle are suspected to play a key role in the global water budget and the mobility of heat-generating elements. We show that ice-VII occurs as inclusions in natural diamond and serves as an indicator for such water-rich regions. Ice-VII, the residue of aqueous fluid present during growth of diamond, crystallizes upon ascent of the host diamonds but remains at pressures as high as 24 gigapascals; it is now recognized as a mineral by the International Mineralogical Association. In particular, ice-VII in diamonds points toward fluid-rich locations in the upper transition zone and around the 660-kilometer boundary. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

  6. Active site mutant transgene confers tolerance to human β-glucuronidase without affecting the phenotype of MPS VII mice

    PubMed Central

    Sly, William S.; Vogler, Carole; Grubb, Jeffrey H.; Zhou, Mi; Jiang, Jinxing; Zhou, Xiao Yan; Tomatsu, Shunji; Bi, Yanhua; Snella, Elizabeth M.

    2001-01-01

    Mucopolysaccharidosis type VII (MPS VII; Sly syndrome) is an autosomal recessive lysosomal storage disorder due to an inherited deficiency of β-glucuronidase. A naturally occurring mouse model for this disease was discovered at The Jackson Laboratory and shown to be due to homozygosity for a 1-bp deletion in exon 10 of the gus gene. The murine model MPS VII (gusmps/mps) has been very well characterized and used extensively to evaluate experimental strategies for lysosomal storage diseases, including bone marrow transplantation, enzyme replacement therapy, and gene therapy. To enhance the value of this model for enzyme and gene therapy, we produced a transgenic mouse expressing the human β-glucuronidase cDNA with an amino acid substitution at the active site nucleophile (E540A) and bred it onto the MPS VII (gusmps/mps) background. We demonstrate here that the mutant mice bearing the active site mutant human transgene retain the clinical, morphological, biochemical, and histopathological characteristics of the original MPS VII (gusmps/mps) mouse. However, they are now tolerant to immune challenge with human β-glucuronidase. This “tolerant MPS VII mouse model” should be useful for preclinical trials evaluating the effectiveness of enzyme and/or gene therapy with the human gene products likely to be administered to human patients with MPS VII. PMID:11226217

  7. Subjective Criteria in Employment Decisions Under Title VII

    ERIC Educational Resources Information Center

    Stacy, Donald R.

    1976-01-01

    Since higher echelon jobs have been drawn into litigation under Title VII, subjective criteria have been employed. The legal ramifications of assessing noncognitive traits such as leadership, aggressiveness, and attitude are discussed. Available from: the University of Georgia School of Law, Athens, Georgia 30602. (LBH)

  8. A systematic review and meta-analysis of diagnostic test of MRA versus MRI for detection superior labrum anterior to posterior lesions type II-VII.

    PubMed

    Arirachakaran, Alisara; Boonard, Manusak; Chaijenkij, Kornkit; Pituckanotai, Kwanchai; Prommahachai, Akom; Kongtharvonskul, Jatupon

    2017-02-01

    To determine the diagnostic performance of magnetic resonance arthrography (MRA) and magnetic resonance imaging (MRI) in superior labrum anterior to posterior lesions (type II-VII) of the shoulder. PubMed and Scopus search engines, an electronic search of articles was performed from inception to February 19, 2016. Diagnostic performance of index tests was compared by the summary area under receiver operator characteristic curve (AUROC). In all, 117 of 493 studies were eligible and 32 studies (2,013 shoulders) and 11 studies (1,498 shoulders) were evaluated with MRA and MRI. The summary sensitivity, specificity, likelihood ratio (positive and negative) and AUROC were 0.87 (95 % confidence interval, CI: 0.82, 0.91), 0.92 (95 %CI: 0.85, 0.95), 10.28 (95 %CI: 5.84, 18.08), 0.14 (95 %CI: 0.10, 0.20) and 0.94 (95 %CI: 0.92, 0.96) respectively for MRA, and 0.76 (95 %CI: 0.61, 0.86), 0.87 (95 %CI: 0.71, 0.95), 5.89 (95 %CI: 2.5, 13.86), 0.28 (95 %CI: 0.17, 0.47) and 0.94 (95 %CI: 0.92, 0.96) respectively for MRI. The diagnostic performance of MRA was superior to MRI by both direct and indirect comparisons for the detection of SLAP lesions.

  9. 20 CFR Appendix Vii to Subpart C... - “Old-Law” Contribution and Benefit Base

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 20 Employees' Benefits 2 2013-04-01 2013-04-01 false âOld-Lawâ Contribution and Benefit Base VII... Appendix VII to Subpart C of Part 404—“Old-Law” Contribution and Benefit Base Explanation: We use these... appendix IV). This is the contribution and benefit base that would have been effective under the Social...

  10. Release of the ENDF/B-VII.1 Evaluated Nuclear Data File

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Brown, David

    2012-06-30

    The Cross Section Evaluation Working Group (CSEWG) released the ENDF/B-VII.1 library on December 22, 2011. The ENDF/B-VII.1 library is CSEWG's latest recommended evaluated nuclear data file for use in nuclear science and technology applications, and incorporates advances made in the five years since the release of ENDF/B-VII.0, including: many new evaluation in the neutron sublibrary (423 in all and over 190 of these contain covariances), new fission product yields and a greatly improved decay data sublibrary. This summary barely touches on the five years worth of advances present in the ENDF/B-VII.1 library. We expect that these changes will lead tomore » improved integral performance in reactors and other applications. Furthermore, the expansion of covariance data in this release will allow for better uncertainty quantification, reducing design margins and costs. The ENDF library is an ongoing and evolving effort. Currently, the ENDF data community embarking on several parallel efforts to improve library management: (1) The adoption of a continuous integration system to provide evaluators 'instant' feedback on the quality of their evaluations and to provide data users with working 'beta' quality libraries in between major releases. (2) The transition to new hierarchical data format - the Generalized Nuclear Data (GND) format. We expect GND to enable new kinds of evaluated data which cannot be accommodated in the legacy ENDF format. (3) The development of data assimilation and uncertainty propagation techniques to enable the consistent use of integral experimental data in the evaluation process.« less

  11. Factor VII deficiency: Unveiling the cellular and molecular mechanisms underlying three model alterations of the enzyme catalytic domain.

    PubMed

    Chollet, Maria Eugenia; Andersen, Elisabeth; Skarpen, Ellen; Myklebust, Christiane F; Koehler, Christian; Morth, Jens Preben; Chuansumrit, Ampaiwan; Pinotti, Mirko; Bernardi, Francesco; Thiede, Bernd; Sandset, Per Morten; Skretting, Grethe

    2018-03-01

    Activated factor (F) VII is a vitamin K-dependent glycoprotein that initiates blood coagulation upon interaction with tissue factor. FVII deficiency is the most common of the rare congenital bleeding disorders. While the mutational pattern has been extensively characterized, the pathogenic molecular mechanisms of mutations, particularly at the intracellular level, have been poorly defined. Here, we aimed at elucidating the mechanisms underlying altered FVII biosynthesis in the presence of three mutation types in the catalytic domain: a missense change, a microdeletion and a frameshift/elongation, associated with severe or moderate to severe phenotypes. Using CHO-K1 cells transiently transfected with expression vectors containing the wild-type FVII cDNA (FVIIwt) or harboring the p.I289del, p.G420V or p.A354V-p.P464Hfs mutations, we found that the secretion of the FVII mutants was severely decreased compared to FVIIwt. The synthesis rate of the mutants was slower than the FVIIwt and delayed, and no degradation of the FVII mutants by proteasomes, lysosomes or cysteine proteases was observed. Confocal immunofluorescence microscopy studies showed that FVII variants were localized into the endoplasmic reticulum (ER) but were not detectable within the Golgi apparatus. These findings suggested that a common pathogenic mechanism, possibly a defective folding of the mutant proteins, was triggered by the FVII mutations. The misfolded state led to impaired trafficking of these proteins causing ER retention, which would explain the low to very low FVII plasma levels observed in patients carrying these mutations. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. The molecular basis of low activity levels of coagulation factor VII: a Brazilian cohort.

    PubMed

    Rabelo, F Y; Jardim, L L; Landau, M B; Gadelha, T; Corrêa, M F B; Pereira, I F M; Rezende, S M

    2015-09-01

    Inherited factor VII (FVII) deficiency is the most common among the rare bleeding disorders. It is transmitted as an autosomal recessive inheritance, due to mutations in the FVII gene (F7). Molecular studies of FVII deficiency are rare in non-Caucasian populations. The aim of the study was to evaluate the molecular basis behind low levels of FVII activity (FVII:C) levels in a cohort of Brazilian patients. A total of 34 patients with low FVII levels were clinically evaluated and submitted to laboratory tests, among these, prothrombin time and FVII:C, with different thromboplastins. All exons and intron/exon boundaries of F7 were amplified and sequenced. A total of 14 genetic alterations were identified, of which six were described previously, c.1091G>A, c.1151C>T, c.-323_-313insCCTATATCCT, c.285G>A, c.525C>T, c.1238G>A and eight (54.0%) and eight were new, c.128G>A, c.252C>T, c.348G>A, c.417G>A, c.426G>A, c.745_747delGTG, c.843G>A and c.805+52C>T. In addition to the mutation c.1091G>A, known as FVII Padua, the mutation c.1151C>T also presented discrepant FVII:C levels when tested with human and rabbit brain thromboplastin. There was no association between phenotype and genotype. Most of the identified genetic alterations found were polymorphisms. Low levels of FVII:C in this population were mostly related to polymorphisms in F7 and associated with a mild clinical phenotype. Mutation c.1151C>T was associated with discrepant levels of FVII:C using different thromboplastins, such as reported with FVII Padua. © 2015 John Wiley & Sons Ltd.

  13. Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage.

    PubMed

    Mayer, Stephan A; Brun, Nikolai C; Begtrup, Kamilla; Broderick, Joseph; Davis, Stephen; Diringer, Michael N; Skolnick, Brett E; Steiner, Thorsten

    2008-05-15

    Intracerebral hemorrhage is the least treatable form of stroke. We performed this phase 3 trial to confirm a previous study in which recombinant activated factor VII (rFVIIa) reduced growth of the hematoma and improved survival and functional outcomes. We randomly assigned 841 patients with intracerebral hemorrhage to receive placebo (268 patients), 20 microg of rFVIIa per kilogram of body weight (276 patients), or 80 microg of rFVIIa per kilogram (297 patients) within 4 hours after the onset of stroke. The primary end point was poor outcome, defined as severe disability or death according to the modified Rankin scale 90 days after the stroke. Treatment with 80 microg of rFVIIa per kilogram resulted in a significant reduction in growth in volume of the hemorrhage. The mean estimated increase in volume of the intracerebral hemorrhage at 24 hours was 26% in the placebo group, as compared with 18% in the group receiving 20 microg of rFVIIa per kilogram (P=0.09) and 11% in the group receiving 80 microg (P<0.001). The growth in volume of intracerebral hemorrhage was reduced by 2.6 ml (95% confidence interval [CI], -0.3 to 5.5; P=0.08) in the group receiving 20 microg of rFVIIa per kilogram and by 3.8 ml (95% CI, 0.9 to 6.7; P=0.009) in the group receiving 80 microg, as compared with the placebo group. Despite this reduction in bleeding, there was no significant difference among the three groups in the proportion of patients with poor clinical outcome (24% in the placebo group, 26% in the group receiving 20 microg of rFVIIa per kilogram, and 29% in the group receiving 80 microg). The overall frequency of thromboembolic serious adverse events was similar in the three groups; however, arterial events were more frequent in the group receiving 80 microg of rFVIIa than in the placebo group (9% vs. 4%, P=0.04). Hemostatic therapy with rFVIIa reduced growth of the hematoma but did not improve survival or functional outcome after intracerebral hemorrhage. (Clinical

  14. Dynamic expression of transcription factor Brn3b during mouse cranial nerve development

    PubMed Central

    Sajgo, Szilard; Ali, Seid; Popescu, Octavian; Badea, Tudor Constantin

    2015-01-01

    During development transcription factor combinatorial codes define a large variety of morphologically and physiologically distinct neurons. Such a combinatorial code has been proposed for the differentiation of projection neurons of the somatic and visceral components of cranial nerves. It is possible that individual neuronal cell types are not specified by unique transcription factors, but rather emerge through the intersection of their expression domains. Brn3a, Brn3b and Brn3c, in combination with each other and/or transcription factors of other families, can define subgroups of Retinal Ganglion Cells (RGC), Spiral and Vestibular Ganglia, inner ear and vestibular hair cell neurons in the vestibuloacoustic system, and groups of somatosensory neurons in the Dorsal Root Ganglia (DRG). In the present study we investigated the expression and potential role of the Brn3b transcription factor in cranial nerves and associated nuclei of the brainstem. We report the dynamic expression of Brn3b in the somatosensory component of cranial nerves II, V, VII and VIII and visceromotor nuclei of nerves VII, IX, X, as well as other brainstem nuclei during different stages of development into adult stage. We find that genetically identified Brn3bKO RGC axons show correct but delayed pathfinding during the early stages of embryonic development. However loss of Brn3b does not affect the anatomy of the other cranial nerves normally expressing this transcription factor. PMID:26356988

  15. 48 CFR 952.227-14 - Rights in data-general. (DOE coverage-alternates VI and VII)

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    .... (DOE coverage-alternates VI and VII) 952.227-14 Section 952.227-14 Federal Acquisition Regulations System DEPARTMENT OF ENERGY CLAUSES AND FORMS SOLICITATION PROVISIONS AND CONTRACT CLAUSES Text of Provisions and Clauses 952.227-14 Rights in data-general. (DOE coverage—alternates VI and VII) Alternate VI...

  16. 48 CFR 952.227-14 - Rights in data-general. (DOE coverage-alternates VI and VII)

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    .... (DOE coverage-alternates VI and VII) 952.227-14 Section 952.227-14 Federal Acquisition Regulations System DEPARTMENT OF ENERGY CLAUSES AND FORMS SOLICITATION PROVISIONS AND CONTRACT CLAUSES Text of Provisions and Clauses 952.227-14 Rights in data-general. (DOE coverage—alternates VI and VII) Alternate VI...

  17. 48 CFR 952.227-14 - Rights in data-general. (DOE coverage-alternates VI and VII)

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    .... (DOE coverage-alternates VI and VII) 952.227-14 Section 952.227-14 Federal Acquisition Regulations System DEPARTMENT OF ENERGY CLAUSES AND FORMS SOLICITATION PROVISIONS AND CONTRACT CLAUSES Text of Provisions and Clauses 952.227-14 Rights in data-general. (DOE coverage—alternates VI and VII) Alternate VI...

  18. Intraoperative use of low-dose recombinant activated factor VII during thoracic aortic operations.

    PubMed

    Andersen, Nicholas D; Bhattacharya, Syamal D; Williams, Judson B; Fosbol, Emil L; Lockhart, Evelyn L; Patel, Mayur B; Gaca, Jeffrey G; Welsby, Ian J; Hughes, G Chad

    2012-06-01

    Numerous studies have supported the effectiveness of recombinant activated factor VII (rFVIIa) for the control of bleeding after cardiac procedures; however safety concerns persist. Here we report the novel use of intraoperative low-dose rFVIIa in thoracic aortic operations, a strategy intended to improve safety by minimizing rFVIIa exposure. Between July 2005 and December 2010, 425 consecutive patients at a single referral center underwent thoracic aortic operations with cardiopulmonary bypass (CPB); 77 of these patients received intraoperative low-dose rFVIIa (≤60 μg/kg) for severe coagulopathy after CPB. Propensity matching produced a cohort of 88 patients (44 received intraoperative low-dose rFVIIa and 44 controls) for comparison. Matched patients receiving intraoperative low-dose rFVIIa got an initial median dose of 32 μg/kg (interquartile range [IQR], 16-43 μg/kg) rFVIIa given 51 minutes (42-67 minutes) after separation from CPB. Patients receiving intraoperative low-dose rFVIIa demonstrated improved postoperative coagulation measurements (partial thromboplastin time 28.6 versus 31.5 seconds; p=0.05; international normalized ratio, 0.8 versus 1.2; p<0.0001) and received 50% fewer postoperative blood product transfusions (2.5 versus 5.0 units; p=0.05) compared with control patients. No patient receiving intraoperative low-dose rFVIIa required postoperative rFVIIa administration or reexploration for bleeding. Rates of stroke, thromboembolism, myocardial infarction, and other adverse events were equivalent between groups. Intraoperative low-dose rFVIIa led to improved postoperative hemostasis with no apparent increase in adverse events. Intraoperative rFVIIa administration in appropriately selected patients may correct coagulopathy early in the course of refractory blood loss and lead to improved safety through the use of smaller rFVIIa doses. Appropriately powered randomized studies are necessary to confirm the safety and efficacy of this approach

  19. Large-scale production and properties of human plasma-derived activated Factor VII concentrate.

    PubMed

    Tomokiyo, K; Yano, H; Imamura, M; Nakano, Y; Nakagaki, T; Ogata, Y; Terano, T; Miyamoto, S; Funatsu, A

    2003-01-01

    An activated Factor VII (FVIIa) concentrate, prepared from human plasma on a large scale, has to date not been available for clinical use for haemophiliacs with antibodies against FVIII and FIX. In the present study, we attempted to establish a large-scale manufacturing process to obtain plasma-derived FVIIa concentrate with high recovery and safety, and to characterize its biochemical and biological properties. FVII was purified from human cryoprecipitate-poor plasma, by a combination of anion exchange and immunoaffinity chromatography, using Ca2+-dependent anti-FVII monoclonal antibody. To activate FVII, a FVII preparation that was nanofiltered using a Bemberg Microporous Membrane-15 nm was partially converted to FVIIa by autoactivation on an anion-exchange resin. The residual FVII in the FVII and FVIIa mixture was completely activated by further incubating the mixture in the presence of Ca2+ for 18 h at 10 degrees C, without any additional activators. For preparation of the FVIIa concentrate, after dialysis of FVIIa against 20 mm citrate, pH 6.9, containing 13 mm glycine and 240 mm NaCl, the FVIIa preparation was supplemented with 2.5% human albumin (which was first pasteurized at 60 degrees C for 10 h) and lyophilized in vials. To inactivate viruses contaminating the FVIIa concentrate, the lyophilized product was further heated at 65 degrees C for 96 h in a water bath. Total recovery of FVII from 15 000 l of plasma was approximately 40%, and the FVII preparation was fully converted to FVIIa with trace amounts of degraded products (FVIIabeta and FVIIagamma). The specific activity of the FVIIa was approximately 40 U/ micro g. Furthermore, virus-spiking tests demonstrated that immunoaffinity chromatography, nanofiltration and dry-heating effectively removed and inactivated the spiked viruses in the FVIIa. These results indicated that the FVIIa concentrate had both high specific activity and safety. We established a large-scale manufacturing process of human plasma

  20. PET Imaging of Tissue Factor in Pancreatic Cancer Using 64Cu-Labeled Active Site-Inhibited Factor VII.

    PubMed

    Nielsen, Carsten H; Jeppesen, Troels E; Kristensen, Lotte K; Jensen, Mette M; El Ali, Henrik H; Madsen, Jacob; Wiinberg, Bo; Petersen, Lars C; Kjaer, Andreas

    2016-07-01

    Tissue factor (TF) is the main initiator of the extrinsic coagulation cascade. However, TF also plays an important role in cancer. TF expression has been reported in 53%-89% of all pancreatic adenocarcinomas, and the expression level of TF has in clinical studies correlated with advanced stage, increased microvessel density, metastasis, and poor overall survival. Imaging of TF expression is of clinical relevance as a prognostic biomarker and as a companion diagnostic for TF-directed therapies currently under clinical development. Factor VII (FVII) is the natural ligand to TF. The purpose of this study was to investigate the possibility of using active site-inhibited FVII (FVIIai) labeled with (64)Cu for PET imaging of TF expression. FVIIai was conjugated to 2-S-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA) and labeled with (64)Cu ((64)Cu-NOTA-FVIIai). Longitudinal in vivo PET imaging was performed at 1, 4, 15, and 36 h after injection of (64)Cu-NOTA-FVIIai in mice with pancreatic adenocarcinomas (BxPC-3). The specificity of TF imaging with (64)Cu-NOTA-FVIIai was investigated in subcutaneous pancreatic tumor models with different levels of TF expression and in a competition experiment. In addition, imaging of orthotopic pancreatic tumors was performed using (64)Cu-NOTA-FVIIai and PET/MRI. In vivo imaging data were supported by ex vivo biodistribution, flow cytometry, and immunohistochemistry. Longitudinal PET imaging with (64)Cu-NOTA-FVIIai showed a tumor uptake of 2.3 ± 0.2, 3.7 ± 0.3, 3.4 ± 0.3, and 2.4 ± 0.3 percentage injected dose per gram at 1, 4, 15, and 36 h after injection, respectively. An increase in tumor-to-normal-tissue contrast was observed over the imaging time course. Competition with unlabeled FVIIai significantly (P < 0.001) reduced the tumor uptake. The tumor uptake observed in models with different TF expression levels was significantly different from each other (P < 0.001) and was in agreement with

  1. Elevation of glycosaminoglycans in the amniotic fluid of a fetus with mucopolysaccharidosis VII

    PubMed Central

    Kubaski, Francyne; Brusius-Facchin, Ana Carolina; Mason, Robert W.; Patel, Pravin; Burin, Maira G.; Michelin-Tirelli, Kristiane; Kessler, Rejane Gus; Bender, Fernanda; Leistner-Segal, Sandra; Moreno, Carolina A.; Cavalcanti, Denise P.; Giugliani, Roberto; Tomatsu, Shunji

    2017-01-01

    Objective The aim of this study was to quantify GAGs in amniotic fluid (AF) from an MPS VII fetus compared with age-matched fetuses obtained from normal pregnancies. Method Disaccharides were measured by liquid chromatography tandem mass spectrometry (LC/MS/MS), compared to age-matched controls. Enzyme assay was performed in AF supernatant or cultured amniocytes. GUSB was analyzed by next generation sequencing using Ion Torrent Personal Genome Machine with a customized panel. Results No activity of β-glucuronidase was detected in fetal cells. The pregnancy was spontaneously terminated in the third trimester. Genetic studies identified a homozygous mutation of p.N379D (c.1135A>G) in the GUSB gene. LC/MS/MS showed that chondroitin sulfate, dermatan sulfate, heparan sulfate, and keratan sulfate levels were markedly increased in the MPS VII AF, compared to those in age-matched control AF (DS, HS, and C6S more than 10 × than age-matched controls; C4S and KS more than 3 times higher). Conclusion This is the first report of specific GAG analysis in AF from an MPS VII fetus, indicating that GAG elevation in AF occurs by 21 weeks of gestation and could be an additional tool for prenatal diagnosis of MPS VII and potentially other MPS types. PMID:28207930

  2. CASMO5 JENDL-4.0 and ENDF/B-VII.1beta4 libraries

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Rhodes, J.; Gheorghiu, N.; Ferrer, R.

    2012-07-01

    This paper details the generation of neutron data libraries for the CASMO5 lattice physics code based on the recently released JENDL-4.0 and ENDF/B-VII.1beta4 nuclear data evaluations. This data represents state-of-the-art nuclear data for late-2011. The key features of the new evaluations are briefly described along with the procedure for processing of this data into CASMO5, 586-energy group neutron data libraries. Finally some CASMO5 results for standard UO{sub 2} and MOX critical experiments for the two new libraries and the current ENDF/B-VII.0 CASMO5 library are presented including the B and W 1810 series, DIMPLE S06A, S06B, TCA reflector criticals with ironmore » plates and the PNL-30-35 MOX criticals. The results show that CASMO5 with the new libraries is performing well for these criticals with a very slight edge in results to the JENDL-4.0 nuclear data evaluation over the ENDF/B-VII.1beta4 evaluation. Work is currently underway to generate a CASMO5 library based on the final ENDF/B-VII.R1 evaluation released Dec. 22, 2011. (authors)« less

  3. Type VII collagen is enriched in the enamel organic matrix associated with the dentin-enamel junction of mature human teeth.

    PubMed

    McGuire, Jacob D; Walker, Mary P; Mousa, Ahmad; Wang, Yong; Gorski, Jeff P

    2014-06-01

    The inner enamel region of erupted teeth is known to exhibit higher fracture toughness and crack growth resistance than bulk phase enamel. However, an explanation for this behavior has been hampered by the lack of compositional information for the residual enamel organic matrix. Since enamel-forming ameloblasts are known to express type VII collagen and type VII collagen null mice display abnormal amelogenesis, the aim of this study was to determine whether type VII collagen is a component of the enamel organic matrix at the dentin-enamel junction (DEJ) of mature human teeth. Immunofluorescent confocal microscopy of demineralized tooth sections localized type VII collagen to the organic matrix surrounding individual enamel rods near the DEJ. Morphologically, immunoreactive type VII collagen helical-bundles resembled the gnarled-pattern of enamel rods detected by Coomassie Blue staining. Western blotting of whole crown or enamel matrix extracts also identified characteristic Mr=280 and 230 kDa type VII dimeric forms, which resolved into 75 and 25 kDa bands upon reduction. As expected, the collagenous domain of type VII collagen was resistant to pepsin digestion, but was susceptible to purified bacterial collagenase. These results demonstrate the inner enamel organic matrix in mature teeth contains macromolecular type VII collagen. Based on its physical association with the DEJ and its well-appreciated capacity to complex with other collagens, we hypothesize that enamel embedded type VII collagen fibrils may contribute not only to the structural resilience of enamel, but may also play a role in bonding enamel to dentin. Copyright © 2014 Elsevier Inc. All rights reserved.

  4. Type VII Collagen is Enriched in the Enamel Organic Matrix Associated with the Dentin-Enamel Junction of Mature Human Teeth

    PubMed Central

    McGuire, Jacob D.; Walker, Mary P.; Mousa, Ahmad; Wang, Yong; Gorski, Jeff P.

    2014-01-01

    The inner enamel region of erupted teeth is known to exhibit higher fracture toughness and crack growth resistance than bulk phase enamel. However, an explanation for this behavior has been hampered by the lack of compositional information for the residual enamel organic matrix. Since enamel-forming ameloblasts are known to express type VII collagen and type VII collagen null mice display abnormal amelogenesis, the aim of this study was to determine whether type VII collagen is a component of the enamel organic matrix at the dentin-enamel junction (DEJ) of mature human teeth. Immunofluorescent confocal microscopy of demineralized tooth sections localized type VII collagen to the organic matrix surrounding individual enamel rods near the DEJ. Morphologically, immunoreactive type VII collagen helical-bundles resembled the gnarled-pattern of enamel rods detected by Coomassie Blue staining. Western blotting of whole crown or enamel matrix extracts also identified characteristic Mr=280 and 230 kDa type VII dimeric forms, which resolved into 75 and 25 kDa bands upon reduction. As expected, the collagenous domain of type VII collagen was resistant to pepsin digestion, but was susceptible to purified bacterial collagenase. These results demonstrate the inner enamel organic matrix in mature teeth contains macromolecular type VII collagen. Based on its physical association with the DEJ and its well-appreciated capacity to complex with other collagens, we hypothesize that enamel embedded type VII collagen fibrils may contribute not only to the structural resilience of enamel, but may also play a role in bonding enamel to dentin. PMID:24594343

  5. Demonstration of resonant photopumping of Mo VII by Mo XII for a VUV laser near 600 {Angstrom}

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Ilcisin, K.J.; Aumayr, F.; Schwob, J.L.

    1993-09-01

    We present data of experiments on the resonant photopumping of Mo VII by Mo XII as a method of generating a coherent VUV source near 600 {angstrom}. The experiment is based on a scheme proposed by Feldman and Reader in which the 4p{sup 6} -- 4p{sup 5}6s transition in Mo VII in resonantly photopumped by the 5s {sup 2}S{sub 1/2} -- 4p {sup 2}P{sub 1/2} transition in Mo XII. Results of the laser produced plasma experiments show the successful enhancement of the population of the Mo VII 4p{sup 5}6s upper lasing level when pumped by an adjacent Mo VII plasma.more » No enhancement was seen in a control experiment where the Mo VII plasma was pumped by a Zr X plasma. Improvements of the intensity of the Mo XII pump source, achieved using an additional pump laser, lead to the generation of a population inversion for the VUV transition.« less

  6. A Joint Model for Vitamin K-Dependent Clotting Factors and Anticoagulation Proteins.

    PubMed

    Ooi, Qing Xi; Wright, Daniel F B; Tait, R Campbell; Isbister, Geoffrey K; Duffull, Stephen B

    2017-12-01

    Warfarin acts by inhibiting the reduction of vitamin K (VK) to its active form, thereby decreasing the production of VK-dependent coagulation proteins. The aim of this research is to develop a joint model for the VK-dependent clotting factors II, VII, IX and X, and the anticoagulation proteins, proteins C and S, during warfarin initiation. Data from 18 patients with atrial fibrillation who had warfarin therapy initiated were available for analysis. Nine blood samples were collected from each subject at baseline, and at 1-5, 8, 15 and 29 days after warfarin initiation and assayed for factors II, VII, IX and X, and proteins C and S. Warfarin concentration-time data were not available. The coagulation proteins data were modelled in a stepwise manner using NONMEM ® Version 7.2. In the first stage, each of the coagulation proteins was modelled independently using a kinetic-pharmacodynamic model. In the subsequent step, the six kinetic-pharmacodynamic models were combined into a single joint model. One patient was administered VK and was excluded from the analysis. Each kinetic-pharmacodynamic model consisted of two parts: (1) a common one-compartment pharmacokinetic model with first-order absorption and elimination for warfarin; and (2) an inhibitory E max model linked to a turnover model for coagulation proteins. In the joint model, an unexpected pharmacodynamic lag was identified and the estimated degradation half-life of VK-dependent coagulation proteins were in agreement with previously published values. The model provided an adequate fit to the observed data. The joint model represents the first work to quantify the influence of warfarin on all six VK-dependent coagulation proteins simultaneously. Future work will expand the model to predict the influence of exogenously administered VK on the time course of clotting factor concentrations after warfarin overdose and during perioperative warfarin reversal procedures.

  7. The adenovirus major core protein VII is dispensable for virion assembly but is essential for lytic infection

    PubMed Central

    Suomalainen, Maarit; Zheng, Yueting; Boucke, Karin

    2017-01-01

    The Adenovirus (Ad) genome within the capsid is tightly associated with a virus-encoded, histone-like core protein—protein VII. Two other Ad core proteins, V and X/μ, also are located within the virion and are loosely associated with viral DNA. Core protein VII remains associated with the Ad genome during the early phase of infection. It is not known if naked Ad DNA is packaged into the capsid, as with dsDNA bacteriophage and herpesviruses, followed by the encapsidation of viral core proteins, or if a unique packaging mechanism exists with Ad where a DNA-protein complex is simultaneously packaged into the virion. The latter model would require an entirely new molecular mechanism for packaging compared to known viral packaging motors. We characterized a virus with a conditional knockout of core protein VII. Remarkably, virus particles were assembled efficiently in the absence of protein VII. No changes in protein composition were evident with VII−virus particles, including the abundance of core protein V, but changes in the proteolytic processing of some capsid proteins were evident. Virus particles that lack protein VII enter the cell, but incoming virions did not escape efficiently from endosomes. This greatly diminished all subsequent aspects of the infectious cycle. These results reveal that the Ad major core protein VII is not required to condense viral DNA within the capsid, but rather plays an unexpected role during virus maturation and the early stages of infection. These results establish a new paradigm pertaining to the Ad assembly mechanism and reveal a new and important role of protein VII in early stages of infection. PMID:28628648

  8. Antimicrobial peptide scolopendrasin VII, derived from the centipede Scolopendra subspinipes mutilans, stimulates macrophage chemotaxis via formyl peptide receptor 1

    PubMed Central

    Park, Yoo Jung; Lee, Ha Young; Jung, Young Su; Park, Joon Seong; Hwang, Jae Sam; Bae, Yoe-Sik

    2015-01-01

    In this study, we report that one of the antimicrobial peptides scolopendrasin VII, derived from Scolopendra subspinipes mutilans, stimulates actin polymerization and the subsequent chemotactic migration of macrophages through the activation of ERK and protein kinase B (Akt) activity. The scolopendrasin VII-induced chemotactic migration of macrophages is inhibited by the formyl peptide receptor 1 (FPR1) antagonist cyclosporine H. We also found that scolopendrasin VII stimulate the chemotactic migration of FPR1-transfected RBL-2H3 cells, but not that of vector-transfected cells; moreover, scolopendrasin VII directly binds to FPR1. Our findings therefore suggest that the antimicrobial peptide scolopendrasin VII, derived from Scolopendra subspinipes mutilans, stimulates macrophages, resulting in chemotactic migration via FPR1 signaling, and the peptide can be useful in the study of FPR1-related biological responses. [BMB Reports 2015; 48(8): 479-484] PMID:26129676

  9. Carbonic anhydrase inhibitors. Comparison of chlorthalidone, indapamide, trichloromethiazide, and furosemide X-ray crystal structures in adducts with isozyme II, when several water molecules make the difference.

    PubMed

    Temperini, Claudia; Cecchi, Alessandro; Scozzafava, Andrea; Supuran, Claudiu T

    2009-02-01

    Thiazide and high ceiling diuretics were recently shown to inhibit all mammalian isoforms of carbonic anhydrase (CA, EC 4.2.1.1) with a very different profile as compared to classical inhibitors, such as acetazolamide, methazolamide, and ethoxzolamide. Some of these structurally related compounds have a very different behavior against the widespread isozyme CA II, with chlorthalidone, trichloromethiazide, and furosemide being efficient inhibitors against CA II (K(I)s of 65-138 nM), whereas indapamide is a much weaker one (K(I) of 2520 nM). Furthermore, some of these diuretics are quite efficient (low nanomolar) inhibitors of other isoforms, for example, chlorthalidone against hCA VB, VII, IX, and XIII; indapamide against CA VII, IX, XII, and XIII, trichloromethiazide against CA VII and IX, and furosemide against CA I and XIV. Examining the four X-ray crystal structures of their CA II adducts, we observed several (2-3) active site water molecules interacting with the chlorthalidone, trichloromethiazide, and furosemide scaffolds which may be responsible for this important difference of activity. Indeed, indapamide bound to CA II has no interactions with active site water molecules. Chlorthalidone bound within the CA II active site is in an enolic (lactimic) tautomeric form, with the enolic OH also participating in two strong hydrogen bonds with Asn67 and a water molecule. The newly evidenced binding modes of these diuretics may be exploited for designing better CA II inhibitors as well as compounds with selectivity/affinity for various isoforms with medicinal chemistry applications.

  10. The MUSE Hubble Ultra Deep Field Survey. VII. Fe II* emission in star-forming galaxies

    NASA Astrophysics Data System (ADS)

    Finley, Hayley; Bouché, Nicolas; Contini, Thierry; Paalvast, Mieke; Boogaard, Leindert; Maseda, Michael; Bacon, Roland; Blaizot, Jérémy; Brinchmann, Jarle; Epinat, Benoît; Feltre, Anna; Marino, Raffaella Anna; Muzahid, Sowgat; Richard, Johan; Schaye, Joop; Verhamme, Anne; Weilbacher, Peter M.; Wisotzki, Lutz

    2017-11-01

    Non-resonant Fe II* (λ2365, λ2396, λ2612, λ2626) emission can potentially trace galactic winds in emission and provide useful constraints to wind models. From the 3.15' × 3.15' mosaic of the Hubble Ultra Deep Field (UDF) obtained with the VLT/MUSE integral field spectrograph, we identify a statistical sample of 40 Fe II* emitters and 50 MgIII (λλ2796,2803) emitters from a sample of 271 [O II]λλ3726,3729 emitters with reliable redshifts from z = 0.85-1.50 down to 2 × 10-18 (3σ) ergs s-1 cm-2 (for [O II]), covering the M⋆ range from 108-1011 M⊙. The Fe II* and Mg II emitters follow the galaxy main sequence, but with a clear dichotomy. Galaxies with masses below 109 M⊙ and star formation rates (SFRs) of ≲ 1 M⊙ yr-1 have MgIII emission without accompanying Fe II* emission, whereas galaxies with masses above 1010 M⊙ and SFRs ≳ 10 M⊙ yr-1 have Fe II* emission without accompanying MgIII emission. Between these two regimes, galaxies have both MgIII and Fe II* emission, typically with MgIII P Cygni profiles. Indeed, the MgIII profile shows a progression along the main sequence from pure emission to P Cygni profiles to strong absorption, due to resonant trapping. Combining the deep MUSE data with HST ancillary information, we find that galaxies with pure MgIII emission profiles have lower SFR surface densities than those with either MgIII P Cygni profiles or Fe II* emission. These spectral signatures produced through continuum scattering and fluorescence, MgIII P Cygni profiles and Fe II* emission, are better candidates for tracing galactic outflows than pure MgIII emission, which may originate from HIII regions. We compare the absorption and emission rest-frame equivalent widths for pairs of FeIII transitions to predictions from outflow models and find that the observations consistently have less total re-emission than absorption, suggesting either dust extinction or non-isotropic outflow geometries.

  11. Biochemical Characterization of Individual Human Glycosylated pro-Insulin-like Growth Factor (IGF)-II and big-IGF-II Isoforms Associated with Cancer

    PubMed Central

    Greenall, Sameer A.; Bentley, John D.; Pearce, Lesley A.; Scoble, Judith A.; Sparrow, Lindsay G.; Bartone, Nicola A.; Xiao, Xiaowen; Baxter, Robert C.; Cosgrove, Leah J.; Adams, Timothy E.

    2013-01-01

    Insulin-like growth factor II (IGF-II) is a major embryonic growth factor belonging to the insulin-like growth factor family, which includes insulin and IGF-I. Its expression in humans is tightly controlled by maternal imprinting, a genetic restraint that is lost in many cancers, resulting in up-regulation of both mature IGF-II mRNA and protein expression. Additionally, increased expression of several longer isoforms of IGF-II, termed “pro” and “big” IGF-II, has been observed. To date, it is ambiguous as to what role these IGF-II isoforms have in initiating and sustaining tumorigenesis and whether they are bioavailable. We have expressed each individual IGF-II isoform in their proper O-glycosylated format and established that all bind to the IGF-I receptor and both insulin receptors A and B, resulting in their activation and subsequent stimulation of fibroblast proliferation. We also confirmed that all isoforms are able to be sequestered into binary complexes with several IGF-binding proteins (IGFBP-2, IGFBP-3, and IGFBP-5). In contrast to this, ternary complex formation with IGFBP-3 or IGFBP-5 and the auxillary protein, acid labile subunit, was severely diminished. Furthermore, big-IGF-II isoforms bound much more weakly to purified ectodomain of the natural IGF-II scavenging receptor, IGF-IIR. IGF-II isoforms thus possess unique biological properties that may enable them to escape normal sequestration avenues and remain bioavailable in vivo to sustain oncogenic signaling. PMID:23166326

  12. Biochemical characterization of individual human glycosylated pro-insulin-like growth factor (IGF)-II and big-IGF-II isoforms associated with cancer.

    PubMed

    Greenall, Sameer A; Bentley, John D; Pearce, Lesley A; Scoble, Judith A; Sparrow, Lindsay G; Bartone, Nicola A; Xiao, Xiaowen; Baxter, Robert C; Cosgrove, Leah J; Adams, Timothy E

    2013-01-04

    Insulin-like growth factor II (IGF-II) is a major embryonic growth factor belonging to the insulin-like growth factor family, which includes insulin and IGF-I. Its expression in humans is tightly controlled by maternal imprinting, a genetic restraint that is lost in many cancers, resulting in up-regulation of both mature IGF-II mRNA and protein expression. Additionally, increased expression of several longer isoforms of IGF-II, termed "pro" and "big" IGF-II, has been observed. To date, it is ambiguous as to what role these IGF-II isoforms have in initiating and sustaining tumorigenesis and whether they are bioavailable. We have expressed each individual IGF-II isoform in their proper O-glycosylated format and established that all bind to the IGF-I receptor and both insulin receptors A and B, resulting in their activation and subsequent stimulation of fibroblast proliferation. We also confirmed that all isoforms are able to be sequestered into binary complexes with several IGF-binding proteins (IGFBP-2, IGFBP-3, and IGFBP-5). In contrast to this, ternary complex formation with IGFBP-3 or IGFBP-5 and the auxillary protein, acid labile subunit, was severely diminished. Furthermore, big-IGF-II isoforms bound much more weakly to purified ectodomain of the natural IGF-II scavenging receptor, IGF-IIR. IGF-II isoforms thus possess unique biological properties that may enable them to escape normal sequestration avenues and remain bioavailable in vivo to sustain oncogenic signaling.

  13. ADRPM-VII applied to the long-range acoustic detection problem

    NASA Technical Reports Server (NTRS)

    Shalis, Edward; Koenig, Gerald

    1990-01-01

    An acoustic detection range prediction model (ADRPM-VII) has been written for IBM PC/AT machines running on the MS-DOS operating system. The software allows the user to predict detection distances of ground combat vehicles and their associated targets when they are involved in quasi-military settings. The program can also calculate individual attenuation losses due to spherical spreading, atmospheric absorption, ground reflection and atmospheric refraction due to temperature and wind gradients while varying parameters effecting the source-receiver problem. The purpose here is to examine the strengths and limitations of ADRPM-VII by modeling the losses due to atmospheric refraction and ground absorption, commonly known as excess attenuation, when applied to the long range detection problem for distances greater than 3 kilometers.

  14. Impact on postoperative bleeding and cost of recombinant activated factor VII in patients undergoing heart transplantation.

    PubMed

    Hollis, Allison L; Lowery, Ashleigh V; Pajoumand, Mehrnaz; Pham, Si M; Slejko, Julia F; Tanaka, Kenichi A; Mazzeffi, Michael

    2016-01-01

    Cardiac transplantation can be complicated by refractory hemorrhage particularly in cases where explantation of a ventricular assist device is necessary. Recombinant activated factor VII (rFVIIa) has been used to treat refractory bleeding in cardiac surgery patients, but little information is available on its efficacy or cost in heart transplant patients. Patients who had orthotopic heart transplantation between January 2009 and December 2014 at a single center were reviewed. Postoperative bleeding and the total costs of hemostatic therapies were compared between patients who received rFVIIa and those who did not. Propensity scores were created and used to control for the likelihood of receiving rFVIIa in order to reduce bias in our risk estimates. Seventy-six patients underwent heart transplantation during the study period. Twenty-one patients (27.6%) received rFVIIa for refractory intraoperative bleeding. There was no difference in postoperative red blood cell transfusion, chest tube output, or surgical re-exploration between patients who received rFVIIa and those who did not, even after adjusting with the propensity score (P = 0.94, P = 0.60, and P = 0.10, respectively). The total cost for hemostatic therapies was significantly higher in the rFVIIa group (median $10,819 vs. $1,985; P < 0.0001). Subgroup analysis of patients who underwent redo-sternotomy with left ventricular assist device explantation did not show any benefit for rFVIIa either. In this relatively small cohort, rFVIIa use was not associated with decreased postoperative bleeding in patients undergoing heart transplantation; however, it led to significantly higher cost.

  15. Oligomeric state regulated trafficking of human platelet-activating factor acetylhydrolase type-II.

    PubMed

    Monillas, Elizabeth S; Caplan, Jeffrey L; Thévenin, Anastasia F; Bahnson, Brian J

    2015-05-01

    The intracellular enzyme platelet-activating factor acetylhydrolase type-II (PAFAH-II) hydrolyzes platelet-activating factor and oxidatively fragmented phospholipids. PAFAH-II in its resting state is mainly cytoplasmic, and it responds to oxidative stress by becoming increasingly bound to endoplasmic reticulum and Golgi membranes. Numerous studies have indicated that this enzyme is essential for protecting cells from oxidative stress induced apoptosis. However, the regulatory mechanism of the oxidative stress response by PAFAH-II has not been fully resolved. Here, changes to the oligomeric state of human PAFAH-II were investigated as a potential regulatory mechanism toward enzyme trafficking. Native PAGE analysis in vitro and photon counting histogram within live cells showed that PAFAH-II is both monomeric and dimeric. A Gly-2-Ala site-directed mutation of PAFAH-II demonstrated that the N-terminal myristoyl group is required for homodimerization. Additionally, the distribution of oligomeric PAFAH-II is distinct within the cell; homodimers of PAFAH-II were localized to the cytoplasm while monomers were associated to the membranes of the endoplasmic reticulum and Golgi. We propose that the oligomeric state of PAFAH-II drives functional protein trafficking. PAFAH-II localization to the membrane is critical for substrate acquisition and effective oxidative stress protection. It is hypothesized that the balance between monomer and dimer serves as a regulatory mechanism of a PAFAH-II oxidative stress response. Copyright © 2015 Elsevier B.V. All rights reserved.

  16. Title VII Sexual Harassment Guidelines and Educational Employment [and] What Can Students Do About Sex Discrimination?

    ERIC Educational Resources Information Center

    Howard, Susan; And Others

    Guidelines concerning sexual harassment of employees at educational institutions under Title VII of the Civil Rights Act of 1964 are considered. November 1980 final interpretive guidelines issued by the Equal Employment Opportunity Commission state that Title VII prohibits sexual harassment of employees, that employers are responsible for the…

  17. Thrombin generation by activated factor VII on platelet activated by different agonists. Extending the cell-based model of hemostasis

    PubMed Central

    Altman, Raul; Scazziota, Alejandra Silvia; Herrera, Maria de Lourdes; Gonzalez, Claudio

    2006-01-01

    Background Platelet activation is crucial in normal hemostasis. Using a clotting system free of external tissue factor, we investigated whether activated Factor VII in combination with platelet agonists increased thrombin generation (TG) in vitro. Methods and results TG was quantified by time parameters: lag time (LT) and time to peak (TTP), and by amount of TG: peak of TG (PTG) and area under thrombin formation curve after 35 minutes (AUC→35min) in plasma from 29 healthy volunteers using the calibrated automated thrombography (CAT) technique. TG parameters were measured at basal conditions and after platelet stimulation by sodium arachidonate (AA), ADP, and collagen (Col). In addition, the effects of recombinant activated FVII (rFVIIa) alone or combined with the other platelet agonists on TG parameters were investigated. We found that LT and TTP were significantly decreased (p < 0.05) and PTG and AUC→35min were significantly increased (p < 0.05) in platelet rich plasma activated with AA, ADP, Col, and rFVIIa compared to non-activated platelet rich plasma from normal subjects (p = 0.01). Furthermore platelet rich plasma activated by the combined effects of rFVIIa plus AA, ADP or Col had significantly reduced LT and TTP and increased AUC→35min (but not PTG) when compared to platelet rich plasma activated with agonists in the absence of rFVIIa. Conclusion Platelets activated by AA, ADP, Col or rFVIIa triggered TG. This effect was increased by combining rFVIIa with other agonists. Our intrinsic coagulation system produced a burst in TG independent of external tissue factor activity an apparent hemostatic effect with little thrombotic capacity. Thus we suggest a modification in the cell-based model of hemostasis. PMID:16630353

  18. Recombinant activated factor VII (NovoSeven): addition to replacement therapy in acute, uncontrolled and life-threatening bleeding.

    PubMed

    Mayo, A; Misgav, M; Kluger, Y; Geenberg, R; Pauzner, D; Klausner, J; Ben-Tal, O

    2004-07-01

    Recombinant activated factor VII (rFVIIa, NovoSeven) has been used off-label for various conditions. A protocol for its use in acute, uncontrolled life-threatening bleeding, was devised and employed. A haematologist/transfusion specialist was assigned as a member of the team. The clinical data were reviewed and summarized. A scoring system for the assessment and monitoring of coagulopathy was employed. Each parameter of prothrombin time (PT), activated partial thromboplastin time (aPTT), platelet number and fibrinogen level was allocated points according to the degree of abnormality. Three scoring levels emerged. Between April 2001 and April 2003, 13 patients received rFVIIa for acute, uncontrolled life-threatening bleeding. Nine of 13 patients remained alive for 15 days or longer after rFVIIa infusion. All patients who experienced a reduction or cessation of bleeding after rFVIIa infusion, also had a lower coagulopathy score after replacement therapy, prior to rFVIIa infusion, compared with their score at rFVIIa request. There was a reduction in the average use of blood products after rFVIIa infusion. The coagulopathy score was statistically predictive of response to rFVIIa and survival. In an area where very little data exists, we report the usefulness of rFVIIa. We propose that transfusion replacement should aim to correct coagulopathy before infusion of rFVIIa and that a haematologist/transfusion specialist should be involved in the management of these patients. A prognostically significant coagulopathy scoring system is offered.

  19. Turning Back the Title VII Clock: The Resegregation of the American Work Force through Validity Generalization.

    ERIC Educational Resources Information Center

    Goldstein, Barry L.; Patterson, Patrick O.

    1988-01-01

    Refers to Title VII of the Civil Rights Act of 1964 and the Supreme Court's disparate impact interpretation of Title VII in Griggs versus Duke Power Company. Contends that attacks on the Griggs decision are legally unsound and that claims made by advocates of validity generalization are scientifically unsupported. (Author/NB)

  20. Title VII funding is associated with more family physicians and more physicians serving the underserved.

    PubMed

    Meyers, D; Fryer, G E; Krol, D; Phillips, R L; Green, L A; Dovey, S M

    2002-08-15

    Title VII funding of departments of family medicine at U.S. medical schools is significantly associated with expansion of the primary care physician workforce and increased accessibility to physicians for the residents of rural and underserved areas. Title VII has been successful in achieving its stated goals and has had an important role in addressing U.S. physician workforce policy issues.

  1. Development of a User Support Package for CPESIM II (A Computer Simulation for CPE (Computer Performance Evaluation) Use.

    DTIC Science & Technology

    1984-12-01

    Appendix D: CPESIM II Student Manual .........D-1 Appendix E: CPESIM II Instructor Manual .......E-1 Appendix F: The Abridged Report..........F-i Bibliography...operating system is implemented on. A student and instructor user’s manual is provided. vii I • - Development of a User Support Package for CPESIM II (a...was a manual one. The student changes should be collected into a database to ease the instructor workload and to provide a "history" of the evolution of

  2. 77 FR 14516 - Lock+ Hydro Friends Fund VII; Notice of Preliminary Permit Application Accepted for Filing and...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-03-12

    ... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission [Project No. 14339-000] Lock+ Hydro Friends Fund VII; Notice of Preliminary Permit Application Accepted for Filing and Soliciting Comments, Motions To Intervene, and Competing Applications On December 22, 2011, Lock+ Hydro Friends Fund VII filed...

  3. Human Adenovirus Infection Causes Cellular E3 Ubiquitin Ligase MKRN1 Degradation Involving the Viral Core Protein pVII.

    PubMed

    Inturi, Raviteja; Mun, Kwangchol; Singethan, Katrin; Schreiner, Sabrina; Punga, Tanel

    2018-02-01

    Human adenoviruses (HAdVs) are common human pathogens encoding a highly abundant histone-like core protein, VII, which is involved in nuclear delivery and protection of viral DNA as well as in sequestering immune danger signals in infected cells. The molecular details of how protein VII acts as a multifunctional protein have remained to a large extent enigmatic. Here we report the identification of several cellular proteins interacting with the precursor pVII protein. We show that the cellular E3 ubiquitin ligase MKRN1 is a novel precursor pVII-interacting protein in HAdV-C5-infected cells. Surprisingly, the endogenous MKRN1 protein underwent proteasomal degradation during the late phase of HAdV-C5 infection in various human cell lines. MKRN1 protein degradation occurred independently of the HAdV E1B55K and E4orf6 proteins. We provide experimental evidence that the precursor pVII protein binding enhances MKRN1 self-ubiquitination, whereas the processed mature VII protein is deficient in this function. Based on these data, we propose that the pVII protein binding promotes MKRN1 self-ubiquitination, followed by proteasomal degradation of the MKRN1 protein, in HAdV-C5-infected cells. In addition, we show that measles virus and vesicular stomatitis virus infections reduce the MKRN1 protein accumulation in the recipient cells. Taken together, our results expand the functional repertoire of the HAdV-C5 precursor pVII protein in lytic virus infection and highlight MKRN1 as a potential common target during different virus infections. IMPORTANCE Human adenoviruses (HAdVs) are common pathogens causing a wide range of diseases. To achieve pathogenicity, HAdVs have to counteract a variety of host cell antiviral defense systems, which would otherwise hamper virus replication. In this study, we show that the HAdV-C5 histone-like core protein pVII binds to and promotes self-ubiquitination of a cellular E3 ubiquitin ligase named MKRN1. This mutual interaction between the pVII and

  4. 25 CFR 36.22 - Standard VII-Elementary instructional program.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 25 Indians 1 2012-04-01 2011-04-01 true Standard VII-Elementary instructional program. 36.22 Section 36.22 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR EDUCATION MINIMUM ACADEMIC STANDARDS FOR THE BASIC EDUCATION OF INDIAN CHILDREN AND NATIONAL CRITERIA FOR DORMITORY SITUATIONS Minimum...

  5. 25 CFR 36.22 - Standard VII-Elementary instructional program.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 25 Indians 1 2013-04-01 2013-04-01 false Standard VII-Elementary instructional program. 36.22 Section 36.22 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR EDUCATION MINIMUM ACADEMIC STANDARDS FOR THE BASIC EDUCATION OF INDIAN CHILDREN AND NATIONAL CRITERIA FOR DORMITORY SITUATIONS Minimum...

  6. 25 CFR 36.22 - Standard VII-Elementary instructional program.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 25 Indians 1 2014-04-01 2014-04-01 false Standard VII-Elementary instructional program. 36.22 Section 36.22 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR EDUCATION MINIMUM ACADEMIC STANDARDS FOR THE BASIC EDUCATION OF INDIAN CHILDREN AND NATIONAL CRITERIA FOR DORMITORY SITUATIONS Minimum...

  7. a New ENDF/B-VII.0 Based Multigroup Cross-Section Library for Reactor Dosimetry

    NASA Astrophysics Data System (ADS)

    Alpan, F. A.; Anderson, S. L.

    2009-08-01

    The latest of the ENDF/B libraries, ENDF/B-VII.0 was released in December 2006. In this paper, the ENDF/B-VII.O evaluations were used in generating a new coupled neutron/gamma multigroup library having the same group structure of VITAMIN-B6, i.e., the 199-neutron, 42-gamma group library. The new library was generated utilizing NJOY99.259 for pre-processing and the AMPX modules for post-processing of cross sections. An ENDF/B-VI.3 based VITAMIN-B6-like library was also generated. The fine-group libraries and the ENDF/B-VI.3 based 47-neutron, 20-gamma group BUGLE-96 library were used with the discrete ordinates code DORT to obtain a three-dimensional synthesized flux distribution from r, r-θ, and r-z models for a standard Westinghouse 3-loop design reactor. Reaction rates were calculated for ex-vessel neutron dosimetry containing 63Cu(n,α)60Co, 46Ti(n,p)46Sc, 54Fe(n,P)54Mn, 58Ni(n,P)58Co, 238U(n,f)137Cs, 237Np(n,f)137Cs, and 59Co(n,γ)60Co (bare and cadmium covered) reactions. Results were compared to measurements. In comparing the 199-neutron, 42-gamma group ENDF/B-VI.3 and ENDF/B-VII.O libraries, it was observed that the ENDF/B-VI.3 based library results were in better agreement with measurements. There is a maximum difference of 7% (for the 63Cu(n,α)60Co reaction rate calculation) between ENDF/B-VI.3 and ENDF/B-VII.O. Differences between ENDF/B-VI.3 and ENDF/B-VII.O libraries are due to 16O, 1H, 90Zr, 91Zr, 92Zr, 238U, and 239Pu evaluations. Both ENDF/B-VI.3 and ENDF/B-VII.O library calculated reaction rates are within 20% of measurement and meet the criterion specified in the U. S. Nuclear Regulatory Commission Regulatory Guide 1.190, "Calculational and Dosimetry Methods for Determining Pressure Vessel Neutron Fluence."

  8. Adenovirus core protein VII contains distinct sequences that mediate targeting to the nucleus and nucleolus, and colocalization with human chromosomes.

    PubMed

    Lee, Tim W R; Blair, G Eric; Matthews, David A

    2003-12-01

    During adenovirus infection, following capsid dissociation, core protein VII enters the host cell nucleus complexed with adenovirus DNA. In order to determine whether protein VII may have an active role in this nuclear import, regions of the preVII gene were amplified by PCR, and further oligonucleotide mutants were designed with site-directed mutation of codons for the basic amino acids arginine and lysine. Fragments were cloned into a mammalian expression plasmid to express the peptides as N-terminal fusions to enhanced green fluorescent protein. Results demonstrate that preVII protein contains both nuclear and nucleolar targeting sequences. Such signals may be important in the delivery of adenovirus DNA to the host cell nucleus during adenovirus infection. Furthermore, the data suggest that protein VII may bind to human chromosomes by means of two distinct domains, one sharing homology with the N-terminal regulatory tail of histone H3.

  9. 76 FR 24471 - Qualified Hydro 26, LLC; Lock+ Hydro Friends Fund VII; Western Minnesota Municipal Power Agency...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-05-02

    ...; 14113-000] Qualified Hydro 26, LLC; Lock+ Hydro Friends Fund VII; Western Minnesota Municipal Power... Hydro), Lock+ Hydro Friends Fund VII (Hydro Friends) and Western Minnesota Municipal Power Agency (WMMPA... 02114; (978) 283-2822. Hydro Friends' proposed Lock and Dam 11 Hydropower Project No. 14112 would...

  10. Recordkeeping and reporting under Title VII and the ADA--EEOC. Final rule.

    PubMed

    1991-07-26

    This final rule is based on two separate Notices of Proposed Rulemaking (NPRM) published on February 13, 1989 (54 FR 6551), and March 5, 1991 (56 FR 9185). This final rule amends 29 CFR part 1602, EEOC's regulations on Recordkeeping and Reporting under title VII of the Civil Rights Act of 1964 (title VII), to add recordkeeping requirements under the Americans with Disabilities Act of 1990 (ADA). It increases the records retention period required in part 1602 for title VII and the ADA from 6 months to one year. The Commission also is adding a new subpart R to part 1602, 29 CFR 1602.56, that will clarify that the Commission has the authority to investigate persons to determine whether they comply with the reporting or recordkeeping requirements of part 1602. In addition, the Commission is making several minor changes to sections 1602.7 and 1602.10. The Commission also is deleting section 1602.14(b) of its title VII recordkeeping regulations, which provides that the section 1602 recordkeeping requirements do not apply to temporary or seasonal positions. Information regarding such employees now must be reported on Standard Form 100 on September 30 of each year, in the same fashion as information regarding permanent employees is reported. Similarly, the Commission is deleting sections 1627.3(b) and 1627.4(a)(2) of the Age Discrimination in Employment Act recordkeeping regulations, which provide for a 90-day retention period for temporary positions, and is clarifying the mandatory nature of such recordkeeping. The Commission is not issuing a final rule on proposed section 1602.57 at this time.

  11. The position of imidazopyridine and metabolic activation are pivotal factors in the antimutagenic activity of novel imidazo[1,2-a]pyridine derivatives.

    PubMed

    El-Sayed, Wael M; Hussin, Warda A; Al-Faiyz, Yasair S; Ismail, Mohamed A

    2013-09-05

    The antimutagenic activity of eight novel imidazo[1,2-a]pyridine derivatives (I-VIII) against sodium azide (NaN3) and benzo[a]pyrene (B[a]P) was evaluated using the Salmonella reverse mutation assay. At non-toxic concentrations (12.5-50 µM), imidazopyridines I, II, III, and V with a terminal imidazopyridine group were mutagenic, while derivatives VII and VIII with a central imidazopyridine group were not mutagenic. Compounds IV, VII, and VIII exerted a moderate antimutagenic activity against NaN3 under pre-exposure conditions, and a strong activity (>40%) against B[a]P in the presence of S9 under both pre- and co-exposure conditions and mostly independent on the dose. Imidazopyridines possibly inhibited the microsomal-dependent activation of B[a]P. The demethylated derivative VII was the most active antimutagen. All imidazopyridines had a low to moderate antioxidant activity. The antibacterial activity of imidazopyridines was sporadic and moderate probably due to the failure of bacteria to convert imidazopyridines into active metabolites. The position of imidazopyridine was a pivotal factor in the mutagenic/antimutagenic activity. The strong antimutagenic compounds were dicationic planar compounds with a centered imidazo[1,2-a]pyridine spacer. With LD50 of 60 mg/kg in mice for both derivatives VII and VIII, it is safe to investigate the anticancer activity of these derivatives in animal models. © 2013 Elsevier B.V. All rights reserved.

  12. Expanding the versatility of phage display I: efficient display of peptide-tags on protein VII of the filamentous phage.

    PubMed

    Løset, Geir Åge; Bogen, Bjarne; Sandlie, Inger

    2011-02-24

    Phage display is a platform for selection of specific binding molecules and this is a clear-cut motivation for increasing its performance. Polypeptides are normally displayed as fusions to the major coat protein VIII (pVIII), or the minor coat protein III (pIII). Display on other coat proteins such as pVII allows for display of heterologous peptide sequences on the virions in addition to those displayed on pIII and pVIII. In addition, pVII display is an alternative to pIII or pVIII display. Here we demonstrate how standard pIII or pVIII display phagemids are complemented with a helper phage which supports production of virions that are tagged with octa FLAG, HIS(6) or AviTag on pVII. The periplasmic signal sequence required for pIII and pVIII display, and which has been added to pVII in earlier studies, is omitted altogether. Tagging on pVII is an important and very useful add-on feature to standard pIII and pVII display. Any phagemid bearing a protein of interest on either pIII or pVIII can be tagged with any of the tags depending simply on choice of helper phage. We show in this paper how such tags may be utilized for immobilization and separation as well as purification and detection of monoclonal and polyclonal phage populations.

  13. 48 CFR 42.1104 - Surveillance requirements.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... following factors: (i) Contract requirements for reporting production progress and performance. (ii) The... contractor's financial capability. (vii) Any supplementary written instructions from the contracting office...

  14. Evaluation of AAV-mediated Gene Therapy for Central Nervous System Disease in Canine Mucopolysaccharidosis VII

    PubMed Central

    Gurda, Brittney L; De Guilhem De Lataillade, Adrien; Bell, Peter; Zhu, Yanqing; Yu, Hongwei; Wang, Ping; Bagel, Jessica; Vite, Charles H; Sikora, Tracey; Hinderer, Christian; Calcedo, Roberto; Yox, Alexander D; Steet, Richard A; Ruane, Therese; O'Donnell, Patricia; Gao, Guangping; Wilson, James M; Casal, Margret; Ponder, Katherine P; Haskins, Mark E

    2016-01-01

    Mucopolysaccharidosis VII (MPS VII) is a lysosomal storage disease arising from mutations in β-d-glucuronidase (GUSB), which results in glycosaminoglycan (GAG) accumulation and a variety of clinical manifestations including neurological disease. Herein, MPS VII dogs were injected intravenously (i.v.) and/or intrathecally (i.t.) via the cisterna magna with AAV9 or AAVrh10 vectors carrying the canine GUSB cDNA. Although i.v. injection alone at 3 days of age resulted in normal cerebrospinal fluid (CSF) GUSB activity, brain tissue homogenates had only ~1 to 6% normal GUSB activity and continued to have elevated GAG storage. In contrast, i.t. injection at 3 weeks of age resulted in CSF GUSB activity 44-fold normal while brain tissue homogenates had >100% normal GUSB activity and reduced GAGs compared with untreated dogs. Markers for secondary storage and inflammation were eliminated in i.t.-treated dogs and reduced in i.v.-treated dogs compared with untreated dogs. Given that i.t.-treated dogs expressed higher levels of GUSB in the CNS tissues compared to those treated i.v., we conclude that i.t. injection of AAV9 or AAVrh10 vectors is more effective than i.v. injection alone in the large animal model of MPS VII. PMID:26447927

  15. Evaluation of AAV-mediated Gene Therapy for Central Nervous System Disease in Canine Mucopolysaccharidosis VII.

    PubMed

    Gurda, Brittney L; De Guilhem De Lataillade, Adrien; Bell, Peter; Zhu, Yanqing; Yu, Hongwei; Wang, Ping; Bagel, Jessica; Vite, Charles H; Sikora, Tracey; Hinderer, Christian; Calcedo, Roberto; Yox, Alexander D; Steet, Richard A; Ruane, Therese; O'Donnell, Patricia; Gao, Guangping; Wilson, James M; Casal, Margret; Ponder, Katherine P; Haskins, Mark E

    2016-02-01

    Mucopolysaccharidosis VII (MPS VII) is a lysosomal storage disease arising from mutations in β-d-glucuronidase (GUSB), which results in glycosaminoglycan (GAG) accumulation and a variety of clinical manifestations including neurological disease. Herein, MPS VII dogs were injected intravenously (i.v.) and/or intrathecally (i.t.) via the cisterna magna with AAV9 or AAVrh10 vectors carrying the canine GUSB cDNA. Although i.v. injection alone at 3 days of age resulted in normal cerebrospinal fluid (CSF) GUSB activity, brain tissue homogenates had only ~1 to 6% normal GUSB activity and continued to have elevated GAG storage. In contrast, i.t. injection at 3 weeks of age resulted in CSF GUSB activity 44-fold normal while brain tissue homogenates had >100% normal GUSB activity and reduced GAGs compared with untreated dogs. Markers for secondary storage and inflammation were eliminated in i.t.-treated dogs and reduced in i.v.-treated dogs compared with untreated dogs. Given that i.t.-treated dogs expressed higher levels of GUSB in the CNS tissues compared to those treated i.v., we conclude that i.t. injection of AAV9 or AAVrh10 vectors is more effective than i.v. injection alone in the large animal model of MPS VII.

  16. Analysis of time series for postal shipments in Regional VII East Java Indonesia

    NASA Astrophysics Data System (ADS)

    Kusrini, DE; Ulama, B. S. S.; Aridinanti, L.

    2018-03-01

    The change of number delivery goods through PT. Pos Regional VII East Java Indonesia indicates that the trend of increasing and decreasing the delivery of documents and non-documents in PT. Pos Regional VII East Java Indonesia is strongly influenced by conditions outside of PT. Pos Regional VII East Java Indonesia so that the prediction the number of document and non-documents requires a model that can accommodate it. Based on the time series plot monthly data fluctuations occur from 2013-2016 then the model is done using ARIMA or seasonal ARIMA and selected the best model based on the smallest AIC value. The results of data analysis about the number of shipments on each product sent through the Sub-Regional Postal Office VII East Java indicates that there are 5 post offices of 26 post offices entering the territory. The largest number of shipments is available on the PPB (Paket Pos Biasa is regular package shipment/non-document ) and SKH (Surat Kilat Khusus is Special Express Mail/document) products. The time series model generated is largely a Random walk model meaning that the number of shipment in the future is influenced by random effects that are difficult to predict. Some are AR and MA models, except for Express shipment products with Malang post office destination which has seasonal ARIMA model on lag 6 and 12. This means that the number of items in the following month is affected by the number of items in the previous 6 months.

  17. Factor VII assay performance: an analysis of the North American Specialized Coagulation Laboratory Association proficiency testing results.

    PubMed

    Zantek, N D; Hsu, P; Refaai, M A; Ledford-Kraemer, M; Meijer, P; Van Cott, E M

    2013-06-01

    The performance of factor VII (FVII) assays currently used by clinical laboratories was examined in North American Specialized Coagulation Laboratory Association (NASCOLA) proficiency tests. Data from 12 surveys conducted between 2008 and 2010, involving 20 unique specimens plus four repeat-tested specimens, were analyzed. The number of laboratories per survey was 49-54 with a total of 1224 responses. Numerous reagent/instrument combinations were used. For FVII > 80 or <40 U/dL, 99.5% of results (859/863) were correctly classified by laboratories as normal/abnormal. Classification of specimens with 40-73 U/dL FVII was heterogeneous. Interlaboratory precision was better for normal specimens (coefficient of variation (CV) 10.7%) than for FVII<20 U/dL (CV 33.1%), with a mean CV of 17.2% per specimen. Intralaboratory precision for repeated specimens demonstrated no significant difference between the paired survey results (mean absolute difference 2.5-5.0 U/dL). For specimens with FVII >50 U/dL, among commonly used methods, one thromboplastin and one calibrator produced results 5-6 U/dL higher and another thromboplastin and calibrator produced results 5-6 U/dL lower than all other methods, and human thromboplastin differed from rabbit by +7.6 U/dL. Preliminary evidence suggests these differences could be due to the calibrator. For FVII <50 U/dL, differences among the commonly used reagents and calibrators were generally not significant. © 2013 Blackwell Publishing Ltd.

  18. VizieR Online Data Catalog: Ba V, Ba VI, and Ba VII oscillator strengths (Rauch+, 2014)

    NASA Astrophysics Data System (ADS)

    Rauch, T.; Werner, K.; Quinet, P.; Kruk, J. W.

    2014-04-01

    table1.dat contains calculated HFR oscillator strengths (loggf) and transition probabilities (gA, in 1/s) in Ba V. CF is the cancellation factor as defined by Cowan (1981). In columns 3 and 6, e is written for even and o for odd. table2.dat contains calculated HFR oscillator strengths (loggf) and transition probabilities (gA, in 1/s) in Ba VI. CF is the cancellation factor as defined by Cowan (1981). In columns 3 and 6, e is written for even and o for odd. table3.dat contains calculated HFR oscillator strengths (loggf) and transition probabilities (gA, in 1/s) in Ba VII. CF is the cancellation factor as defined by Cowan (1981). In columns 3 and 6, e is written for even and o for odd. (3 data files).

  19. Outcome of laparoscopic ovariohysterectomy or ovariectomy in dogs with von Willebrand disease or factor VII deficiency: 20 cases (2012-2014).

    PubMed

    Keeshen, Thomas P; Case, J Brad; Runge, Jeffrey J; Singh, Ameet; Mayhew, Philipp D; Steffey, Michele A; Culp, William T N

    2017-11-01

    OBJECTIVE To describe surgical techniques and perioperative management of dogs with von Willebrand disease (VWD) or factor VII (FVII) deficiency undergoing laparoscopic ovariohysterectomy or ovariectomy and evaluate outcomes. DESIGN Retrospective case series. ANIMALS 20 client-owned dogs with VWD (n = 16) or FVII deficiency (4). PROCEDURES Dogs with VWD or FVII deficiency that underwent laparoscopic ovariohysterectomy or ovariectomy between 2012 and 2014 were retrospectively identified via a multi-institutional review of medical records. RESULTS Median expression of von Willebrand factor was 19% (interquartile range, 18% to 30%). All 16 dogs with VWD were Doberman Pinschers, and all were pretreated with desmopressin; 4 also received cryoprecipitate. One of 4 dogs with FVII deficiency received plasma preoperatively, and 1 was treated with desmopressin; 2 dogs received no preoperative treatment. Laparoscopic ovariectomy was performed in 9 dogs with VWD and 2 dogs with FVII deficiency, laparoscopic ovariectomy with gastropexy was performed in 6 dogs with VWD and 1 dog with FVII deficiency, and laparoscopic-assisted ovariohysterectomy was performed in 1 dog with VWD and 1 dog with FVII deficiency. Iatrogenic splenic laceration requiring conversion to laparotomy occurred during trocar insertion in 1 dog with VWD. No postoperative complications, including signs of hemorrhage, were reported for any dogs. CONCLUSIONS AND CLINICAL RELEVANCE Laparoscopic ovariohysterectomy or ovariectomy in dogs with VWD or FVII deficiency pretreated with desmopressin, cryoprecipitate, or plasma transfusions were not associated with clinical signs of hemorrhage, suggesting that minimally invasive ovariohysterectomy or ovariectomy may be considered in female dogs affected with these coagulopathies.

  20. Hypoxia induces cancer-associated cAMP/PKA signalling through HIF-mediated transcriptional control of adenylyl cyclases VI and VII.

    PubMed

    Simko, Veronika; Iuliano, Filippo; Sevcikova, Andrea; Labudova, Martina; Barathova, Monika; Radvak, Peter; Pastorekova, Silvia; Pastorek, Jaromir; Csaderova, Lucia

    2017-08-31

    Hypoxia is a phenomenon often arising in solid tumours, linked to aggressive malignancy, bad prognosis and resistance to therapy. Hypoxia-inducible factor-1 has been identified as a key mediator of cell and tissue adaptation to hypoxic conditions through transcriptional activation of many genes involved in glucose metabolism and other cancer-related processes, such as angiogenesis, cell survival and cell invasion. Cyclic adenosine 3'5'-monophosphate is one of the most ancient and evolutionarily conserved signalling molecules and the cAMP/PKA signalling pathway plays an important role in cellular adaptation to hypoxia. We have investigated possible new mechanisms behind hypoxic activation of the cAMP/PKA pathway. For the first time, we have shown that hypoxia induces transcriptional up-regulation of the system of adenylyl cyclases, enzymes responsible for cAMP production, in a panel of carcinoma cell lines of various origin. Our data prove functional relevance of the hypoxic increase of adenylyl cyclases VI and VII at least partially mediated by HIF-1 transcription factor. We have identified adenylyl cyclase VI and VII isoforms as mediators of cellular response to hypoxia, which led to the elevation of cAMP levels and enhanced PKA activity, with an impact on cell migration and pH regulation.

  1. An investigation of the factor structure of the beck depression inventory-II in anorexia nervosa.

    PubMed

    Fuss, Samantha; Trottier, Kathryn; Carter, Jacqueline

    2015-01-01

    Symptoms of depression frequently co-occur with eating disorders and have been associated with negative outcomes. Self-report measures such as the Beck Depression Inventory-II (BDI-II) are commonly used to assess for the presence of depressive symptoms in eating disorders, but the instrument's factor structure in this population has not been examined. The purposes of this study were to explore the factor structure of the BDI-II in a sample of individuals (N = 437) with anorexia nervosa undergoing inpatient treatment and to examine changes in depressive symptoms on each of the identified factors following a course of treatment for anorexia nervosa in order to provide evidence supporting the construct validity of the measure. Exploratory factor analysis revealed that a three-factor model reflected the best fit for the data. Confirmatory factor analysis was used to validate this model against competing models and the three-factor model exhibited strong model fit characteristics. BDI-II scores were significantly reduced on all three factors following inpatient treatment, which supported the construct validity of the scale. The BDI-II appears to be reliable in this population, and the factor structure identified through this analysis may offer predictive utility for identifying individuals who may have more difficulty achieving weight restoration in the context of inpatient treatment. Copyright © 2014 John Wiley & Sons, Ltd and Eating Disorders Association. Copyright © 2014 John Wiley & Sons, Ltd and Eating Disorders Association.

  2. Molecular analysis of patients with {Beta}-glucuronidase deficiency presenting as hydrops fetalis or as early mucopolysaccharidosis VII

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Vervoort, R.; Liebaers, I.; Lissens, W.

    1996-03-01

    Although not all mucopolysaccharidosis type VII (MPS VII) neonates present with hydrops fetalis or with related symptoms, hydrops fetalis is a common form of presentation of this mucopolysaccharidosis. We used reverse-transcription-PCR-SSCP and direct sequencing to screen for mutations in the human {beta}-glucuronidase cDNA of 17 MPS VII patients with severe presentation of the disease. Mutations resulting in an unstable mRNA were detected in genomic DNA with direct sequencing of the PCR-amplified {beta}-glucuronidase exons. We found extensive genetic heterogeneity in MPS VII alleles: in addition to 6 of 12 previously reported mutations (L176F, R216W, R357X, R382C, W507X, and W627C), we detectedmore » 14 undescribed mutations in the {beta}-glucuronidase coding region that produce MPS VII alleles (G136R, E150K, S312X, Y320S, Y320C, H351Y, R382H, R374C, R435P, R477W, G572D, Y508C, K606N, and 1900{Delta}GA). The mutations in hydropic fetuses were widely scattered in the {beta}-glucuronidase gene. Analysis of three polymorphic sites of the mutant alleles (1766T/C, 1972C/T, and a new 1091+27C/G polymorphism) allowed exclusion of identity by descent for some recurrent mutations. Three of four mutations introducing a premature translation stop codon were found to affect mRNA abundance and/or structure. Expression studies provided evidence for the causal relationship between each of the mutations found in MPS VII alleles and the enzyme deficiency, in that all mutations identified exhibited markedly reduced enzyme activity expressed in COS7 cells following transfection with the mutant cDNA. 52 refs., 4 figs., 5 tabs.« less

  3. Molecular analysis of patients with beta-glucuronidase deficiency presenting as hydrops fetalis or as early mucopolysaccharidosis VII.

    PubMed Central

    Vervoort, R.; Islam, M. R.; Sly, W. S.; Zabot, M. T.; Kleijer, W. J.; Chabas, A.; Fensom, A.; Young, E. P.; Liebaers, I.; Lissens, W.

    1996-01-01

    Although not all mucopolysaccharidosis type VII (MPS VII) neonates present with hydrops fetalis or with related symptoms, hydrops fetalis is a common form of presentation of this mucopolysaccharidosis. We used reverse-transcription-PCR-SSCP and direct sequencing to screen for mutations in the human beta-glucuronidase cDNA of 17 MPS VII patients with severe presentation of the disease. Mutations resulting in an unstable mRNA were detected in genomic DNA with direct sequencing of the PCR-amplified beta-glucuronidase exons. We found extensive genetic heterogeneity in MPS VII alleles: in addition to 6 or 12 previously reported mutations (L176F, R216W, R357X, R382C, W507X, and W627C), we detected 14 undescribed mutations in the beta-glucuronidase coding region that produce MPS VII alleles (G136R, E150K, S312X, Y320S, Y320C, H351Y, R382H, R374C, R435P, R477W, G572D, Y508C, K606N and 1900 delta GA). The mutations in hydropic fetuses were widely scattered in the beta-glucuronidase gene. Analysis of three polymorphic sites of the mutant alleles (1766T/C, 1972C/T and a new 1091+27C/G polymorphism) allowed exclusion of identity by descent for some recurrent mutations. Three of four mutations introducing a premature translation stop codon were found to affect mRNA abundance and/or structure. Expression studies provided evidence for the causal relationship between each of the mutations found in MPS VII alleles and the enzyme deficiency, in that all mutations identified exhibited markedly reduced enzyme activity expressed in COS7 cells following transfection with the mutant cDNA. Images Figure 2 Figure 3A Figure 3BC Figure 4 PMID:8644704

  4. Evaluation Design 1977-1978 ESEA Title VII Bilingual Program.

    ERIC Educational Resources Information Center

    Matuszek, Paula; And Others

    A design for the evaluation of ESEA Title VII bilingual programs in the Austin Independent School District is presented. The following topics are included: (1) Evaluation Design Review Form; (2) decision questions including the actual questions addressed on three levels: the Office of Education-Level, the system-level and the project-level; (3) a…

  5. VVER-440 and VVER-1000 reactor dosimetry benchmark - BUGLE-96 versus ALPAN VII.0

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Duo, J. I.

    2011-07-01

    Document available in abstract form only, full text of document follows: Analytical results of the vodo-vodyanoi energetichesky reactor-(VVER-) 440 and VVER-1000 reactor dosimetry benchmarks developed from engineering mockups at the Nuclear Research Inst. Rez LR-0 reactor are discussed. These benchmarks provide accurate determination of radiation field parameters in the vicinity and over the thickness of the reactor pressure vessel. Measurements are compared to calculated results with two sets of tools: TORT discrete ordinates code and BUGLE-96 cross-section library versus the newly Westinghouse-developed RAPTOR-M3G and ALPAN VII.0. The parallel code RAPTOR-M3G enables detailed neutron distributions in energy and space in reducedmore » computational time. ALPAN VII.0 cross-section library is based on ENDF/B-VII.0 and is designed for reactor dosimetry applications. It uses a unique broad group structure to enhance resolution in thermal-neutron-energy range compared to other analogous libraries. The comparison of fast neutron (E > 0.5 MeV) results shows good agreement (within 10%) between BUGLE-96 and ALPAN VII.O libraries. Furthermore, the results compare well with analogous results of participants of the REDOS program (2005). Finally, the analytical results for fast neutrons agree within 15% with the measurements, for most locations in all three mockups. In general, however, the analytical results underestimate the attenuation through the reactor pressure vessel thickness compared to the measurements. (authors)« less

  6. 77 FR 64400 - Order of Succession for HUD Region VII

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-10-19

    ... Urban Development, designates the Order of Succession for the Kansas City Regional Office and its Field... DEPARTMENT OF HOUSING AND URBAN DEVELOPMENT [FR-5550-D-10] Order of Succession for HUD Region VII..., Assistant General Counsel, Administrative Law Division, U.S. Department of Housing and Urban Development...

  7. Evaluation of the International Barrier Corporation's Mark VII median barrier.

    DOT National Transportation Integrated Search

    1992-01-01

    The International Barrier Corporation's (IBC) Mark VII median barrier consists of a steel frame (10 ft long, 42 in high, and 44 in wide at its widest point) filled with sand and covered with a top plate. The barrier has the ability to absorb some of ...

  8. Nonredundant functions of Arabidopsis LecRK-V.2 and LecRK-VII.1 in controlling stomatal immunity and jasmonate-mediated stomatal closure.

    PubMed

    Yekondi, Shweta; Liang, Fu-Chun; Okuma, Eiji; Radziejwoski, Amandine; Mai, Hsien-Wei; Swain, Swadhin; Singh, Prashant; Gauthier, Mathieu; Chien, Hsiao-Chiao; Murata, Yoshiyuki; Zimmerli, Laurent

    2018-04-01

    Stomatal immunity restricts bacterial entry to leaves through the recognition of microbe-associated molecular patterns (MAMPs) by pattern-recognition receptors (PRRs) and downstream abscisic acid and salicylic acid signaling. Through a reverse genetics approach, we characterized the function of the L-type lectin receptor kinase-V.2 (LecRK-V.2) and -VII.1 (LecRK-VII.1). Analyses of interactions with the PRR FLAGELLIN SENSING2 (FLS2) were performed by co-immunoprecipitation and bimolecular fluorescence complementation and whole-cell patch-clamp analyses were used to evaluate guard cell Ca 2+ -permeable cation channels. The Arabidopsis thaliana LecRK-V.2 and LecRK-VII.1 and notably their kinase activities were required for full activation of stomatal immunity. Knockout lecrk-V.2 and lecrk-VII.1 mutants were hyper-susceptible to Pseudomonas syringae infection and showed defective stomatal closure in response to bacteria or to the MAMPs flagellin and EF-Tu. By contrast, Arabidopsis over-expressing LecRK-V.2 or LecRK-VII.1 demonstrated a potentiated stomatal immunity. LecRK-V.2 and LecRK-VII.1 are shown to be part of the FLS2 PRR complex. In addition, LecRK-V.2 and LecRK-VII.1 were critical for methyl jasmonate (MeJA)-mediated stomatal closure, notably for MeJA-induced activation of guard cell Ca 2+ -permeable cation channels. This study highlights the role of LecRK-V.2 and LecRK-VII.1 in stomatal immunity at the FLS2 PRR complex and in MeJA-mediated stomatal closure. © 2017 The Authors. New Phytologist © 2017 New Phytologist Trust.

  9. The Effect of Neonatal Gene Therapy with a Gamma Retroviral Vector on Cardiac Valve Disease in Mucopolysaccharidosis VII Dogs after a Decade

    PubMed Central

    Bigg, Paul W.; Sleeper, Meg M.; O’Donnell, Patricia A.; Liu, Yuli; Wu, Susan; Casal, Margret L.; Haskins, Mark E.; Ponder, Katherine P.

    2013-01-01

    Mucopolysaccharidosis VII (MPS VII) is due to deficient activity of the lysosomal enzyme β-glucuronidase (GUSB) and results in the accumulation of glycosaminoglycans (GAGs). This study determined the long-term effect of neonatal intravenous injection of a gamma retroviral vector (RV) on cardiac valve disease in MPS VII dogs. Transduced hepatocytes secreted GUSB into blood for up to 11 years at levels similar to or greater than those achieved with enzyme replacement therapy (ERT). Valve regurgitation and thickening were scored from 0 (normal) to +4 (severely abnormal). At 1 year, untreated MPS VII dogs had mitral regurgitation, mitral valve thickening, aortic regurgitation, and aortic valve thickening scores of 2.3±0.7, 2.3±0.6, 1.8±0.5, and 1.6±0.7, respectively, which were higher than the values of 0.6±0.1, 0.1±0.4, 0.3±0.8, and 0.1±0.4, respectively, in treated MPS VII dogs. Treated MPS VII dogs maintained low aortic regurgitation and aortic valve thickening scores for their lifetime. Although mitral regurgitation and mitral valve thickening scores increased to 2.0 at ≥8 years of age in the treated MPS VII dogs, older normal dogs from the colony had similar scores, making it difficult to assess mitral valve disease. Older treated dogs had calcification within the mitral and aortic valve annulus, while GUSB staining demonstrated enzyme activity within the mitral valve. We conclude that neonatal RV-mediated gene therapy reduced cardiac valve disease in MPS VII dogs for up to 11 years, and propose that neonatal initiation of ERT should have a similar effect. PMID:23860311

  10. Improving Bilingual Program Management. A Handbook for Title VII Directors.

    ERIC Educational Resources Information Center

    DeGeorge, George P., Ed.

    Filled with practical advice and workable techniques and strategies to help bilingual program directors deal with the problems they face, this handbook brings together ideas and suggestions from Title VII program directors, state coordinators, and superintendents with experience in bilingual programs. The handbook, written in question and answer…

  11. Two novel cases of cerebral haemorrhages at the neonatal period associated with inherited factor VII deficiency, one of them revealing a new nonsense mutation (Ser52Stop).

    PubMed

    Giansily-Blaizot, Muriel; Aguilar-Martinez, Patricia; Briquel, Marie-Elisabeth; d'Oiron, Roseline; De Maistre, Emmanuel; Epelbaum, Serge; Schved, Jean-François

    2003-02-01

    Factor VII (FVII) is a plasma glycoprotein that plays a key role in the initiation of blood coagulation cascade. Inherited FVII deficiency is a rare autosomal recessive disorder with a wide heterogeneous clinical pattern. The severe form may be associated with intracranial haemorrhages occurring closely to birth with a high mortality rate. In the present article, we report two novel cases of neonatal intracerebral bleeding associated with FVII activity levels below 1% of normal. FVII genotyping investigations revealed particular genotypes including the deleterious Cys135Arg mutation and a novel Ser52Stop nonsense mutation at the homozygous state. Both mutations, through different mechanisms, are expected to be inconsistent with the production of functional FVII. These putative mechanisms are discussed through a review of the literature on phenotypic and genotypic characteristics of cerebral haemorrhages in severe inherited FVII deficiency.

  12. Expression and fast preparation of biologically active recombinant human coagulation factor VII in CHO-K1 cells.

    PubMed

    Xiao, W; Li, C Q; Xiao, X P; Lin, F Z

    2013-12-16

    Human coagulation factor VII (FVII) plays an important role in the blood coagulation process and exists in micro amounts in human plasma; therefore, any attempt at the large-scale production of FVII in significant quantities is challenging. The purpose of this study was to express and obtain biologically active recombinant FVII (rFVII) from Chinese hamster ovary K1 (CHO-K1) cells. The full-length FVII cDNA was isolated from a HepG2 cell line and then subcloned in pcDNA3.1 to construct an expression vector, pcDNA-FVII. CHO-K1 cells were transfected with 1 µg pcDNA-FVII. The cell line that stably expressed secretory FVII was screened using 900 µg/mL G418. The FVII copy number in CHO-K1 cells was detected by quantitative polymerase chain reaction (qPCR). The rFVII was purified in ligand affinity chromatography medium. The purified protein was detected by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blot analysis. The biological activity of the purified FVII protein was determined by a prothrombin time assay. Three cell lines that permanently expressed rFVII were screened. The qPCR results demonstrated that each CHO-K1 cell harbored two FVII DNA copies. The SDS-PAGE and Western blot analysis showed that the purified protein was about 50 kDa. The purity of the target protein was 95%. The prothrombin time assay indicated that the FVII-specific activity of rFVII was 2573 ± 75 IU/mg. This method enabled the fast preparation of high-purity rFVII from CHO-K1 cells, and the purified protein had good biological activity.

  13. Free energy models for ice VII and liquid water derived from pressure, entropy, and heat capacity relations

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Myint, Philip C.; Benedict, Lorin X.; Belof, Jonathan L.

    Here, we present equations of state relevant to conditions encountered in ramp and multiple-shock compression experiments of water. These experiments compress water from ambient conditions to pressures as high as about 14 GPa and temperatures of up to several hundreds of Kelvin. Water may freeze into ice VII during this process. Although there are several studies on the thermodynamic properties of ice VII, an accurate and analytic free energy model from which all other properties may be derived in a thermodynamically consistent manner has not been previously determined. We have developed such a free energy model for ice VII thatmore » is calibrated with pressure-volume-temperature measurements and melt curve data. Furthermore, we show that liquid water in the pressure and temperature range of interest is well-represented by a simple Mie-Grüneisen equation of state. Our liquid water and ice VII equations of state are validated by comparing to sound speed and Hugoniot data. Although they are targeted towards ramp and multiple-shock compression experiments, we demonstrate that our equations of state also behave reasonably well at pressures and temperatures that lie somewhat beyond those found in the experiments.« less

  14. Free energy models for ice VII and liquid water derived from pressure, entropy, and heat capacity relations

    DOE PAGES

    Myint, Philip C.; Benedict, Lorin X.; Belof, Jonathan L.

    2017-08-28

    Here, we present equations of state relevant to conditions encountered in ramp and multiple-shock compression experiments of water. These experiments compress water from ambient conditions to pressures as high as about 14 GPa and temperatures of up to several hundreds of Kelvin. Water may freeze into ice VII during this process. Although there are several studies on the thermodynamic properties of ice VII, an accurate and analytic free energy model from which all other properties may be derived in a thermodynamically consistent manner has not been previously determined. We have developed such a free energy model for ice VII thatmore » is calibrated with pressure-volume-temperature measurements and melt curve data. Furthermore, we show that liquid water in the pressure and temperature range of interest is well-represented by a simple Mie-Grüneisen equation of state. Our liquid water and ice VII equations of state are validated by comparing to sound speed and Hugoniot data. Although they are targeted towards ramp and multiple-shock compression experiments, we demonstrate that our equations of state also behave reasonably well at pressures and temperatures that lie somewhat beyond those found in the experiments.« less

  15. Synthesis of organically templated nanoporous tin (II/IV) phosphate for radionuclide and metal sequestration

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Wellman, Dawn M.; Mattigod, Shas V.; Parker, Kent E.

    2006-03-20

    Nanoporous tin (II/IV) phosphate materials, with spherical morphology, have been synthesized using cetyltrimethylammonium chloride (CH3(CH2)15N(CH3)3Cl) as the surfactant. The structure of the material is stable at 500°C; however, partial oxidation of the material occurs with redox conversion of Sn2+ to Sn4+, resulting in a mixed Sn(II)/ Sn(IV) material. Preliminary batch contact studies were conducted to assess the effectiveness of nanoporous tin phosphate, NP-SnPO, in sequestering redox sensitive metals and radionuclides, technetium(VII), neptunium(V), thorium(IV), and a toxic metal, chromium(VI), from aqueous matrices. Results indicate tin (II) phosphate removed > 95% of all contaminants investigated from solution.

  16. Statistics and Title VII Proof: Prima Facie Case and Rebuttal.

    ERIC Educational Resources Information Center

    Whitten, David

    1978-01-01

    The method and means by which statistics can raise a prima facie case of Title VII violation are analyzed. A standard is identified that can be applied to determine whether a statistical disparity is sufficient to shift the burden to the employer to rebut a prima facie case of discrimination. (LBH)

  17. The effect of neonatal gene therapy with a gamma retroviral vector on cardiac valve disease in mucopolysaccharidosis VII dogs after a decade.

    PubMed

    Bigg, Paul W; Sleeper, Meg M; O'Donnell, Patricia A; Liu, Yuli; Wu, Susan; Casal, Margret L; Haskins, Mark E; Ponder, Katherine P

    2013-11-01

    Mucopolysaccharidosis VII (MPS VII) is due to deficient activity of the lysosomal enzyme β-glucuronidase (GUSB) and results in the accumulation of glycosaminoglycans (GAGs). This study determined the long-term effect of neonatal intravenous injection of a gamma retroviral vector (RV) on cardiac valve disease in MPS VII dogs. Transduced hepatocytes secreted GUSB into the blood for up to 11 years at levels similar to or greater than those achieved with enzyme replacement therapy (ERT). Valve regurgitation and thickening were scored from 0 (normal) to +4 (severely abnormal). At 1 year, untreated MPS VII dogs had mitral regurgitation, mitral valve thickening, aortic regurgitation, and aortic valve thickening scores of 2.3 ± 0.7, 2.3 ± 0.6, 1.8 ± 0.5, and 1.6 ± 0.7, respectively, which were higher than the values of 0.6 ± 0.1, 0.1 ± 0.4, 0.3 ± 0.8, and 0.1 ± 0.4, respectively, in treated MPS VII dogs. Treated MPS VII dogs maintained low aortic regurgitation and aortic valve thickening scores in their lifetime. Although mitral regurgitation and mitral valve thickening scores increased to 2.0 at ≥ 8 years of age in the treated MPS VII dogs, older normal dogs from the colony had similar scores, making it difficult to assess mitral valve disease. Older treated dogs had calcification within the mitral and the aortic valve annulus, while GUSB staining demonstrated enzyme activity within the mitral valve. We conclude that neonatal RV-mediated gene therapy reduced cardiac valve disease in MPS VII dogs for up to 11 years, and propose that neonatal initiation of ERT should have a similar effect. © 2013.

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

    PubMed

    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.

  19. Heterozygous congenital Factor VII deficiency with the 9729del4 mutation, associated with severe spontaneous intracranial bleeding in an adolescent male.

    PubMed

    Cramer, Thomas J; Anderson, Kristin; Navaz, Karanjia; Brown, Justin M; Mosnier, Laurent O; von Drygalski, Annette

    2016-03-01

    In congenital Factor (F) VII deficiency bleeding phenotype and intrinsic FVII activity levels don't always correlate. Patients with FVII activity levels <30% appear to have a higher bleeding propensity, but bleeding can also occur at higher FVII activity levels. Reasons for bleeding at higher FVII activity levels are unknown, and it remains challenging to manage such patients clinically. A 19year old male with spontaneous intracranial hemorrhage and FVII activity levels of 44%, requiring emergent surgical intervention and a strategy for FVII replacement. Genotyping showed the rare heterozygous FVII 9729del4 mutation. Bleed evacuation was complicated by epidural abscess requiring craniectomy, bone graft procedures, and prolonged administration of recombinant human (rh) activated FVII (FVIIa). The patient recovered without neurological deficits, and remains on prophylactic low dose treatment with rhFVIIa in relation to risky athletic activities. For clinicians, it is important to recognize that effects of rhFVIIa within these pathways are independent of its contribution to blood clot formation and cannot be assessed by clotting assays. Reduced FVII levels should therefore not be dismissed, as even a mild reduction may result in spontaneous bleeding. Treatment of mild FVII deficiency requires a careful case-by-case approach, based on the clinical scenario. Copyright © 2015 Elsevier Inc. All rights reserved.

  20. Recombinant activated factor VII in the treatment of non-haemophilia patients: physician under-reporting of thromboembolic adverse events.

    PubMed

    Hsia, C C; Zurawska, J H; Tong, M Z Y; Eckert, K; McAlister, V C; Chin-Yee, I H

    2009-02-01

    The objective of this study was to determine if clinically important thromboembolic adverse events (TAEs) because of recombinant activated factor VII (rFVIIa) administration are being under-reported. rFVIIa is a potent haemostatic agent with a short half-life of 2.6 h that is increasingly used in 'off-label' situations. Retrospective review of 94 patients who received rFVIIa during 1 January 2003 to 30 June 2007 was carried out at a tertiary care centre. Sixty-nine patients, 32 females and 37 males, mean age 55 years (18-84 years), satisfied study criteria of off-label usage. This was a high-risk population with 33 (48%) deaths. A mean dose of 8.2 mg (2.4-19.2 mg) was administered in two average divided doses. Thirty-six potential TAEs were identified in 29 patients, and of these, 12 patients had TAEs deemed to be rFVIIa related and were identified on average 8.8 days after exposure to rFVIIa. Forty-eight (70%) physician questionnaires were completed; however, no TAEs were reported in these questionnaires or on chart review. Potential clinically significant TAEs are being under-reported by treating physicians. Until further evidence, we suggest the urgent need to develop consensus recommendations for utilization and required follow up to monitor the safety of rFVIIa and that at a minimum, all use of rFVIIa should be regulated through a gate-keeping mechanism that ensures adherence to these policies. Furthermore, prospective registries and trials are necessary to evaluate the efficacy and safety of rFVIIa in off-label settings.

  1. Inhalation Toxicology. VII. Times To Incapacitation and Death for Rats Exposed Continuously to Atmospheric Acrolein Vapor

    DTIC Science & Technology

    1986-05-01

    DOT FMAM-6/5INHALATION TOXICOLOGY : Office of Aviation Medicine VII. Times to Incapacitation and Washington, D.C. 20591 D ahfrR t x oe Continuously to...Accession No. 3. Recipient’s Catalog No. pOT/FAA/AM-86/5 ,4%__ _____ 4. T,tle and Subtoie S. Report Doate INHALATION TOXICOLOGY : VII. TIMES TO...Statement " Combustion toxicology ; smoke; irritant This document is available to the public gas; time-to-incapacitation; time-to- through the National

  2. On the Factor Structure of the Beck Depression Inventory-II: G Is the Key

    ERIC Educational Resources Information Center

    Brouwer, Danny; Meijer, Rob R.; Zevalkink, Jolien

    2013-01-01

    The Beck Depression Inventory-II (BDI-II; Beck, Steer, & Brown, 1996) is intended to measure severity of depression, and because items represent a broad range of depressive symptoms, some multidimensionality exists. In recent factor-analytic studies, there has been a debate about whether the BDI-II can be considered as one scale or whether…

  3. Corrective GUSB transfer to the canine mucopolysaccharidosis VII cornea using a helper-dependent canine adenovirus vector

    PubMed Central

    Serratrice, Nicolas; Cubizolle, Aurelie; Ibanes, Sandy; Mestre-Francés, Nadine; Bayo-Puxan, Neus; Creyssels, Sophie; Gennetier, Aurelie; Bernex, Florence; Verdier, Jean-Michel; Haskins, Mark E.; Couderc, Guilhem; Malecaze, Francois; Kalatzis, Vasiliki; Kremer, Eric J.

    2015-01-01

    Corneal transparency is maintained, in part, by specialized fibroblasts called keratocytes, which reside in the fibrous lamellae of the stroma. Corneal clouding, a condition that impairs visual acuity, is associated with numerous diseases, including mucopolysaccharidosis (MPS) type VII. MPS VII is due to deficiency in β-glucuronidase (β-glu) enzymatic activity, which leads to accumulation of glycosaminoglycans (GAGs), and secondary accumulation of gangliosides. Here, we tested the efficacy of canine adenovirus type 2 (CAV-2) vectors to transduce keratocyte in vivo in mice and nonhuman primates, and ex vivo in dog and human corneal explants. Following efficacy studies, we asked if we could treat corneal clouding by the injection a helper-dependent (HD) CAV-2 vector (HD-RIGIE) harboring the human cDNA coding for β-glu (GUSB) in the canine MPS VII cornea. β-Glu activity, GAG content, and lysosome morphology and physiopathology were analyzed. We found that HD-RIGIE injections efficiently transduced coxsackievirus adenovirus receptor-expressing keratocytes in the four species and, compared to mock-injected controls, improved the pathology in the canine MPS VII cornea. The key criterion to corrective therapy was the steady controlled release of β-glu and its diffusion throughout the collagen-dense stroma. These data support the continued evaluation of HD CAV-2 vectors to treat diseases affecting corneal keratocytes. PMID:24607662

  4. RISK FACTORS FOR HTLV-II INFECTION IN PERUVIAN MEN WHO HAVE SEX WITH MEN

    PubMed Central

    ZUNT, JOSEPH R.; LA ROSA, ALBERTO M.; PEINADO, JESÚS; LAMA, JAVIER R.; SUAREZ, LUIS; PUN, MONICA; CABEZAS, CESAR; SANCHEZ, JORGE

    2009-01-01

    Human T-cell lymphotropic virus type-II (HTLV-II) infection is endemic in indigenous groups in the Americas and injection drug users (IDUs) worldwide. In Peru, HTLV-II infection was previously identified in two indigenous Amazonians. We examined risk factors for HTLV-II infection in 2,703 Peruvian men who have sex with men (MSM): 35 (1.3%) were HTLV-II positive. HTLV-II infection was associated with syphilis, HSV-2 infection, unprotected receptive anal intercourse, and older age. This is the first report of HTLV-II in a non-indigenous non-IDU population in Peru. Additional studies are needed to determine if HTLV-II is a sexually transmitted infection in this and other sexually active populations. PMID:16687704

  5. 29 CFR 1620.27 - Relationship to the Equal Pay Act of title VII of the Civil Rights Act.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 29 Labor 4 2010-07-01 2010-07-01 false Relationship to the Equal Pay Act of title VII of the Civil... OPPORTUNITY COMMISSION THE EQUAL PAY ACT § 1620.27 Relationship to the Equal Pay Act of title VII of the Civil... equal pay under the Equal Pay Act has no relationship to whether the employee is in the lower paying job...

  6. 29 CFR 1605.2 - Reasonable accommodation without undue hardship as required by section 701(j) of title VII of the...

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... Regulations Relating to Labor (Continued) EQUAL EMPLOYMENT OPPORTUNITY COMMISSION GUIDELINES ON DISCRIMINATION... address other obligations under title VII not to discriminate on grounds of religion, nor other provisions... to discrimination prohibited by title VII on the bases of race, color, sex, and national origin also...

  7. 29 CFR 1605.2 - Reasonable accommodation without undue hardship as required by section 701(j) of title VII of the...

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... Regulations Relating to Labor (Continued) EQUAL EMPLOYMENT OPPORTUNITY COMMISSION GUIDELINES ON DISCRIMINATION... address other obligations under title VII not to discriminate on grounds of religion, nor other provisions... to discrimination prohibited by title VII on the bases of race, color, sex, and national origin also...

  8. 29 CFR 1605.2 - Reasonable accommodation without undue hardship as required by section 701(j) of title VII of the...

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... Regulations Relating to Labor (Continued) EQUAL EMPLOYMENT OPPORTUNITY COMMISSION GUIDELINES ON DISCRIMINATION... address other obligations under title VII not to discriminate on grounds of religion, nor other provisions... to discrimination prohibited by title VII on the bases of race, color, sex, and national origin also...

  9. 29 CFR 1605.2 - Reasonable accommodation without undue hardship as required by section 701(j) of title VII of the...

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... Regulations Relating to Labor (Continued) EQUAL EMPLOYMENT OPPORTUNITY COMMISSION GUIDELINES ON DISCRIMINATION... address other obligations under title VII not to discriminate on grounds of religion, nor other provisions... to discrimination prohibited by title VII on the bases of race, color, sex, and national origin also...

  10. Quantitative proteomics identify an association between extracellular matrix degradation and immunopathology of genotype VII Newcastle disease virus in the spleen in chickens.

    PubMed

    Hu, Zenglei; Gu, Han; Hu, Jiao; Hu, Shunlin; Wang, Xiaoquan; Liu, Xiaowen; Jiao, Xinan; Liu, Xiufan

    2018-06-15

    Pathogenesis of genotype VII Newcastle disease virus (NDV) is characterized with remarkable immunopathology in the spleen in chickens. However, the mechanism for this unique pathological phenotype is not fully understood. Previous transcriptomics data showed that genotype VII NDV JS5/05 caused a greater downregulation of extracellular matrix (ECM) genes than genotype IV virus Herts/33 in the spleen. In this study, the role of ECM in pathology of genotype VII NDV was investigated using quantitative proteomics. Pathology studies showed that JS5/05 caused severe immunopathology characterized with remarkable necrosis in the spleen, whereas Herts/33 only induced mild pathological changes. The ECM was firstly enriched from the spleens and ECM proteins of different categories were identified by LC-MS/MS. Quantitative proteomic analysis showed that JS5/05 caused a significant disruption of ECM integrity and molecular composition compared to Herts/33. Particularly, JS5/05 induced a more remarkable collagen breakdown in the spleen compared to Herts/33. Moreover, matrix metalloproteinase (MMP)-13 and -14 were significantly upregulated by JS5/05 infection. KEGG pathway analysis suggested that differential regulation of ECM proteins by JS5/05 and Herts/33 may impact pathology through different pathways. Therefore, our results suggested that MMP upregulation and consequent ECM degradation contribute to immunopathology of genotype VII NDV in the spleen. Pathogenesis of genotype VII NDV is characterized with severe immunopathology in the spleen in chickens. Elucidating the mechanism of this pathology phenotype is critical to understand pathogenesis of genotype VII NDV. Here, we present the proteomic data of an important non-cellular compartment, the extracellular matrix (ECM), in the spleen from chickens infected with genotype VII and IV NDVs. Our results suggest that significant upregulation of matrix metalloproteinases by genotype VII NDV and consequent disruption of ECM

  11. Ionization correction factors for H II regions in blue compact dwarf galaxies

    NASA Astrophysics Data System (ADS)

    Holovatyi, V. V.; Melekh, B. Ya.

    2002-08-01

    Energy distributions in the spectra of the ionizing nuclei of H II regions beyond λ <= 91.2 nm were calculated. A grid of photoionization models of 270 H II regions was constructed. The free parameters of the model grid are the hydrogen density nH in the nebular gas, filling factor, energy Lc-spectrum of ionizing nuclei, and metallicity. The chemical composition from the studies of Izotov et al. were used for model grid initialization. The integral linear spectra calculated for the photoionization models were used to determine the concentration ne, temperatures Te of electrons, and ionic concentrations n(A+i)/n(H+) by the nebular gas diagnostic method. The averaged relative ionic abundances n(A+i)/n(H+) thus calculated were used to determine new expressions for ionization correction factors which we recommend for the determination of abundances in the H II regions of blue compact dwarf galaxies.

  12. Bovine adenovirus 3 core protein precursor pVII localizes to mitochondria, and modulates ATP synthesis, mitochondrial Ca2+ and mitochondrial membrane potential.

    PubMed

    Anand, Sanjeev K; Gaba, Amit; Singh, Jaswant; Tikoo, Suresh K

    2014-02-01

    Viruses modulate the functions of mitochondria by translocating viral proteins to the mitochondria. Subcellular fractionation and sensitivity to proteinase K/Triton X-100 treatment of mitochondrial fractions of bovine adenovirus (BAdV)-3-infected/transfected cells suggested that core protein pVII localizes to the mitochondria and contains a functional mitochondrial localization signal. Moreover, mitochondrial localization of BAdV-3 pVII appears to help in the retention of mitochondrial Ca(2+), inducing a significant increase in the levels of ATP and maintaining the mitochondrial membrane potential (MMP) in transfected cells. In contrast, mitochondrial localization of BAdV-3 pVII has no significant effect on the levels of cytoplasmic Ca(2+) and reactive oxygen species production in the transfected cells. Consistent with these results, expression of pVII in transfected cells treated with staurosporine decreased significantly the activation of caspase-3. Our results suggested that BAdV-3 pVII localizes to mitochondria, and interferes with apoptosis by inhibiting loss of the MMP and by increasing mitochondrial Ca(2+) and ATP production.

  13. Hemostatic and neuroprotective effects of human recombinant activated factor VII therapy after traumatic brain injury in pigs

    PubMed Central

    Zhang, Jun; Groff, Robert F.; Chen, Xiao-Han; Browne, Kevin D.; Huang, Jason; Schwartz, Eric D.; Meaney, David F.; Johnson, Victoria E.; Stein, Sherman C.; Rojkjaer, Rasmus; Smith, Douglas H.

    2012-01-01

    Human recombinant activated factor-VII (rFVIIa) has been used successfully in the treatment of spontaneous intracerebral hemorrhage. In addition, there is increasing interest in its use to treat uncontrolled bleeding of other origins, including trauma. The aim of this study was to evaluate the safety and potential effectiveness of rFVIIa to mitigate bleeding using a clinically relevant model of traumatic brain injury (TBI) in the pig. A double injury model was chosen consisting of (1) an expanding cerebral contusion induced by the application of negative pressure to the exposed cortical surface and (2) a rapid rotational acceleration of the head to induce diffuse axonal injury (DAI). Injuries were performed on 10 anesthetized pigs. Five minutes after injury, 720 μg/kg rFVIIa (n = 5) or vehicle control (n = 5) was administered intravenously. Magnetic resonance imaging (MRI) studies were performed within 30 min and at 3 days post-TBI to determine the temporal expansion of the cerebral contusion. Euthanasia and histopathologic analysis were performed at day 3. This included observations for hippocampal neuronal degeneration, axonal pathology and microclot formation. The expansion of contusion volume over the 3 days post-injury period was reduced significantly in animals treated with rFVIIa compared to vehicle controls. Surprisingly, immunohistochemical analysis demonstrated that the number of dead/dying hippocampal neurons and axonal pathology was reduced substantially by rFVIIa treatment compared to vehicle. In addition, there was no difference in the extent of microthrombi between groups. rFVIIa treatment after TBI in the pig reduced expansion of hemorrhagic cerebral contusion volume without exacerbating the severity of microclot formation. Finally, rFVIIa treatment provided a surprising neuroprotective effect by reducing hippocampal neuron degeneration as well as the extent of DAI. PMID:18291370

  14. Epidemiology of multiple sclerosis in US veterans: VII. Risk factors for MS.

    PubMed

    Kurtzke, J F; Page, W F

    1997-01-01

    In previous papers of this series, we explored the epidemiology of MS, examining the effects of race, sex, geography, latitude and climate, migration, age at onset, population ancestry, and individual ethnicity on the risk of MS, using an unusually large cohort of MS cases and pre-illness matched controls comprising US veterans of World War II (WWII) and the Korean Conflict (KC). In this paper, we examine primarily the effect of other factors on the risk of MS in this cohort and their relation to those previously studied. We found here that latitude tier of residence at entry into active duty (EAD), years of education, and socioeconomic class (coded from occupation) were similarly associated with MS risk among white men, black men, and white women. Higher levels of each factor showed increased MS risk. Multivariate analyses indicated that for white male WWII subjects an urban address, 9 or more years of education, uncorrected visual acuity less than 20/20 at EAD, a more northern latitude, and a higher proportion of the subject's EAD state population reporting Swedish ancestry each significantly increased the risk of MS. White male KC subjects showed roughly the same patterns, except that uncorrected visual acuity less than 20/20 was associated with lower MS risk (ancestry/ethnicity was not studied). For black male WWII and KC subjects combined, a similar analysis (omitting ancestry/ethnicity) showed that only latitude at EAD and 9 or more years of education were independently associated with a significantly higher MS risk, and for WWII plus KC white women (also without ancestry/ethnicity), only latitude was a significant risk factor in these multivariate analyses. The smaller number of subjects, especially in these last two groups, limited the power to detect statistically significant risks in these last analyses. Similarities to white men of WWII in univariate analyses for all other groups suggest that findings for the former would otherwise apply to the latter

  15. Large proteoglycan complexes and disturbed collagen architecture in the corneal extracellular matrix of mucopolysaccharidosis type VII (Sly syndrome).

    PubMed

    Young, Robert D; Liskova, Petra; Pinali, Christian; Palka, Barbara P; Palos, Michalis; Jirsova, Katerina; Hrdlickova, Enkela; Tesarova, Marketa; Elleder, Milan; Zeman, Jiri; Meek, Keith M; Knupp, Carlo; Quantock, Andrew J

    2011-08-24

    Deficiencies in enzymes involved in proteoglycan (PG) turnover underlie a number of rare mucopolysaccharidoses (MPS), investigations of which can considerably aid understanding of the roles of PGs in corneal matrix biology. Here, the authors analyze novel pathologic changes in MPS VII (Sly syndrome) to determine the nature of PG-collagen associations in stromal ultrastructure. Transmission electron microscopy and electron tomography were used to investigate PG-collagen architectures and interactions in a cornea obtained at keratoplasty from a 22-year-old man with MPS VII, which was caused by a compound heterozygous mutation in the GUSB gene. Transmission electron microscopy showed atypical morphology of the epithelial basement membrane and Bowman's layer in MPS VII. Keratocytes were packed with cytoplasmic vacuoles containing abnormal glycosaminoglycan (GAG) material, and collagen fibrils were thinner than in normal cornea and varied considerably throughout anterior (14-32 nm), mid (13-42 nm), and posterior (17-39 nm) regions of the MPS VII stroma. PGs viewed in three dimensions were striking in appearance in that they were significantly larger than PGs in normal cornea and formed highly extended linkages with multiple collagen fibrils. Cellular changes in the MPS VII cornea resemble those in other MPS. However, the wide range of collagen fibril diameters throughout the stroma and the extensive matrix presence of supranormal-sized PG structures appear to be unique features of this disorder. The findings suggest that the accumulation of stromal chondroitin-, dermatan-, and heparan-sulfate glycosaminoglycans in the absence of β-glucuronidase-mediated degradation can modulate collagen fibrillogenesis.

  16. The Economics of Enforcement of Title VII of the Civil Rights Act of 1964. Discussion Papers No. 313-75.

    ERIC Educational Resources Information Center

    Beller, Andrea H.

    The purpose of this paper is to estimate the effects of enforcement of Title VII to determine whether and to what extent it has helped to achieve the elimination of employment discrimination. The model developed in this paper is considered to depart from those of previous Title VII studies in two ways. First, it incorporates the effects of the…

  17. Coincidences between O VI and O VII Lines: Insights from High-resolution Simulations of the Warm-hot Intergalactic Medium

    NASA Astrophysics Data System (ADS)

    Cen, Renyue

    2012-07-01

    With high-resolution (0.46 h -1 kpc), large-scale, adaptive mesh-refinement Eulerian cosmological hydrodynamic simulations we compute properties of O VI and O VII absorbers from the warm-hot intergalactic medium (WHIM) at z = 0. Our new simulations are in broad agreement with previous simulations with ~40% of the intergalactic medium being in the WHIM. Our simulations are in agreement with observed properties of O VI absorbers with respect to the line incidence rate and Doppler-width-column-density relation. It is found that the amount of gas in the WHIM below and above 106 K is roughly equal. Strong O VI absorbers are found to be predominantly collisionally ionized. It is found that (61%, 57%, 39%) of O VI absorbers of log N(O VI) cm2 = (12.5-13, 13-14, > 14) have T < 105 K. Cross correlations between galaxies and strong [N(O VI) > 1014 cm-2] O VI absorbers on ~100-300 kpc scales are suggested as a potential differentiator between collisional ionization and photoionization models. Quantitative prediction is made for the presence of broad and shallow O VI lines that are largely missed by current observations but will be detectable by Cosmic Origins Spectrograph observations. The reported 3σ upper limit on the mean column density of coincidental O VII lines at the location of detected O VI lines by Yao et al. is above our predicted value by a factor of 2.5-4. The claimed observational detection of O VII lines by Nicastro et al., if true, is 2σ above what our simulations predict.

  18. Cetuximab in treatment of metastatic colorectal cancer: final survival analyses and extended RAS data from the NORDIC-VII study.

    PubMed

    Guren, Tormod Kyrre; Thomsen, Maria; Kure, Elin H; Sorbye, Halfdan; Glimelius, Bengt; Pfeiffer, Per; Österlund, Pia; Sigurdsson, Fridbjörn; Lothe, Inger Marie Bowitz; Dalsgaard, Astrid Marie; Skovlund, Eva; Christoffersen, Thoralf; Tveit, Kjell Magne

    2017-05-09

    The NORDIC-VII study is a randomised phase III trial of cetuximab plus continuous or intermittent fluorouracil, folinic acid, and oxaliplatin (Nordic FLOX) vs FLOX alone in first-line treatment of metastatic colorectal cancer. The present report presents an updated and final survival analysis with BRAF and extended RAS mutational status, 5 years after the primary analysis. A total of 566 patients were included in the intention-to-treat (ITT) population of the NORDIC-VII study. Updated survival status was obtained from 176 patients who were alive in the primary survival analyses. Samples from 223 tumours previously found to be KRAS (exon 2) and BRAF (V600E) wild-type, were re-analysed for KRAS (exons 3 and 4) and NRAS (exons 2-4) mutations. Including the extended RAS analyses, RAS and BRAF mutational status was available from 457 patients (81% of the ITT population). RAS was mutated in 46% and BRAF in 12% of the tumours. RAS and BRAF, if mutated, were negative prognostic factors. The updated analyses confirmed the finding of the primary report that cetuximab did not provide any additional benefit when added to FLOX in patients with RAS/BRAF wild-type tumours, neither on progression-free nor overall survival. However, the outcomes in a subset of patients, which, after the first eight treatment cycles, received cetuximab alone, suggested a beneficial effect of cetuximab monotherapy. Adding cetuximab to Nordic FLOX did not provide any clinical benefit, but the data suggested an effect of cetuximab monotherapy in patients with RAS/BRAF wild-type tumours in the NORDIC-VII cohort. The data were compatible with a negative interaction between cetuximab and the Nordic FLOX chemotherapy backbone.

  19. Ten-year experience of recombinant activated factor VII use in surgical patients with congenital haemophilia with inhibitors or acquired haemophilia in Japan.

    PubMed

    Takedani, H; Shima, M; Horikoshi, Y; Koyama, T; Fukutake, K; Kuwahara, M; Ishiguro, N

    2015-05-01

    Patients with congenital haemophilia with inhibitors or acquired haemophilia are at risk of bleeding complications during surgery. In these patients, replacement therapy for the missing coagulation factor is ineffective, and a bypassing agent such as recombinant activated factor VII (rFVIIa) is required to manage bleeding. To evaluate the safety and haemostatic efficacy of rFVIIa treatment in Japanese patients with congenital haemophilia with inhibitors to FVIII/FIX or acquired haemophilia undergoing surgery. Postmarketing surveillance data from May 2000 to March 2010 were analysed to assess the haemostatic efficacy of 38 procedures in 22 patients with congenital haemophilia A, 13 procedures in seven patients with congenital haemophilia B, and five procedures in five patients with acquired haemophilia. Postoperative bleeding control was judged to be effective (bleeding was stopped completely or reduced considerably) for 34/38 procedures (89%) in patients with congenital haemophilia A, 10/13 procedures (77%) in patients with congenital haemophilia B, and 4/5 procedures (80%) in patients with acquired haemophilia. Tranexamic acid was used concomitantly for 36/56 procedures (64%). Safety was analysed for 66 procedures in 37 patients. Adverse effects potentially related to rFVIIa treatment included mild superficial thrombophlebitis, mild decrease in platelet count, and mild elevation of the serum alanine transaminase level in one patient each. All adverse effects resolved without treatment. Administration of rFVIIa provided adequate haemostasis without serious adverse effects in the majority of cases. The efficacy and safety data in Japanese patients were similar to previously published data from other countries. © 2014 The Authors. Haemophilia Published by John Wiley & Sons Ltd.

  20. ENDF/B-VII.1 Neutron Cross Section Data Testing with Critical Assembly Benchmarks and Reactor Experiments

    NASA Astrophysics Data System (ADS)

    Kahler, A. C.; MacFarlane, R. E.; Mosteller, R. D.; Kiedrowski, B. C.; Frankle, S. C.; Chadwick, M. B.; McKnight, R. D.; Lell, R. M.; Palmiotti, G.; Hiruta, H.; Herman, M.; Arcilla, R.; Mughabghab, S. F.; Sublet, J. C.; Trkov, A.; Trumbull, T. H.; Dunn, M.

    2011-12-01

    The ENDF/B-VII.1 library is the latest revision to the United States' Evaluated Nuclear Data File (ENDF). The ENDF library is currently in its seventh generation, with ENDF/B-VII.0 being released in 2006. This revision expands upon that library, including the addition of new evaluated files (was 393 neutron files previously, now 423 including replacement of elemental vanadium and zinc evaluations with isotopic evaluations) and extension or updating of many existing neutron data files. Complete details are provided in the companion paper [M. B. Chadwick et al., "ENDF/B-VII.1 Nuclear Data for Science and Technology: Cross Sections, Covariances, Fission Product Yields and Decay Data," Nuclear Data Sheets, 112, 2887 (2011)]. This paper focuses on how accurately application libraries may be expected to perform in criticality calculations with these data. Continuous energy cross section libraries, suitable for use with the MCNP Monte Carlo transport code, have been generated and applied to a suite of nearly one thousand critical benchmark assemblies defined in the International Criticality Safety Benchmark Evaluation Project's International Handbook of Evaluated Criticality Safety Benchmark Experiments. This suite covers uranium and plutonium fuel systems in a variety of forms such as metallic, oxide or solution, and under a variety of spectral conditions, including unmoderated (i.e., bare), metal reflected and water or other light element reflected. Assembly eigenvalues that were accurately predicted with ENDF/B-VII.0 cross sections such as unmoderated and uranium reflected 235U and 239Pu assemblies, HEU solution systems and LEU oxide lattice systems that mimic commercial PWR configurations continue to be accurately calculated with ENDF/B-VII.1 cross sections, and deficiencies in predicted eigenvalues for assemblies containing selected materials, including titanium, manganese, cadmium and tungsten are greatly reduced. Improvements are also confirmed for selected

  1. A novel missense mutation close to the charge-stabilizing system in a patient with congenital factor VII deficiency.

    PubMed

    Jiang, Minghua; Wang, Zhaoyue; Yu, Ziqiang; Bai, Xia; Su, Jian; Cao, Lijuan; Zhang, Wei; Ruan, Changgeng

    2011-06-01

    Congenital factor VII (FVII) deficiency is a rare autosomal recessive bleeding disorder. Its clinical manifestation and mutational spectrum are highly variable. The purpose of this study was to identify and characterize the mutation causing the FVII deficiency in a Chinese patient and his family. The FVII gene was analyzed by genomic DNA sequencing, and the FVII levels in patient's plasma were measured with an enzyme-linked immunoabsorbent assay (ELISA) and one-stage prothrombin time based method. In addition, the FVII-Phe190 mutant identified in the pedigree was expressed in the HEK293 cells, and the subcellular localization experiments in the Chinese hamster ovary (CHO) cells were performed. The patient had a prolonged prothrombin time and low levels of both FVII antigen and activity, and two heterozygous mutations were identified in F7 gene (NG-009262.1): a g.15975 G>A in the splice receptor site of intron 6 and a novel g.16750 C>T in exon 8 resulting in Ser190 to Phe190 replacement. In expression experiments, the reduced antigen and activity levels of FVII-Phe190 in the culture medium were found, whereas an ELISA and Western blotting analysis of FVII revealed that mutant FVII-Phe190 was synthesized in the cells as the wild-type FVII-Ser190. And FVII-Phe190 was found in endoplasmic reticulum and Golgi apparatus. Compound heterozygous mutations in F7 gene should be responsible for the FVII deficiency in this patient. The FVII-Phe190 can normally be synthesized and transported from endoplasmic reticulum to Golgi apparatus, but degraded or inefficiently secreted.

  2. Enhanced recombinant factor VII expression in Chinese hamster ovary cells by optimizing signal peptides and fed-batch medium.

    PubMed

    Peng, Lin; Yu, Xiao; Li, Chengyuan; Cai, Yanfei; Chen, Yun; He, Yang; Yang, Jianfeng; Jin, Jian; Li, Huazhong

    2016-04-01

    Signal peptides play an important role in directing and efficiently transporting secretory proteins to their proper locations in the endoplasmic reticulum of mammalian cells. The aim of this study was to enhance the expression of recombinant coagulation factor VII (rFVII) in CHO cells by optimizing the signal peptides and type of fed-batch culture medium used. Five sub-clones (O2, I3, H3, G2 and M3) with different signal peptide were selected by western blot (WB) analysis and used for suspension culture. We compared rFVII expression levels of 5 sub-clones and found that the highest rFVII expression level was obtained with the IgK signal peptide instead of Ori, the native signal peptide of rFVII. The high protein expression of rFVII with signal peptide IgK was mirrored by a high transcription level during suspension culture. After analyzing culture and feed media, the combination of M4 and F4 media yielded the highest rFVII expression of 20 mg/L during a 10-day suspension culture. After analyzing cell density and cell cycle, CHO cells feeding by F4 had a similar percentage of cells in G0/G1 and a higher cell density compared to F2 and F3. This may be the reason for high rFVII expression in M4+F4. In summary, rFVII expression was successfully enhanced by optimizing the signal peptide and fed-batch medium used in CHO suspension culture. Our data may be used to improve the production of other therapeutic proteins in fed-batch culture.

  3. 8 CFR 233.6 - Aliens entering Guam or the Commonwealth of the Northern Mariana Islands pursuant to Title VII of...

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... the Northern Mariana Islands pursuant to Title VII of Public Law 110-229, âConsolidated Natural Resources Act of 2008.â 233.6 Section 233.6 Aliens and Nationality DEPARTMENT OF HOMELAND SECURITY... of the Northern Mariana Islands pursuant to Title VII of Public Law 110-229, “Consolidated Natural...

  4. 8 CFR 233.6 - Aliens entering Guam or the Commonwealth of the Northern Mariana Islands pursuant to Title VII of...

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... the Northern Mariana Islands pursuant to Title VII of Public Law 110-229, âConsolidated Natural Resources Act of 2008.â 233.6 Section 233.6 Aliens and Nationality DEPARTMENT OF HOMELAND SECURITY... of the Northern Mariana Islands pursuant to Title VII of Public Law 110-229, “Consolidated Natural...

  5. 8 CFR 233.6 - Aliens entering Guam or the Commonwealth of the Northern Mariana Islands pursuant to Title VII of...

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... the Northern Mariana Islands pursuant to Title VII of Public Law 110-229, âConsolidated Natural Resources Act of 2008.â 233.6 Section 233.6 Aliens and Nationality DEPARTMENT OF HOMELAND SECURITY... of the Northern Mariana Islands pursuant to Title VII of Public Law 110-229, “Consolidated Natural...

  6. 8 CFR 233.6 - Aliens entering Guam or the Commonwealth of the Northern Mariana Islands pursuant to Title VII of...

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... the Northern Mariana Islands pursuant to Title VII of Public Law 110-229, âConsolidated Natural Resources Act of 2008.â 233.6 Section 233.6 Aliens and Nationality DEPARTMENT OF HOMELAND SECURITY... of the Northern Mariana Islands pursuant to Title VII of Public Law 110-229, “Consolidated Natural...

  7. 8 CFR 233.6 - Aliens entering Guam or the Commonwealth of the Northern Mariana Islands pursuant to Title VII of...

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... the Northern Mariana Islands pursuant to Title VII of Public Law 110-229, âConsolidated Natural Resources Act of 2008.â 233.6 Section 233.6 Aliens and Nationality DEPARTMENT OF HOMELAND SECURITY... of the Northern Mariana Islands pursuant to Title VII of Public Law 110-229, “Consolidated Natural...

  8. A Novel GUSB Mutation in Brazilian Terriers with Severe Skeletal Abnormalities Defines the Disease as Mucopolysaccharidosis VII

    PubMed Central

    Hytönen, Marjo K.; Arumilli, Meharji; Lappalainen, Anu K.; Kallio, Heli; Snellman, Marjatta; Sainio, Kirsi; Lohi, Hannes

    2012-01-01

    Hundreds of different human skeletal disorders have been characterized at molecular level and a growing number of resembling dysplasias with orthologous genetic defects are being reported in dogs. This study describes a novel genetic defect in the Brazilian Terrier breed causing a congenital skeletal dysplasia. Affected puppies presented severe skeletal deformities observable within the first month of life. Clinical characterization using radiographic and histological methods identified delayed ossification and spondyloepiphyseal dysplasia. Pedigree analysis suggested an autosomal recessive disorder, and we performed a genome-wide association study to map the disease locus using Illumina’s 22K SNP chip arrays in seven cases and eleven controls. A single association was observed near the centromeric end of chromosome 6 with a genome-wide significance after permutation (pgenome  = 0.033). The affected dogs shared a 13-Mb homozygous region including over 200 genes. A targeted next-generation sequencing of the entire locus revealed a fully segregating missense mutation (c.866C>T) causing a pathogenic p.P289L change in a conserved functional domain of β-glucuronidase (GUSB). The mutation was confirmed in a population of 202 Brazilian terriers (p = 7,71×10−29). GUSB defects cause mucopolysaccharidosis VII (MPS VII) in several species and define the skeletal syndrome in Brazilian Terriers. Our results provide new information about the correlation of the GUSB genotype to phenotype and establish a novel canine model for MPS VII. Currently, MPS VII lacks an efficient treatment and this model could be utilized for the development and validation of therapeutic methods for better treatment of MPS VII patients. Finally, since almost one third of the Brazilian terrier population carries the mutation, breeders will benefit from a genetic test to eradicate the detrimental disease from the breed. PMID:22815736

  9. Delayed presentation of traumatic facial nerve (CN VII) paralysis.

    PubMed

    Napoli, Anthony M; Panagos, Peter

    2005-11-01

    Facial nerve paralysis (Cranial Nerve VII, CN VII) can be a disfiguring disorder with profound impact upon the patient. The etiology of facial nerve paralysis may be congenital, iatrogenic, or result from neoplasm, infection, trauma, or toxic exposure. In the emergency department, the most common cause of unilateral facial paralysis is Bell's palsy, also known as idiopathic facial paralysis (IFP). We report a case of delayed presentation of unilateral facial nerve paralysis 3 days after sustaining a traumatic head injury. Re-evaluation and imaging of this patient revealed a full facial paralysis and temporal bone fracture extending into the facial canal. Because cranial nerve injuries occur in approximately 5-10% of head-injured patients, a good history and physical examination is important to differentiate IFP from another etiology. Newer generation high-resolution computed tomography (CT) scans are commonly demonstrating these fractures. An understanding of this complication, appropriate patient follow-up, and early involvement of the Otolaryngologist is important in management of these patients. The mechanism as well as the timing of facial nerve paralysis will determine the proper evaluation, consultation, and management for the patient. Patients with total or immediate paralysis as well as those with poorly prognostic audiogram results are good candidates for surgical repair.

  10. Optimization of Lyophilized Plasma for Use in Combat Casualties

    DTIC Science & Technology

    2013-01-21

    SD. (Fib: fibrinogen, FII: Factor II, FV: Factor V, FVII : Factor VII, FVIII: Factor VIII, FIX: Factor IX, FX: Factor X, FXI: Factor XI, FXII...coagulation factor activity. Twenty swine were anesthetized and subjected to a validated model of polytrauma and hemorrhagic shock. They were...to assess inflammatory markers. Major Findings: 50%LP had higher electrolyte concentrations, osmolarity, and increased coagulation factor activity

  11. Title VII and Preferential Treatment: Response to EEOC Affirmative Action Guidelines.

    ERIC Educational Resources Information Center

    Schaffrau, Andrew J.

    1979-01-01

    Argues that Title VII prohibits preferential treatment of any group unless ordered by a court pursuant to a judicial finding of unlawful discrimination and unless the preferential treatment is limited to providing relief to judicially identified victims of that discrimination. Available from Georgetown Law Journal, 600 New Jersey Avenue,…

  12. Youth Suicidal Behavior

    MedlinePlus

    ... ii Risk Factors* Mental illness Substance abuse iv Firearms in the household vi Previous suicide attempts viii ... connectedness iii Safe schools v Reduced access to firearms vii Academic achievement ix Self-esteem xi Talking ...

  13. Efficacy and safety of recombinant activated factor vii in major surgical procedures: systematic review and meta-analysis of randomized clinical trials.

    PubMed

    Ranucci, Marco; Isgrò, Giuseppe; Soro, Giorgio; Conti, Daniela; De Toffol, Barbara

    2008-03-01

    To investigate the efficacy and safety of recombinant activated factor VII (rFVIIa) treatment in patients undergoing major surgical procedures. Relevant studies were searched in BioMedCentral, CENTRAL, PubMed, and PubMed Central. Only randomized controlled trials on humans undergoing major surgery were included. Efficacy was determined as the rate of patients receiving allogeneic packed red blood cells; safety was assessed in terms of thromboembolic complications and mortality rate. We followed the Cochrane Collaboration method for data extraction and internal validity procedures, as well as the Quality of Reporting of Meta-analyses statement. Seven randomized controlled trials met the inclusion criteria. Treatment with rFVIIa is associated with a reduced risk of receiving allogeneic packed red blood cells (odds ratio, 0.29; 95% confidence interval, 0.10-0.80). In a subgroup analysis, only patients receiving at least 50 mug/kg of rFVIIa had a significant benefit (odds ratio, 0.43; 95% confidence interval, 0.23-0.78). No differences in thromboembolic complications and mortality rates were observed. Treatment with rFVIIa is effective in reducing the rate of patients undergoing transfusion with allogeneic packed red blood cells. However, the cost-benefit ratio is favorable only in patients who need a huge number of packed red blood cell units. No safety concerns arise from the present study.

  14. Heptavalent Actinide Tetroxides NpO 4 – and PuO 4 –: Oxidation of Pu(V) to Pu(VII) by Adding an Electron to PuO 4

    DOE PAGES

    Gibson, John K.; de Jong, Wibe A.; Dau, Phuong D.; ...

    2017-11-14

    The highest known actinide oxidation states are Np(VII) and Pu(VII), both of which have been identified in solution and solid compounds. Recently a molecular Np(VII) complex, NpO 3(NO 3) 2-, was prepared and characterized in the gas phase. In accord with the lower stability of heptavalent Pu, no Pu(VII) molecular species has been identified. Reported here are the gas-phase syntheses and characterizations of NpO 4 - and PuO 4 -. Reactivity studies and density functional theory computations indicate the heptavalent metal oxidation state in both. This is the first instance of Pu(VII) in the absence of stabilizing effects due tomore » condensed phase solvation or crystal fields. Here, the results indicate that addition of an electron to neutral PuO 4, which has a computed electron affinity of 2.56 eV, counterintuitively results in oxidation of Pu(V) to Pu(VII), concomitant with superoxide reduction.« less

  15. Heptavalent Actinide Tetroxides NpO 4 – and PuO 4 –: Oxidation of Pu(V) to Pu(VII) by Adding an Electron to PuO 4

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Gibson, John K.; de Jong, Wibe A.; Dau, Phuong D.

    The highest known actinide oxidation states are Np(VII) and Pu(VII), both of which have been identified in solution and solid compounds. Recently a molecular Np(VII) complex, NpO 3(NO 3) 2-, was prepared and characterized in the gas phase. In accord with the lower stability of heptavalent Pu, no Pu(VII) molecular species has been identified. Reported here are the gas-phase syntheses and characterizations of NpO 4 - and PuO 4 -. Reactivity studies and density functional theory computations indicate the heptavalent metal oxidation state in both. This is the first instance of Pu(VII) in the absence of stabilizing effects due tomore » condensed phase solvation or crystal fields. Here, the results indicate that addition of an electron to neutral PuO 4, which has a computed electron affinity of 2.56 eV, counterintuitively results in oxidation of Pu(V) to Pu(VII), concomitant with superoxide reduction.« less

  16. Vehicle infrastructure integration (VII) based road-condition warning system for highway collision prevention.

    DOT National Transportation Integrated Search

    2009-05-01

    As a major ITS initiative, the Vehicle Infrastructure Integration (VII) program is to revolutionize : transportation by creating an enabling communication infrastructure that will open up a wide range of : safety applications. The road-condition warn...

  17. Confirmatory Factor Analysis of the KABC-II in Preschool Children

    ERIC Educational Resources Information Center

    Morgan, Kimberly E.; Rothlisberg, Barbara A.; McIntosh, David E.; Hunt, Madeline S.

    2009-01-01

    The present study assessed the Kaufman Assessment Battery for Children, Second Edition (KABC-II) in relation to the synthesized Cattell-Horn-Carroll (CHC) theory of intelligence with a preschool sample. Participants were 200 preschool children between four and five years of age. A confirmatory factor analysis (CFA) was conducted, and different…

  18. Influence of blood lipids on global coagulation test results.

    PubMed

    Kim, Jung-Ah; Kim, Ji-Eun; Song, Sang Hoon; Kim, Hyun Kyung

    2015-01-01

    High levels of blood lipids have been associated with high levels of coagulation factors. We investigated whether blood lipids influence the results of global coagulation tests, including prothrombin time (PT), activated partial thromboplastin time (aPTT), and thrombin generation assay (TGA). PT, aPTT, and TGA, along with procoagulant and anticoagulant factors, were measured in 488 normal individuals. Vitamin K status was assessed with prothrombin-induced by vitamin K absence-II (PIVKA-II). The procoagulant factors II, VII, IX, X, and XI and anticoagulant factors protein C and protein S showed significant correlations with triglyceride, and the procoagulant factors II, V, VII, IX, X, XI, and XII and anticoagulant factors antithrombin and protein C correlated with total cholesterol. There were no correlations of blood lipid levels with PIVKA-II levels. Subjects with high triglyceride levels (≥200 mg/dL) showed shorter PT values than those with lower triglyceride levels. However, aPTT value was not changed in terms of blood lipid levels. In both 1 and 5 pM tissue factor-induced TGAs, subjects in the high-triglyceride or high-cholesterol groups (≥240 mg/dL) had high levels of lag time, time-to-peak, and endogenous thrombin potential. Total cholesterol was a significant determinant of PT and TGA values. High blood lipids were related with increased coagulation activity in a normal population. Our findings are expected to help interpret the global coagulation test results in individuals with high lipid levels.

  19. The Chinese Bilingual Pilot Program, ESEA Title VII, 1974: Program Guide.

    ERIC Educational Resources Information Center

    San Francisco Unified School District, CA.

    The 1965 Elementary Secondary Education Act Title VII Chinese Bilingual Pilot Program is a bilingual/bicultural program the purpose of which is to provide for the special educational needs of children who have limited English-speaking ability, who come from environments where the dominant language is one other than English, and who come from…

  20. OATYC Journal, Vol. VII, Nos 1-2, Fall 1981-Spring 1982.

    ERIC Educational Resources Information Center

    Fullen, James, Ed.

    1982-01-01

    "OATYC Journal," which is published by the Ohio Association of Two-Year Colleges, is designed as a forum for the exchange of concepts, methods, and findings relevant to the two-year college classroom. Along with commentaries and letters of reaction from the readership, the two issues of volume VII include the following articles: (1)…

  1. Effect of Organic Substances on the Efficiency of Fe(Ii) to Fe(Iii) Oxidation and Removal of Iron Compounds from Groundwater in the Sedimentation Process

    NASA Astrophysics Data System (ADS)

    Krupińska, Izabela

    2017-09-01

    One of the problems with iron removal from groundwater is organic matter. The article presents the experiments involved groundwater samples with a high concentration of total iron - amounting to 7.20 mgFe/dm3 and an increased amount of organic substances (TOC from 5.50 to 7.50 mgC/dm3). The water samples examined differed in terms of the value of the ratio of the TOC concentration and the concentration of total iron (D). It was concluded that with increase in the coexistence ratio of organic substances and total iron in water (D = [TOC]/[Fetot]), efficiency of Fe(II) to Fe(III) oxidization with dissolved oxygen decreased, while the oxidation time was increasing. This rule was not demonstrated for potassium manganate (VII) when used as an oxidizing agent. The application of potassium manganate (VII) for oxidation of Fe(II) ions produced the better results in terms of total iron concentration reduction in the sedimentation process than the oxidation with dissolved oxygen.

  2. Employment discrimination implications of genetic screening in the workplace under Title VII and the Rehabilitation Act.

    PubMed

    Canter, E F

    1984-01-01

    The emergence of genetic screening techniques will permit employers to exclude hypersusceptible individuals from potentially hazardous workplace environments. The denial of employment opportunities to these individuals, however, may constitute discrimination. This Note analyzes genetic screening cases with respect to currently available remedies contained in Title VII of the Civil Rights Act of 1964 and the Rehabilitation Act of 1973. The Note concludes that Title VII claims may succeed but only in limited circumstances and that Rehabilitation Act claims will encounter numerous obstacles to relief. Additionally, the Note discusses some of the implications of the use of genetic screening in the workplace.

  3. Testing of ENDF71x: A new ACE-formatted neutron data library based on ENDF/B-VII.1

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Gardiner, S. J.; Conlin, J. L.; Kiedrowski, B. C.

    The ENDF71x library [1] is the most thoroughly tested set of ACE-format data tables ever released by the Nuclear Data Team at Los Alamos National Laboratory (LANL). It is based on ENDF/B-VII. 1, the most recently released set of evaluated nuclear data files produced by the US Cross Section Evaluation Working Group (CSEWG). A variety of techniques were used to test and verify the ENDF7 1x library before its public release. These include the use of automated checking codes written by members of the Nuclear Data Team, visual inspections of key neutron data, MCNP6 calculations designed to test data formore » every included combination of isotope and temperature as comprehensively as possible, and direct comparisons between ENDF71x and previous ACE library releases. Visual inspection of some of the most important neutron data revealed energy balance problems and unphysical discontinuities in the cross sections for some nuclides. Doppler broadening of the total cross sections with increasing temperature was found to be qualitatively correct. Test calculations performed using MCNP prompted two modifications to the MCNP6 source code and also exposed bad secondary neutron yields for {sup 231,233}Pa that are present in both ENDF/B-VII.1 and ENDF/B-VII.0. A comparison of ENDF71x with its predecessor ACE library, ENDF70, showed that dramatic changes have been made in the neutron cross section data for a number of isotopes between ENDF/B-VII.0 and ENDF/B-VII.1. Based on the results of these verification tests and the validation tests performed by Kahler, et al. [2], the ENDF71x library is recommended for use in all Monte Carlo applications. (authors)« less

  4. Screening Study on Feasibility of Standards of Performance ...

    EPA Pesticide Factsheets

    ... VII ittttl w.xi Itl lln-.virc li .-illy Im 61,1, | ell to I III' ptl.rv'NS wt'l^lil | I linll.1l I"lis il|'|>l I- ^O f.'thl*' I,i fi,,,-l, M M.tir,-.-: ... 3 Industrial Factors K. Factor K is the ...

  5. Differential functional readthrough over homozygous nonsense mutations contributes to the bleeding phenotype in coagulation factor VII deficiency.

    PubMed

    Branchini, A; Ferrarese, M; Lombardi, S; Mari, R; Bernardi, F; Pinotti, M

    2016-10-01

    Essentials Potentially null homozygous Factor(F)7 nonsense mutations are associated to variable bleeding symptoms. Readthrough of p.Ser112X (life-threatening) and p.Cys132X (moderate) stop codons was investigated. Readthrough-mediated insertion of wild-type or tolerated residues produce functional proteins. Functional readthrough over homozygous F7 nonsense mutations contributes to the bleeding phenotype. Background Whereas the rare homozygous nonsense mutations causing factor (F)VII deficiency may predict null conditions that are almost completely incompatible with life, they are associated with appreciable differences in hemorrhagic symptoms. The misrecognition of premature stop codons (readthrough) may account for variable levels of functional full-length proteins. Objectives To experimentally evaluate the basal and drug-induced levels of FVII resulting from the homozygous p.Cys132X and p.Ser112X nonsense mutations that are associated with moderate (132X) or life-threatening (112X) symptoms, and that are predicted to undergo readthrough with (132X) or without (112X) production of wild-type FVII. Methods We transiently expressed recombinant FVII (rFVII) nonsense and missense variants in human embryonic kidney 293 cells, and evaluated secreted FVII protein and functional levels by ELISA, activated FX generation, and coagulation assays. Results The levels of functional FVII produced by p.Cys132X and p.Ser112X mutants (rFVII-132X, 1.1% ± 0.2% of wild-type rFVII; rFVII-112X, 0.5% ± 0.1% of wild-type rFVII) were compatible with the occurrence of spontaneous readthrough, which was magnified by the addition of G418 - up to 12% of the wild-type value for the rFVII-132X nonsense variant. The predicted missense variants arising from readthrough abolished (rFVII-132Trp/Arg) or reduced (rFVII-112Trp/Cys/Arg, 22-45% of wild-type levels) secretion and function. These data suggest that the appreciable rescue of p.Cys132X function was driven by reinsertion of the wild

  6. A high ratio of insulin-like growth factor II/insulin-like growth factor binding protein 2 messenger RNA as a marker for anaplasia in meningiomas.

    PubMed

    Nordqvist, A C; Peyrard, M; Pettersson, H; Mathiesen, T; Collins, V P; Dumanski, J P; Schalling, M

    1997-07-01

    Insulin-like growth factors (IGFs) I and II have been implicated as autocrine or paracrine growth promoters. These growth factors bind to specific receptors, and the response is modulated by interaction with IGF-binding proteins (IGFBPs). We observed a strong correlation between anaplastic/atypical histopathology and a high IGF-II/IGFBP-2 mRNA ratio in a set of 68 sporadic meningiomas. A strong correlation was also found between clinical outcome and IGF-II/IGFBP-2 ratio, whereas previously used histochemical markers were less correlated to outcome. We suggest that a high IGF-II/IGFBP-2 mRNA ratio may be a sign of biologically aggressive behavior in meningiomas that can influence treatment strategies. We propose that low IGFBP-2 levels in combination with increased levels of IGF-II would result in more free IGF-II and consequently greater stimulation of proliferation.

  7. 40 CFR Appendix Vii to Part 86 - Standard Bench Cycle (SBC)

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... VII to Part 86—Standard Bench Cycle (SBC) 1. The standard bench aging durability procedures [Ref. § 86.1823-08(d)] consist of aging a catalyst-oxygen-sensor system on an aging bench which follows the standard bench cycle (SBC) described in this appendix. 2. The SBC requires use of an aging bench with an...

  8. Differences in N-glycosylation of recombinant human coagulation factor VII derived from BHK, CHO, and HEK293 cells.

    PubMed

    Böhm, Ernst; Seyfried, Birgit K; Dockal, Michael; Graninger, Michael; Hasslacher, Meinhard; Neurath, Marianne; Konetschny, Christian; Matthiessen, Peter; Mitterer, Artur; Scheiflinger, Friedrich

    2015-09-18

    BACKGROUND & Recombinant factor VII (rFVII), the precursor molecule for recombinant activated FVII (rFVIIa), is, due to its need for complex post translational modifications, produced in mammalian cells. To evaluate the suitability of a human cell line in order to produce rFVII with post-translational modifications as close as possible to pdFVII, we compared the biochemical properties of rFVII synthesized in human embryonic kidney-derived (HEK)293 cells (HEK293rFVII) with those of rFVII expressed in Chinese hamster ovary (CHO, CHOrFVII) and baby hamster kidney (BHK, BHKrFVII) cells, and also with those of plasma derived FVII (pdFVII), using various analytical methods. rFVII was purified from selected production clones derived from BHK, CHO, and HEK293 cells after stable transfection, and rFVII isolates were analyzed for protein activity, impurities and post-translational modifications. RESULTS & The analytical results showed no apparent gross differences between the various FVII proteins, except in their N-linked glycosylation pattern. Most N-glycans found on rFVII produced in HEK293 cells were not detected on rFVII from CHO and BHK cells, or, somewhat unexpectedly, on pdFVII; all other protein features were similar. HEK293rFVII glycans were mainly characterized by a higher structural variety and a lower degree of terminal sialylation, and a high amount of terminal N-acetyl galactosamines (GalNAc). All HEK293rFVII oligosaccharides contained one or more fucoses (Fuc), as well as hybrid and high mannose (Man) structures. From all rFVII isolates investigated, CHOrFVII contained the highest degree of sialylation and no terminal GalNAc, and CHO cells were therefore assumed to be the best option for the production of rFVII.

  9. Impact of Title VII Training Programs on Community Health Center Staffing and National Health Service Corps Participation

    PubMed Central

    Rittenhouse, Diane R.; Fryer, George E.; Phillips, Robert L.; Miyoshi, Thomas; Nielsen, Christine; Goodman, David C.; Grumbach, Kevin

    2008-01-01

    PURPOSE Community health centers (CHCs) are a critical component of the health care safety net. President Bush’s recent effort to expand CHC capacity coincides with difficulty recruiting primary care physicians and substantial cuts in federal grant programs designed to prepare and motivate physicians to practice in underserved settings. This article examines the association between physicians’ attendance in training programs funded by Health Resources and Services Administration (HRSA) Title VII Section 747 Primary Care Training Grants and 2 outcome variables: work in a CHC and participation in the National Health Service Corps Loan Repayment Program (NHSC LRP). METHODS We linked the 2004 American Medical Association Physician Master-file to HRSA Title VII grants files, Medicare claims data, and data from the NHSC. We then conducted retrospective analyses to compare the proportions of physicians working in CHCs among physicians who either had or had not attended Title VII–funded medical schools or residency programs and to determine the association between having attended Title VII–funded residency programs and subsequent NHSC LRP participation. RESULTS Three percent (5,934) of physicians who had attended Title VII–funded medical schools worked in CHCs in 2001–2003, compared with 1.9% of physicians who attended medical schools without Title VII funding (P<.001). We found a similar association between Title VII funding during residency and subsequent work in CHCs. These associations remained significant (P<.001) in logistic regression models controlling for NHSC participation, public vs private medical school, residency completion date, and physician sex. A strong association was also found between attending Title VII–funded residency programs and participation in the NHSC LRP, controlling for year completed training, physician sex, and private vs public medical school. CONCLUSIONS Continued federal support of Title VII training grant programs is

  10. 75 FR 23263 - Alta Wind I, LLC; Alta Wind II, LLC; Alta Wind III, LLC; Alta Wind IV, LLC; Alta Wind V, LLC...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-05-03

    ... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission [Docket No. EL10-62-000] Alta Wind I, LLC; Alta Wind II, LLC; Alta Wind III, LLC; Alta Wind IV, LLC; Alta Wind V, LLC; Alta Wind VI, LLC; Alta Wind VII, LLC; Alta Wind VIII, LLC; Alta Windpower Development, LLC; TGP Development Company, LLC...

  11. Vascular Induction of a Disintegrin and Metalloprotease 17 by Angiotensin II Through Hypoxia Inducible Factor

    PubMed Central

    Obama, Takashi; Takayanagi, Takehiko; Kobayashi, Tomonori; Bourne, Allison M.; Elliott, Katherine J.; Charbonneau, Martine; Dubois, Claire M.

    2015-01-01

    BACKGROUND A disintegrin and metalloprotease 17 (ADAM17) is a membrane-spanning metalloprotease overexpressed in various cardiovascular diseases such as hypertension and atherosclerosis. However, little is known regarding the regulation of ADAM17 expression in the cardiovascular system. Here, we test our hypothesis that angiotensin II induces ADAM17 expression in the vasculature. METHODS Cultured vascular smooth muscle cells were stimulated with 100nM angiotensin II. Mice were infused with 1 μg/kg/minute angiotensin II for 2 weeks. ADAM17 expression was evaluated by a promoter–reporter construct, quantitative polymerase chain reaction, immunoblotting, and immunohistochemistry. RESULTS In vascular smooth muscle cells, angiotensin II increased ADAM17 protein expression, mRNA, and promoter activity. We determined that the angiotensin II response involves hypoxia inducible factor 1α and a hypoxia responsive element. In angiotensin II–infused mice, marked induction of ADAM17 and hypoxia inducible factor 1α was seen in vasculatures in heart and kidney, as well as in aortae, by immunohistochemistry. CONCLUSIONS Angiotensin II induces ADAM17 expression in the vasculatures through a hypoxia inducible factor 1α–dependent transcriptional upregulation, potentially contributing to end-organ damage in the cardiovascular system. PMID:24871629

  12. Model of a ternary complex between activated factor VII, tissue factor and factor IX.

    PubMed

    Chen, Shu-wen W; Pellequer, Jean-Luc; Schved, Jean-François; Giansily-Blaizot, Muriel

    2002-07-01

    Upon binding to tissue factor, FVIIa triggers coagulation by activating vitamin K-dependent zymogens, factor IX (FIX) and factor X (FX). To understand recognition mechanisms in the initiation step of the coagulation cascade, we present a three-dimensional model of the ternary complex between FVIIa:TF:FIX. This model was built using a full-space search algorithm in combination with computational graphics. With the known crystallographic complex FVIIa:TF kept fixed, the FIX docking was performed first with FIX Gla-EGF1 domains, followed by the FIX protease/EGF2 domains. Because the FIXa crystal structure lacks electron density for the Gla domain, we constructed a chimeric FIX molecule that contains the Gla-EGF1 domains of FVIIa and the EGF2-protease domains of FIXa. The FVIIa:TF:FIX complex has been extensively challenged against experimental data including site-directed mutagenesis, inhibitory peptide data, haemophilia B database mutations, inhibitor antibodies and a novel exosite binding inhibitor peptide. This FVIIa:TF:FIX complex provides a powerful tool to study the regulation of FVIIa production and presents new avenues for developing therapeutic inhibitory compounds of FVIIa:TF:substrate complex.

  13. Investigation of inconsistent ENDF/B-VII.1 independent and cumulative fission product yields with proposed revisions

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Pigni, Marco T; Francis, Matthew W; Gauld, Ian C

    A recent implementation of ENDF/B-VII. independent fission product yields and nuclear decay data identified inconsistencies in the data caused by the use of updated nuclear scheme in the decay sub-library that is not reflected in legacy fission product yield data. Recent changes in the decay data sub-library, particularly the delayed neutron branching fractions, result in calculated fission product concentrations that are incompatible with the cumulative fission yields in the library, and also with experimental measurements. A comprehensive set of independent fission product yields was generated for thermal and fission spectrum neutron induced fission for 235,238U and 239,241Pu in order tomore » provide a preliminary assessment of the updated fission product yield data consistency. These updated independent fission product yields were utilized in the ORIGEN code to evaluate the calculated fission product inventories with experimentally measured inventories, with particular attention given to the noble gases. An important outcome of this work is the development of fission product yield covariance data necessary for fission product uncertainty quantification. The evaluation methodology combines a sequential Bayesian method to guarantee consistency between independent and cumulative yields along with the physical constraints on the independent yields. This work was motivated to improve the performance of the ENDF/B-VII.1 library in the case of stable and long-lived cumulative yields due to the inconsistency of ENDF/B-VII.1 fission p;roduct yield and decay data sub-libraries. The revised fission product yields and the new covariance data are proposed as a revision to the fission yield data currently in ENDF/B-VII.1.« less

  14. Angiotensin II induces tumor necrosis factor biosynthesis in the adult mammalian heart through a protein kinase C-dependent pathway.

    PubMed

    Kalra, Dinesh; Sivasubramanian, Natarajan; Mann, Douglas L

    2002-05-07

    Previous studies suggest that angiotensin II (Ang II) upregulates the expression of tumor necrosis factor (TNF) in nonmyocyte cell types; however, the effect of Ang II on TNF expression in the adult mammalian heart is not known. To determine whether Ang II was sufficient to provoke TNF biosynthesis in the adult heart, we examined the effects of Ang II in isolated buffer-perfused Langendorff feline hearts. Ang II (10(-7) mol/L) treatment resulted in a time- and dose-dependent increase in myocardial TNF mRNA and protein biosynthesis in the heart as well as in cultured adult cardiac myocytes. The effects of Ang II on myocardial TNF mRNA and protein synthesis were mediated through the angiotensin type 1 receptor (AT1R), insofar as an AT1R antagonist (AT1a) blocked the effects of Ang II, whereas an angiotensin type 2 receptor (AT2R) antagonist (AT2a) had no effect. Stimulation with Ang II led to the activation of nuclear factor-kappaB and activator protein-1 (AP-1), two transcription factors that are important for TNF gene expression. Nuclear factor-kappaB activation was accompanied by phosphorylation of IkappaBalpha on serine 32 as well as degradation of IkappaBalpha, suggesting that the effects of Ang II were mediated through an IkappaBalpha-dependent pathway. The important role of protein kinase C (PKC) was suggested by studies in which a phorbol ester triggered TNF biosynthesis, and a PKC inhibitor abrogated Ang II-induced TNF biosynthesis. These studies suggest that Ang II provokes TNF biosynthesis in the adult mammalian heart through a PKC-dependent pathway.

  15. SLY1 and Syntaxin 18 specify a distinct pathway for procollagen VII export from the endoplasmic reticulum

    PubMed Central

    Nogueira, Cristina; Erlmann, Patrik; Villeneuve, Julien; Santos, António JM; Martínez-Alonso, Emma; Martínez-Menárguez, José Ángel; Malhotra, Vivek

    2014-01-01

    TANGO1 binds and exports Procollagen VII from the endoplasmic reticulum (ER). In this study, we report a connection between the cytoplasmic domain of TANGO1 and SLY1, a protein that is required for membrane fusion. Knockdown of SLY1 by siRNA arrested Procollagen VII in the ER without affecting the recruitment of COPII components, general protein secretion, and retrograde transport of the KDEL-containing protein BIP, and ERGIC53. SLY1 is known to interact with the ER-specific SNARE proteins Syntaxin 17 and 18, however only Syntaxin 18 was required for Procollagen VII export. Neither SLY1 nor Syntaxin 18 was required for the export of the equally bulky Procollagen I from the ER. Altogether, these findings reveal the sorting of bulky collagen family members by TANGO1 at the ER and highlight the existence of different export pathways for secretory cargoes one of which is mediated by the specific SNARE complex containing SLY1 and Syntaxin 18. DOI: http://dx.doi.org/10.7554/eLife.02784.001 PMID:24842878

  16. A STUDY OF THE CONCURRENT VALIDITY OF THE MINNESOTA TESTS OF CREATIVE THINKING, ABBR. FORM VII, FOR EIGHTH GRADE INDUSTRIAL ARTS STUDENTS.

    ERIC Educational Resources Information Center

    DUENK, LESTER G.

    THE PRIMARY OBJECTIVE OF THIS STUDY WAS TO ESTABLISH THE CONCURRENT VALIDITY OF THE MINNESOTA TESTS OF CREATIVE THINKING, ABBREVIATED FORM VII, (MTCT VII) BY DETERMINING THE RELATIONSHIP BETWEEN ITS SCORES AND CREATIVE ABILITY AS MEASURED BY ACCUMULATED TEACHER RATINGS OF INDUSTRIAL ARTS PROJECTS AND INVESTIGATOR-DEVELOPED TESTS OF CREATIVITY. THE…

  17. Resveratrol prevents angiotensin II-induced hypertrophy of vascular smooth muscle cells through the transactivation of growth factor receptors.

    PubMed

    Hossain, Ekhtear; Anand-Srivastava, Madhu B

    2017-08-01

    We previously showed that augmented levels of endogenous angiotensin II (AngII) contribute to vascular smooth muscle cell (VSMC) hypertrophy through the transactivation of growth factor receptors in spontaneously hypertensive rats. Resveratrol (RV), a polyphenolic component of red wine, has also been shown to attenuate AngII-evoked VSMC hypertrophy; however, the molecular mechanism mediating this response is obscure. The present study was therefore undertaken to examine whether RV could prevent AngII-induced VSMC hypertrophy through the transactivation of growth factor receptor and associated signaling pathways. AngII treatment of VSMC enhanced the protein synthesis that was attenuated towards control levels by RV pretreatment as well as by the inhibitors of NADPH oxidase, c-Src, and growth factor receptors. Furthermore, RV pretreatment also inhibited enhanced levels of superoxide anion, NADPH oxidase activity, increased expression of NADPH oxidase subunits, and phosphorylation of c-Src, EGF-R, PDGE-R, ERK1/2, and AKT1/2. In conclusion, these results indicate that RV attenuates AngII-induced VSMC hypertrophy through the inhibition of enhanced oxidative stress and activation of c-Src, growth factor receptors, and MAPK/AKT signaling. We suggest that RV could be used as a therapeutic agent in the treatment of vascular complications associated with hypertension and hypertrophy.

  18. The next phase of Title VII funding for training primary care physicians for America's health care needs.

    PubMed

    Phillips, Robert L; Turner, Barbara J

    2012-01-01

    Health care reform will add millions of Americans to the ranks of the insured; however, their access to health care is threatened by a deep decline in the production of primary care physicians. Poorer access to primary care risks poorer health outcomes and higher costs. Meeting this increased demand requires a major investment in primary care training. Title VII, Section 747 of the Public Health Service Act previously supported the growth of the health care workforce but has been severely cut over the past 2 decades. New and expanded Title VII initiatives are required to increase the production of primary care physicians; establish high-functioning academic, community-based training practices; increase the supply of well-trained primary care faculty; foster innovation and rigorous evaluation of these programs; and ultimately to improve the responsiveness of teaching hospitals to community needs. To accomplish these goals, Congress should act on the Council on Graduate Medical Education's recommendation to increase funding for Title VII, Section 747 roughly 14-fold to $560 million annually. This amount represents a small investment in light of the billions that Medicare currently spends to support graduate medical education, and both should be held to account for meeting physician workforce needs. Expansion of Title VII, Section 747 with the goal of improving access to primary care would be an important part of a needed, broader effort to counter the decline of primary care. Failure to launch such a national primary care workforce revitalization program will put the health and economic viability of our nation at risk.

  19. [Case report. Phenprocoumon (Marcumar, Falithrom) as an unusual reason for coumarin poisoning in a dog].

    PubMed

    Lutze, G; Römhild, W; Elwert, J; Leppelt, J; Kutschmann, K

    2003-01-01

    Coumarin poisoning in dogs is not unusual and is in most cases caused by warfarin, a coumarin derivative which is used as a rodenticide. Competitive inhibition of vitamin K with an incomplete synthesis of the coagulation factors II, VII, IX and X can lead to a significant bleeding tendency. We observed a 3-year old male West Highland White Terrier with a reduced general condition and dyspnoea together with a massive haemothorax. Administration of vitamin K1 (3 mg/kg) led to a rapid improvement of the condition. Coagulation analysis revealed a prolonged activated recalcification time (ARCT), prothrombin time (PT) and aPTT with uncharacteristic thrombin time (TT); factor II, VII and X activities were reduced while factor V activity was normal, all of which are characteristic for coumarin poisoning. HPLC did not reveal the presence of warfarin but of phenoprocoumon, a drug used for thromboembolic prophylaxis in humans. This observation has not been described for dogs to date.

  20. Detection of O VII Lambda 1522 in IUE Spectra of Planetary Nebula Nuclei and Other Hot Stars

    NASA Technical Reports Server (NTRS)

    Feibelman, Walter A.

    1999-01-01

    We present the first detection of O VII lambda 1522 emission or absorption from archival IUE spectra in 14 planetary nebula nuclei and three PG 1159-type stars. The n = 5 approaching 6 transition of O VII was determined by Kruk & Werner and observed by them in the spectrum of the very hot PG 1159-type star H1504+65 from data obtained with the Hopkins Ultraviolet Telescope (HUT). Emission-line fluxes or absorption equivalent widths as well as radial velocities for the program stars are presented. The precise rest wavelength for the 5 approaching 6 transition requires further investigation.

  1. ANTIGENIC STRUCTURE OF THE ACTINOMYCETALES VII.

    PubMed Central

    Kwapinski, J. B.

    1964-01-01

    Kwapinski, J. B. (The University of New England, Armidale, Australia). Antigenic structure of the Actinomycetales. VII. Chemical and serological similarities of cell walls from 100 Actinomycetales strains. J. Bacteriol. 88:1211–1219. 1964.—Cell walls prepared mechanically from 100 strains of Actinomycetales were studied by chromatographic and serological methods. The cell walls of Actinomyces were found to be serologically related to those of the corynebacteria and to some strains of mycobacteria and nocardiae. The cell walls of nocardiae appeared to be more closely related to those of the mycobacteria, Streptomyces, Micromonospora, and Waksmania. The cell walls of Micromonospora and Waksmania showed certain serological similarities to those of Thermoactinomyces and nocardiae. Micropolyspora was antigenically different from other species of the Actinomycetales. Three serological groups of mycobacteria and four groups of nocardiae were distinguished. PMID:14234773

  2. Insulin-Like growth factor-II (IGF-II) prevents proinflammatory cytokine-induced apoptosis and significantly improves islet survival after transplantation.

    PubMed

    Hughes, Amy; Mohanasundaram, Daisy; Kireta, Svjetlana; Jessup, Claire F; Drogemuller, Chris J; Coates, P Toby H

    2013-03-15

    The early loss of functional islet mass (50-70%) due to apoptosis after clinical transplantation contributes to islet allograft failure. Insulin-like growth factor (IGF)-II is an antiapoptotic protein that is highly expressed in β-cells during development but rapidly decreases in postnatal life. We used an adenoviral (Ad) vector to overexpress IGF-II in isolated rat islets and investigated its antiapoptotic action against exogenous cytokines interleukin-1β- and interferon-γ-induced islet cell death in vitro. Using an immunocompromised marginal mass islet transplant model, the ability of Ad-IGF-II-transduced rat islets to restore euglycemia in nonobese diabetic/severe combined immunodeficient diabetic recipients was assessed. Ad-IGF-II transduction did not affect islet viability or function. Ad-IGF-II cytokine-treated islets exhibited decreased cell death (40% ± 2.8%) versus Ad-GFP and untransduced control islets (63.2% ± 2.5% and 53.6% ± 2.3%, respectively). Ad-IGF-II overexpression during cytokine treatment resulted in a marked reduction in terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive apoptotic cells (8.3% ± 1.4%) versus Ad-GFP control (41% ± 4.2%) and untransduced control islets (46.5% ± 6.2%). Western blot analysis confirmed that IGF-II inhibits apoptosis via activation of the phosphatidylinositol 3-kinase/Akt signaling pathway. Transplantation of IGF-II overexpressing islets under the kidney capsule of diabetic mice restored euglycemia in 77.8% of recipients compared with 18.2% and 47.5% of Ad-GFP and untransduced control islet recipients, respectively (P<0.05, log-rank [Mantel-Cox] test). Antiapoptotic IGF-II decreases apoptosis in vitro and significantly improved islet transplant outcomes in vivo. Antiapoptotic gene transfer is a potentially powerful tool to improve islet survival after transplantation.

  3. Recombinant activated factor VII in the treatment of bleeds and for the prevention of surgery-related bleeding in congenital haemophilia with inhibitors.

    PubMed

    Santagostino, Elena; Escobar, Miguel; Ozelo, Margareth; Solimeno, Luigi; Arkhammar, Per; Lee, Hye Youn; Rosu, Gabriela; Giangrande, Paul

    2015-06-01

    The availability of recombinant activated factor VII (rFVIIa, eptacog alfa activated) has greatly advanced the care of patients with haemophilia A or B who have developed inhibitors against the infused replacement factor. Recombinant FVIIa is licensed for the on-demand treatment of bleeding episodes and the prevention of bleeding in surgery or invasive procedures in patients with congenital haemophilia with inhibitors. This article attempts to review in detail the extensive evidence of rFVIIa in congenital haemophilia patients with inhibitors. Patients with acute bleeding episodes are best treated on demand at home, to achieve the short- and long-term benefits of rapid bleed control. Key prospective studies have shown that rFVIIa achieves consistently high efficacy rates in the management of acute (including joint) bleeds in inhibitor patients in the home treatment setting. Substantial post-approval data from key registries also support the on-demand efficacy profile of rFVIIa established by the prospective clinical trials. The availability of rFVIIa has allowed major surgery to become a reality for inhibitor patients. Studies in key surgery, including orthopaedic procedures, have found that rFVIIa provides consistently high efficacy rates. Importantly, the wealth of data does not raise any unexpected safety concerns surrounding rFVIIa use; this is likely because rFVIIa is a recombinant product with a localised mechanism of action at the site of vascular injury. In summary, rFVIIa is established as an effective and well-tolerated first-line treatment for on-demand bleeding control and bleed prevention during minor and major (including elective orthopaedic) surgery in inhibitor patients. Use of rFVIIa has been a major step towards narrowing the gap in outcomes between inhibitor patients and non-inhibitor patients. Copyright © 2015 Elsevier Ltd. All rights reserved.

  4. Optimizing Cr(VI) and Tc(VII) remediation through nano-scale biomineral engineering

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Cutting, R. S.; Coker, V. S.; Telling, N. D.

    2009-09-09

    To optimize the production of biomagnetite for the bioremediation of metal oxyanion contaminated waters, the reduction of aqueous Cr(VI) to Cr(III) by two biogenic magnetites and a synthetic magnetite was evaluated under batch and continuous flow conditions. Results indicate that nano-scale biogenic magnetite produced by incubating synthetic schwertmannite powder in cell suspensions of Geobacter sulfurreducens is more efficient at reducing Cr(VI) than either biogenic nano-magnetite produced from a suspension of ferrihydrite 'gel' or synthetic nano-scale Fe{sub 3}O{sub 4} powder. Although X-ray Photoelectron Spectroscopy (XPS) measurements obtained from post-exposure magnetite samples reveal that both Cr(III) and Cr(VI) are associated with nanoparticlemore » surfaces, X-ray Magnetic Circular Dichroism (XMCD) studies indicate that some Cr(III) has replaced octahedrally coordinated Fe in the lattice of the magnetite. Inductively Coupled Plasma-Atomic Emission Spectrometry (ICP-AES) measurements of total aqueous Cr in the associated solution phase indicated that, although the majority of Cr(III) was incorporated within or adsorbed to the magnetite samples, a proportion ({approx}10-15 %) was released back into solution. Studies of Tc(VII) uptake by magnetites produced via the different synthesis routes also revealed significant differences between them as regards effectiveness for remediation. In addition, column studies using a {gamma}-camera to obtain real time images of a {sup 99m}Tc(VII) radiotracer were performed to visualize directly the relative performances of the magnetite sorbents against ultra-trace concentrations of metal oxyanion contaminants. Again, the magnetite produced from schwertmannite proved capable of retaining more ({approx}20%) {sup 99m}Tc(VII) than the magnetite produced from ferrihydrite, confirming that biomagnetite production for efficient environmental remediation can be fine-tuned through careful selection of the initial Fe(III) mineral

  5. Influence of Blood Lipids on Global Coagulation Test Results

    PubMed Central

    Kim, Jung-Ah; Kim, Ji-Eun; Song, Sang Hoon

    2015-01-01

    Background High levels of blood lipids have been associated with high levels of coagulation factors. We investigated whether blood lipids influence the results of global coagulation tests, including prothrombin time (PT), activated partial thromboplastin time (aPTT), and thrombin generation assay (TGA). Methods PT, aPTT, and TGA, along with procoagulant and anticoagulant factors, were measured in 488 normal individuals. Vitamin K status was assessed with prothrombin-induced by vitamin K absence-II (PIVKA-II). Results The procoagulant factors II, VII, IX, X, and XI and anticoagulant factors protein C and protein S showed significant correlations with triglyceride, and the procoagulant factors II, V, VII, IX, X, XI, and XII and anticoagulant factors antithrombin and protein C correlated with total cholesterol. There were no correlations of blood lipid levels with PIVKA-II levels. Subjects with high triglyceride levels (≥200 mg/dL) showed shorter PT values than those with lower triglyceride levels. However, aPTT value was not changed in terms of blood lipid levels. In both 1 and 5 pM tissue factor-induced TGAs, subjects in the high-triglyceride or high-cholesterol groups (≥240 mg/dL) had high levels of lag time, time-to-peak, and endogenous thrombin potential. Total cholesterol was a significant determinant of PT and TGA values. Conclusion High blood lipids were related with increased coagulation activity in a normal population. Our findings are expected to help interpret the global coagulation test results in individuals with high lipid levels. PMID:25553275

  6. The mannose 6-phosphate-binding sites of M6P/IGF2R determine its capacity to suppress matrix invasion by squamous cell carcinoma cells

    PubMed Central

    Probst, Olivia C.; Karayel, Evren; Schida, Nicole; Nimmerfall, Elisabeth; Hehenberger, Elisabeth; Puxbaum, Verena; Mach, Lukas

    2013-01-01

    The M6P (mannose 6-phosphate)/IGF2R (insulin-like growth factor II receptor) interacts with a variety of factors that impinge on tumour invasion and metastasis. It has been shown that expression of wild-type M6P/IGF2R reduces the tumorigenic and invasive properties of receptor-deficient SCC-VII squamous cell carcinoma cells. We have now used mutant forms of M6P/IGF2R to assess the relevance of the different ligand-binding sites of the receptor for its biological activities in this cellular system. The results of the present study demonstrate that M6P/IGF2R does not require a functional binding site for insulin-like growth factor II for inhibition of anchorage-independent growth and matrix invasion by SCC-VII cells. In contrast, the simultaneous mutation of both M6P-binding sites is sufficient to impair all cellular functions of the receptor tested. These findings highlight that the interaction between M6P/IGF2R and M6P-modified ligands is not only important for intracellular accumulation of lysosomal enzymes and formation of dense lysosomes, but is also crucial for the ability of the receptor to suppress SCC-VII growth and invasion. The present study also shows that some of the biological activities of M6P/IGF2R in SCC-VII cells strongly depend on a functional M6P-binding site within domain 3, thus providing further evidence for the non-redundant cellular functions of the individual carbohydrate-binding domains of the receptor. PMID:23347038

  7. VizieR Online Data Catalog: Effective collision strengths of Si VII (Sossah+, 2014)

    NASA Astrophysics Data System (ADS)

    Sossah, A. M.; Tayal, S. S.

    2017-08-01

    The purpose of present work is to calculate more accurate data for Si VII by using highly accurate target descriptions and by including a sufficient number of target states in the close-coupling expansion. We also included fine-structure effects in the close-coupling expansions to account for the relativistic effects. We used the B-spline Breit-Pauli R-matrix (BSR) codes (Zatsarinny 2006CoPhC.174..273Z) in our scattering calculations. The present method utilizes the term-dependent non-orthogonal orbital sets for the description of the target wave functions and scattering functions. The collisional and radiative parameters have been calculated for all forbidden and allowed transitions between the lowest 92 LSJ levels of 2s22p4, 2s2p5, 2p6, 2s22p33s, 2s22p33p, 2s22p33d, and 2s2p43s configurations of Si VII. (3 data files).

  8. Assessment of bone dysplasia by micro-CT and glycosaminoglycan levels in mouse models for mucopolysaccharidosis type I, IIIA, IVA, and VII

    PubMed Central

    Rowan, Daniel J.; Tomatsu, Shunji; Grubb, Jeffrey H.; Montaño, Adriana M.; Sly, William S.

    2012-01-01

    Summary Mucopolysaccharidoses (MPS) are a group of lysosomal storage diseases caused by mutations in lysosomal enzymes involved in degradation of glycosaminoglycans (GAGs). Patients with MPS grow poorly and become physically disabled due to systemic bone disease. While many of the major skeletal effects in mouse models for MPS have been described, no detailed analysis that compares GAGs levels and characteristics of bone by micro-CT has been done. The aims of this study were to assess severity of bone dysplasia among four MPS mouse models (MPS I, IIIA, IVA and VII), to determine the relationship between severity of bone dysplasia and serum keratan sulfate (KS) and heparan sulfate (HS) levels in those models, and to explore the mechanism of KS elevation in MPS I, IIIA, and VII mouse models. Clinically, MPS VII mice had the most severe bone pathology; however, MPS I and IVA mice also showed skeletal pathology. MPS I and VII mice showed severe bone dysplasia, higher bone mineral density, narrowed spinal canal, and shorter sclerotic bones by micro-CT and radiographs. Serum KS and HS levels were elevated in MPS I, IIIA, and VII mice. Severity of skeletal disease displayed by micro-CT, radiographs and histopathology correlated with the level of KS elevation. We showed that elevated HS levels in MPS mouse models could inhibit N-acetylgalactosamine-6-sulfate sulfatase enzyme. These studies suggest that KS could be released from chondrocytes affected by accumulation of other GAGs and that KS could be useful as a biomarker for severity of bone dysplasia in MPS disorders. PMID:22971960

  9. Effects on coagulation factor production following primary hepatomitogen-induced direct hyperplasia.

    PubMed

    Tatsumi, Kohei; Ohashi, Kazuo; Taminishi, Sanae; Takagi, Soichi; Utoh, Rie; Yoshioka, Akira; Shima, Midori; Okano, Teruo

    2009-11-14

    To investigate the molecular mechanisms involved in coagulation factor expression and/or function during direct hyperplasia (DH)-mediated liver regeneration. Direct hyperplasia-mediated liver regeneration was induced in female C57BL/6 mice by administering 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP), a representative hepatomitogen. Mice were weighed and sacrificed at various time points [Day 0 (D0: prior to injection), 3 h, D1, D2, D3, and D10] after TCPOBOP administration to obtain liver and blood samples. Using the RNA samples extracted from the liver, a comprehensive analysis was performed on the hepatic gene expression profiling of coagulation-related factors by real-time RT-PCR (fibrinogen, prothrombin, factors V, VII, VIII, IX, X, XI, XII, XIIIbeta, plasminogen, antithrombin, protein C, protein S, ADAMTS13, and VWF). The corresponding plasma levels of coagulation factors (fibrinogen, prothrombin, factors V, VII, VIII, IX, X, XI, XII, XIII, and VWF) were also analyzed and compared with their mRNA levels. Gavage administration of TCPOBOP (3 mg/kg body weight) resulted in a marked and gradual increase in the weight of the mouse livers relative to the total body weight to 220% by D10 relative to the D0 (control) ratios. At the peak of liver regeneration (D1 and D2), the gene expression levels for most of the coagulation-related factors (fibrinogen, prothrombin, factors V, VII, VIII, IX, XI, XII, XIIIbeta, plasminogen, antithrombin, protein C, ADAMTS13, VWF) were found to be down-regulated in a time-dependent manner, and gradually recovered by D10 to the basal levels. Only mRNA levels of factor X and protein S failed to show any decrease during the regenerative phase. As for the plasma levels, 5 clotting factors (prothrombin, factors VIII, IX, XI, and XII) demonstrated a significant decrease (P<0.05) during the regeneration phase compared with D0. Among these 5 factors, factor IX and factor XI showed the most dramatic decline in their activities by about

  10. Gene Delivery of Activated Factor VII Using Alternative Adeno-Associated Virus Serotype Improves Hemostasis in Hemophiliac Mice with FVIII Inhibitors and Adeno-Associated Virus Neutralizing Antibodies.

    PubMed

    Sun, Junjiang; Hua, Baolai; Chen, Xiaojing; Samulski, Richard J; Li, Chengwen

    2017-08-01

    While therapeutic expression of coagulation factors from adeno-associated virus (AAV) vectors has been successfully achieved in patients with hemophilia, neutralizing antibodies to the vector and inhibitory antibodies to the transgene severely limit efficacy. Indeed, approximately 40% of mice transduced with human factor VIII using the AAV8 serotype developed inhibitory antibodies to factor VIII (FVIII inhibitor), as well as extremely high titers (≥1:500) of neutralizing antibodies to AAV8. To correct hemophilia in these mice, AAV9, a serotype with low in vitro cross-reactivity (≤1:5) to anti-AAV8, was used to deliver mouse-activated factor VII (mFVIIa). It was found that within 6 weeks of systemic administration of 2 × 10 13 particles/kg of AAV9/mFVIIa, hemophiliac mice with FVIII inhibitors and neutralizing antibodies (NAb) to AAV8 achieved hemostasis comparable to that in wild-type mice, as measured by rotational thromboelastometry. A level of 737 ng/mL mFVIIa was achieved after AAV9/mFVIIa adminstration compared to around 150 ng/mL without vector treatment, and concomitantly prothrombin time was shortened. Tissues collected after intra-articular hemorrhage from FVIII-deficient mice and mice with FVIII inhibitors were scored 4.7 and 5.5, respectively, on a scale of 0-10, indicating significant pathological damage. However, transduction with AAV9/mFVIIa decreased pathology scores to 3.6 and eliminated hemosiderin iron deposition in the synovium in most mice. Collectively, these results suggest that application of alternative serotypes of AAV vector to deliver bypassing reagents has the potential to correct hemophilia and prevent hemoarthrosis, even in the presence of FVIII inhibitor and neutralizing antibodies to AAV.

  11. Self-diffusion of protons in H{sub 2}O ice VII at high pressures: Anomaly around 10 GPa

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Noguchi, Naoki, E-mail: noguchi-n@okayama-u.ac.jp; Okuchi, Takuo

    2016-06-21

    The self-diffusion of ice VII in the pressure range of 5.5–17 GPa and temperature range of 400–425 K was studied using micro Raman spectroscopy and a diamond anvil cell. The diffusion was monitored by observing the distribution of isotope tracers: D{sub 2}O and H{sub 2}{sup 18}O. The diffusion coefficient of hydrogen reached a maximum value around 10 GPa. It was two orders of magnitude greater at 10 GPa than at 6 GPa. Hydrogen diffusion was much faster than oxygen diffusion, which indicates that protonic diffusion is the dominant mechanism for the diffusion of hydrogen in ice VII. This mechanism ismore » in remarkable contrast to the self-diffusion in ice I{sub h} that is dominated by an interstitial mechanism for the whole water molecule. An anomaly around 10 GPa in ice VII indicates that the rate-determining process for the proton diffusion changes from the diffusion of ionic defects to the diffusion of rotational defects, which was suggested by proton conductivity measurements and molecular dynamics simulations.« less

  12. Central Nervous System Delivery of Helper-Dependent Canine Adenovirus Corrects Neuropathology and Behavior in Mucopolysaccharidosis Type VII Mice

    PubMed Central

    Ariza, Lorena; Giménez-Llort, Lydia; Cubizolle, Aurélie; Pagès, Gemma; García-Lareu, Belén; Serratrice, Nicolas; Cots, Dan; Thwaite, Rosemary; Chillón, Miguel; Kremer, Eric J.

    2014-01-01

    Abstract Canine adenovirus type 2 vectors (CAV-2) are promising tools to treat global central nervous system (CNS) disorders because of their preferential transduction of neurons and efficient retrograde axonal transport. Here we tested the potential of a helper-dependent CAV-2 vector expressing β-glucuronidase (HD-RIGIE) in a mouse model of mucopolysaccharidosis type VII (MPS VII), a lysosomal storage disease caused by deficiency in β-glucuronidase activity. MPS VII leads to glycosaminoglycan accumulation into enlarged vesicles in peripheral tissues and the CNS, resulting in peripheral and neuronal dysfunction. After intracranial administration of HD-RIGIE, we show long-term expression of β-glucuronidase that led to correction of neuropathology around the injection site and in distal areas. This phenotypic correction correlated with a decrease in secondary-elevated lysosomal enzyme activity and glycosaminoglycan levels, consistent with global biochemical correction. Moreover, HD-RIGIE-treated mice show significant cognitive improvement. Thus, injections of HD-CAV-2 vectors in the brain allow a global and sustained expression and may have implications for brain therapy in patients with lysosomal storage disease. PMID:24299455

  13. 30 CFR 250.916 - What are the CVA's primary duties during the design phase?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ...) Stress analyses; (vi) Material designations; (vii) Soil and foundation conditions; (viii) Safety factors... INTERIOR OFFSHORE OIL AND GAS AND SULPHUR OPERATIONS IN THE OUTER CONTINENTAL SHELF Platforms and... pipeline risers, and riser tensioning systems; (ii) Turrets and turret-and-hull interfaces; (iii...

  14. The transcription factor ETS-1 regulates angiotensin II-stimulated fibronectin production in mesangial cells.

    PubMed

    Hua, Ping; Feng, Wenguang; Rezonzew, Gabriel; Chumley, Phillip; Jaimes, Edgar A

    2012-06-01

    Angiotensin II (ANG II) produced as result of activation of the renin-angiotensin system (RAS) plays a critical role in the pathogenesis of chronic kidney disease via its hemodynamic effects on the renal microcirculation as well as by its nonhemodynamic actions including the production of extracellular matrix proteins such as fibronectin, a multifunctional extracellular matrix protein that plays a major role in cell adhesion and migration as well as in the development of glomerulosclerosis. ETS-1 is an important transcription factor essential for normal kidney development and glomerular integrity. We previously showed that ANG II increases ETS-1 expression and is required for fibronectin production in mesangial cells. In these studies, we determined that ANG II induces phosphorylation of ETS-1 via activation of the type 1 ANG II receptor and that Erk1/2 and Akt/PKB phosphorylation are required for these effects. In addition, we characterized the role of ETS-1 on the transcriptional activation of fibronectin production in mesangial cells. We determined that ETS-1 directly activates the fibronectin promoter and by utilizing gel shift assays and chromatin immunoprecipitation assays identified two different ETS-1 binding sites that promote the transcriptional activation of fibronectin in response to ANG II. In addition, we identified the essential role of CREB and its coactivator p300 on the transcriptional activation of fibronectin by ETS-1. These studies unveil novel mechanisms involved in RAS-induced production of the extracellular matrix protein fibronectin in mesangial cells and establish the role of the transcription factor ETS-1 as a direct mediator of these effects.

  15. Essential roles of angiotensin II in vascular endothelial growth factor expression in sleep apnea syndrome.

    PubMed

    Takahashi, Susumu; Nakamura, Yutaka; Nishijima, Tsuguo; Sakurai, Shigeru; Inoue, Hiroshi

    2005-09-01

    Hypoxia-induced endothelial cell dysfunction has been implicated in increased cardiovascular disease associated with obstructive sleep apnea syndrome (OSAS). OSAS mediates hypertension by stimulating angiotensin II (Ang II) production. Hypoxia and Ang II are the major stimuli of vascular endothelial growth factor (VEGF), which is a potent angiogenic cytokine and also contributes to the atherogenic process itself. We observed serum Ang II and VEGF levels and peripheral blood mononuclear cell (PBMC) and neutrophil VEGF expression. Compared to controls, subjects with OSAS had significantly increased levels of serum Ang II and VEGF and VEGF mRNA expression in their leukocytes. To examine whether Ang II stimulates VEGF expression in OSAS, we treated PBMCs obtained from control subjects with Ang II and with an Ang II receptor type 1 (AT(1)) blocker, olmesartan. We observed an increased expression of VEGF in the Ang II-stimulated PBMCs and decreased in VEGF mRNA and protein expression in the PBMCs treated with olmesartan. These findings suggest that the Ang II-AT(1) receptors pathway potentially are involved in OSAS and VEGF-induced vascularity and that endothelial dysfunction might be linked to this change in Ang II activity within leukocytes of OSAS patients.

  16. The Next Phase of Title VII Funding for Training Primary Care Physicians for America’s Health Care Needs

    PubMed Central

    Phillips, Robert L.; Turner, Barbara J.

    2012-01-01

    Health care reform will add millions of Americans to the ranks of the insured; however, their access to health care is threatened by a deep decline in the production of primary care physicians. Poorer access to primary care risks poorer health outcomes and higher costs. Meeting this increased demand requires a major investment in primary care training. Title VII, Section 747 of the Public Health Service Act previously supported the growth of the health care workforce but has been severely cut over the past 2 decades. New and expanded Title VII initiatives are required to increase the production of primary care physicians; establish high-functioning academic, community-based training practices; increase the supply of well-trained primary care faculty; foster innovation and rigorous evaluation of these programs; and ultimately to improve the responsiveness of teaching hospitals to community needs. To accomplish these goals, Congress should act on the Council on Graduate Medical Education’s recommendation to increase funding for Title VII, Section 747 roughly 14-fold to $560 million annually. This amount represents a small investment in light of the billions that Medicare currently spends to support graduate medical education, and both should be held to account for meeting physician workforce needs. Expansion of Title VII, Section 747 with the goal of improving access to primary care would be an important part of a needed, broader effort to counter the decline of primary care. Failure to launch such a national primary care workforce revitalization program will put the health and economic viability of our nation at risk. PMID:22412009

  17. Exploratory Factor Analysis of the Beck Anxiety Inventory and the Beck Depression Inventory-II in a Psychiatric Outpatient Population

    PubMed Central

    2018-01-01

    Background To further understand the relationship between anxiety and depression, this study examined the factor structure of the combined items from two validated measures for anxiety and depression. Methods The participants were 406 patients with mixed psychiatric diagnoses including anxiety and depressive disorders from a psychiatric outpatient unit at a university-affiliated medical center. Responses of the Beck Anxiety Inventory (BAI), Beck Depression Inventory (BDI)-II, and Symptom Checklist-90-Revised (SCL-90-R) were analyzed. We conducted an exploratory factor analysis of 42 items from the BAI and BDI-II. Correlational analyses were performed between subscale scores of the SCL-90-R and factors derived from the factor analysis. Scores of individual items of the BAI and BDI-II were also compared between groups of anxiety disorder (n = 185) and depressive disorder (n = 123). Results Exploratory factor analysis revealed the following five factors explaining 56.2% of the total variance: somatic anxiety (factor 1), cognitive depression (factor 2), somatic depression (factor 3), subjective anxiety (factor 4), and autonomic anxiety (factor 5). The depression group had significantly higher scores for 12 items on the BDI while the anxiety group demonstrated higher scores for six items on the BAI. Conclusion Our results suggest that anxiety and depressive symptoms as measured by the BAI and BDI-II can be empirically differentiated and that particularly items of the cognitive domain in depression and those of physical domain in anxiety are noteworthy. PMID:29651821

  18. Evidence of a Structural Defect in Ice VII and the Side Chain Dependent Response of Small Model Peptides to Increased Pressure

    PubMed Central

    Scott, J. Nathan; Vanderkooi, Jane M.

    2014-01-01

    The effect of high pressure on the OH stretch of dilute HOD in D2O was examined using high pressure FTIR. It was found that at pressures directly above the ice VI to ice VII transition, ice VII displays a splitting in the OH absorption indicative of differing hydrogen bonding environments. This result is contrary to published structures of ice VII in which each OH oscillator should experience an identical electronic environment. The anomalous band was found to decrease in absorbance and finally disappear at ~43.0 kbar. In addition, the pressure response of the amide I′ and II′ bands of three small model peptides was examined. Analysis of these bands’ response to increased pressure indicates significant side chain dependence of their structural rearrangement, which may play a role in the composition of full length proteins of barophilic organisms. PMID:21740637

  19. Chemical Analysis of the Moon at the Surveyor VII Landing Site: Preliminary Results.

    PubMed

    Turkevich, A L; Franzgrote, E J; Patterson, J H

    1968-10-04

    The alpha-scattering experiment aboard Surveyor VII has provided a chemical analysis of the moon in the area of the crater Tycho. The preliminary results indicate a chemical composition similar to that already found at two mare sites, but with a lower concentration of elements of the iron group (titanium through copper).

  20. Photometric and spectral evolution of the symbiotic eclipsing variable V1329 Cygni at a late stage of its nova-like outburst

    NASA Astrophysics Data System (ADS)

    Arkhipova, V. P.; Esipov, V. F.; Ikonnikova, N. P.; Komissarova, G. V.

    2015-03-01

    The photoelectric UBV observations of the peculiar symbiotic star V1329 Cyg performed at the Crimean Station of the SAI-MSU during 245 nights over the period 2003-2014 are presented. The star's light curves since 1973 from the Crimean observations are shown. The brightness decline after its outburst over the last 40 years was . The phase color curves at phases 0.2 and 0.8 have maxima. Their qualitative interpretation in terms of the model of interacting winds in symbiotic binary star systems is proposed. The orbital period of the binary system has been redetermined. The spectroscopic observations at the 125-cm telescope of the Crimean Station from 1994 to 2014 have confirmed the change in the system's emission spectrum with orbital phase. The HI, He I, and Fe II line fluxes clearly trace the orbital motion. The Balmer hydrogen lines as well as the continuum at λ6000 and the V-band flux change by a factor of ˜3.5 from minimum to maximum light. The neutral helium lines change by a factor of 5. The high-excitation He II, [FeVII], [Ca VII] lines and the Raman O VI λ6825 line have shown changes in the fluxes by a factor of ˜2-3 weakly correlating with the orbital phase. The equivalent widths of the HI and He I lines are maximal at the star's maximum light and have distinct minima at phases 0.2 and 0.8, while the equivalent widths of the He II, [FeVII], and [CaVII] lines are minimal in the range of phases 0.2-0.8. The question about the location of the permitted and forbidden line emission zones in the binary system V1329 Cyg is discussed. The evolution of the emission spectrum for V1329 Cyg from 1980 to 2014 has been studied on the basis of new and archival data. A gradual decrease in the absolute fluxes of the nebular emission lines has been detected. The [O III] and [Fe VII] lines have weakened significantly. However, the [Fe X] λ6375 Å line has appeared and gradually strengthened, suggesting an increase in the degree of gas ionization in the line formation zone.

  1. The Beck Depression Inventory-II: Testing for Measurement Equivalence and Factor Mean Differences across Hong Kong and American Adolescents

    ERIC Educational Resources Information Center

    Byrne, Barbara M.; Stewart, Sunita M.; Kennard, Betsy D.; Lee, Peter W. H.

    2007-01-01

    Working within the framework of a confirmatory factor analytic (CFA) model, this study adds another dimension to construct validation of both the Beck Depression Inventory-II (BDI-II; Beck, Steer, & Brown, 1996) and a Chinese version of the BDI-II (C-BDI-II; Chinese Behavioral Sciences Society, 2000). Specifically, we tested for measurement…

  2. Employment Discrimination--"Sex Discrimination" under Title VII Includes Differential Treatment of Pregnancy Related Disabilities.

    ERIC Educational Resources Information Center

    Harpool, M. Douglas

    1980-01-01

    Public Law 95-555, which expands the definition of sex discrimination in Title VII of the Civil Rights Act of 1964, reverses the judicial determination that pregnancy is not a sex-based attribute. Available from School of Law, University of Missouri-Columbia, Columbia, MO 65211. (Author/IRT)

  3. Program Impact Evaluations: An Introduction for Managers of Title VII Projects. A Draft Guidebook.

    ERIC Educational Resources Information Center

    Bissell, Joan S.

    Intended to assist administrators in the planning, management, and utilization of evaluation, this guidebook is designed as an introduction and supplement to other evaluation materials for bilingual education programs being developed under federal sponsorship, including evaluation models for Title VII projects. General information is provided on…

  4. E.E.O.C. v. Mississippi College: The Applicability of Title VII to Sectarian Schools.

    ERIC Educational Resources Information Center

    Burleson, Bruce

    1981-01-01

    Section 702 of Title VII partially exempts religious educational institutions, allowing them to give employment preference to individuals of a particular religion. The conflict with First Amendment rights of sectarian schools and claims of nonsectarian schools are discussed. (MSE)

  5. [Establishment of nude mouse model with ovarian carcinomaand the effect of Paris Phyllin VII combined with silica nano complex on the inhibition and the antioxidant ability of ovarian carcinoma in nude mice].

    PubMed

    Chen, Jun; Wang, Bihang; Zhang, Jialing; Yang, Ruiqi; Fan, Limei

    2015-08-04

    To establish the research model of ovarian carcinoma in nude mice, and to explore the effect of Paris Phyllin VII combined with silica nano complex on the inhibition and the antioxidant ability of ovarian carcinoma in nude mice. Nude mice models with ovarian carcinoma were established by axillary subcutaneous inoculation of human SKOV3/DDP resistant ovarian cancer cell 200 µl and were used in the experiment. Treating the nude mice with Paris Phyllin VII combined with silica nano complex by gavage for 15 days to observe the weight change of the nude mice, tumor inhibition effect and changes of serum antioxidant capacity. Compared with the negative control group, tumor inhibition rate increased significantly in Paris Phyllin VII combined with silica nano complex treatment group, and was higher than that in both Paris Phyllin VII treatment only and silica nano composites treatment only group. The serum superoxide dismutase (SOD) and total antioxidant capacity (T-AOC) level of Paris Phyllin VII combined with silica nano complex treatment group was significantly higher than that of control group, Paris Phyllin VII treatment only and silica nano composites treatment only group. The serum malonaldehyde (MDA) level of Paris Phyllin VII combined with silica nano complex treatment group was significantly lower than that of the negative control group. Paris Phyllin VII combined with silica nano complex treatment can inhibit the ovarian carcinoma in nude mice, which may mediate by the enhancement of antioxidant capability in nude mice with ovarian cancer.

  6. Adenovirus Core Protein VII Protects the Viral Genome from a DNA Damage Response at Early Times after Infection▿

    PubMed Central

    Karen, Kasey A.; Hearing, Patrick

    2011-01-01

    Adenovirus has a linear, double-stranded DNA genome that is perceived by the cellular Mre11-Rad50-Nbs1 (MRN) DNA repair complex as a double-strand break. If unabated, MRN elicits a double-strand break repair response that blocks viral DNA replication and ligates the viral genomes into concatemers. There are two sets of early viral proteins that inhibit the MRN complex. The E1B-55K/E4-ORF6 complex recruits an E3 ubiquitin ligase and targets MRN proteins for proteasome-dependent degradation. The E4-ORF3 protein inhibits MRN through sequestration. The mechanism that prevents MRN recognition of the viral genome prior to the expression of these early proteins was previously unknown. Here we show a temporal correlation between the loss of viral core protein VII from the adenovirus genome and a gain of checkpoint signaling due to the double-strand break repair response. While checkpoint signaling corresponds to the recognition of the viral genome, core protein VII binding to and checkpoint signaling at viral genomes are largely mutually exclusive. Transcription is known to release protein VII from the genome, and the inhibition of transcription shows a decrease in checkpoint signaling. Finally, we show that the nuclease activity of Mre11 is dispensable for the inhibition of viral DNA replication during a DNA damage response. These results support a model involving the protection of the incoming viral genome from checkpoint signaling by core protein VII and suggest that the induction of an MRN-dependent DNA damage response may inhibit adenovirus replication by physically masking the origins of DNA replication rather than altering their integrity. PMID:21345950

  7. Effect of fusion protein cleavage site sequence on generation of a genotype VII Newcastle disease virus vaccine.

    PubMed

    Manoharan, Vinoth K; Varghese, Berin P; Paldurai, Anandan; Samal, Siba K

    2018-01-01

    Newcastle disease (ND) causes severe economic loss to poultry industry worldwide. Frequent outbreaks of ND in commercial chickens vaccinated with live vaccines suggest a need to develop improved vaccines that are genetically matched against circulating Newcastle disease virus (NDV) strains. In this study, the fusion protein cleavage site (FPCS) sequence of NDV strain Banjarmasin/010 (Banj), a genotype VII NDV, was individually modified using primer mutagenesis to those of avian paramyxovirus (APMV) serotypes 2, 7 and 8 and compared with the recombinant Banjarmasin (rBanj) with avirulent NDV LaSota cleavage site (rBanj-LaSota). These FPCS mutations changed the in vitro cell-to-cell fusion activity and made rBanj FPCS mutant viruses highly attenuated in chickens. When chickens immunized with the rBanj FPCS mutant viruses and challenged with the virulent Banj, there was reduced challenge virus shedding observed compared to chickens immunized with the heterologous vaccine strain LaSota. Among the genotype VII NDV Banj vaccine candidates, rBanj-LaSota and rBanj containing FPCS of APMV-8 induced highest neutralizing antibody titers and protected chickens with reduced challenge virus shedding. These results show the effect of the F protein cleavage site sequence in generating genotype VII matched NDV vaccines.

  8. Recombinant factor VIIa (eptacog alfa): a review of its use in congenital hemophilia with inhibitors, acquired hemophilia, and other congenital bleeding disorders.

    PubMed

    Croom, Katherine F; McCormack, Paul L

    2008-01-01

    Recombinant factor VIIa (NovoSeven; also known as recombinant activated factor VII or eptacog alfa) is structurally similar to human plasma-derived coagulation factor VIIa, but is manufactured using DNA biotechnology. Recombinant factor VIIa interacts with thrombin-activated platelets to produce a thrombin burst leading to accelerated fibrin clot formation localized to the site of vascular injury. It is approved in many countries for use as an intravenous hemostatic agent in patients with congenital hemophilia with inhibitors, and also for acquired hemophilia, factor VII deficiency, and Glanzmann thrombasthenia in some countries. Studies have shown it to be effective and generally well tolerated when used intravenously to treat bleeding episodes or provide hemostatic cover during surgery in patients with congenital hemophilia with inhibitors, acquired hemophilia, factor VII deficiency or Glanzmann thrombasthenia. Based on available data, its efficacy in terms of patient-assessed response may be similar to that of activated prothrombin complex concentrate (aPCC), but treatment with a single 270 microg/kg dose of recombinant factor VIIa might reduce the need for rescue therapy compared with aPCC. Recombinant factor VIIa is not immunogenic in patients with hemophilia, does not produce an anamnestic response in hemophilia patients with inhibitors, and has very low thrombogenicity. It is recommended in guidelines as the treatment of choice for bleeds in patients with hemophilia B with high-responding inhibitors and for patients with factor VII deficiency, and is also a first-line therapeutic option for high-responder hemophilia A patients with inhibitors and those with acquired hemophilia. Cost data from pharmacoeconomic analyses support its use in hemophilia patients with inhibitors. Thus, recombinant factor VIIa is a valuable treatment option for patients with these rare, but potentially serious, bleeding disorders.

  9. Massive oral bleeding after full-mouth extraction in a patient with B-cell lymphocytic leukemia/small lymphocytic lymphoma reversed with recombinant activated factor VII.

    PubMed

    Sprenker, Collin; Omar, Hesham R; Powless, R Andrew; Mangar, Devanand; Camporesi, Enrico

    2016-02-01

    Full-mouth extraction can be associated with intraoral bleeding, which usually is controlled with local hemostatic measures. Recombinant activated factor VII (rFVIIa) occasionally is used to stop bleeding in a variety of off-label indications, with the main argument curtailing its use being thrombotic events. The authors describe the use of rFVIIa for bleeding after full-mouth extraction in a patient with undiagnosed B-cell lymphocytic leukemia/small lymphocytic lymphoma. A 72-year-old man underwent full-mouth extraction (18 teeth). The next day, the patient experienced massive oral bleeding. The authors administered tranexamic acid, aminocaproic acid, and a total of 12 units of packed red blood cells in addition to local hemostatic measures without control of bleeding. On postoperative day 10, the authors administered 5,000 micrograms of rFVIIa, and within 2 hours oral the bleeding ceased. The authors performed flow cytometry and diagnosed B-cell lymphocytic leukemia/small lymphocytic lymphoma. Unexplained massive oral bleeding despite adequate local hemostatic measures should prompt further investigations for underlying bleeding or coagulation disorders. The authors describe the successful use of rFVIIa in massive oral bleeding. Further studies are mandatory to study the effectiveness of this drug for this off-label indication. Copyright © 2016 American Dental Association. Published by Elsevier Inc. All rights reserved.

  10. Energy levels and radiative rates for transitions in Fe V, Co VI and Ni VII

    NASA Astrophysics Data System (ADS)

    Aggarwal, K. M.; Bogdanovich, P.; Keenan, F. P.; Kisielius, R.

    2017-03-01

    Energy levels, Landé g-factors and radiative lifetimes are reported for the lowest 182 levels of the 3d4, 3d34s and 3d34p configurations of Fe V, Co VI and Ni VII. Additionally, radiative rates (A-values) have been calculated for the E1, E2 and M1 transitions among these levels. The calculations have been performed in a quasi-relativistic approach (QR) with a very large configuration interaction (CI) wavefunction expansion, which has been found to be necessary for these ions. Our calculated energies for all ions are in excellent agreement with the available measurements, for most levels. Discrepancies among various calculations for the radiative rates of E1 transitions in Fe V are up to a factor of two for stronger transitions (f ≥ 0.1), and larger (over an order of magnitude) for weaker ones. The reasons for these discrepancies have been discussed and mainly are due to the differing amount of CI and methodologies adopted. However, there are no appreciable discrepancies in similar data for M1 and E2 transitions, or the g-factors for the levels of Fe V, the only ion for which comparisons are feasible.

  11. Law as a Teacher of Society: Reflections on Title VII after Fifty Years

    ERIC Educational Resources Information Center

    Little, Andrew

    2016-01-01

    The Civil Rights Act of 1964 has worked to reshape American society for more than fifty years through arguably its most important subpart, Title VII, which prohibits discrimination in employment. This article is not so much an attempt to join the chorus of scholars offering reflections on the statute after five decades, as it is an attempt to…

  12. Treatment of refractory bleeding after cardiac operations with low-dose recombinant activated factor VII (NovoSeven): a propensity score analysis.

    PubMed

    Gelsomino, Sandro; Lorusso, Roberto; Romagnoli, Stefano; Bevilacqua, Sergio; De Cicco, Giuseppe; Billè, Giuseppe; Stefàno, Pierluigi; Gensini, Gian Franco

    2008-01-01

    Recombinant activated factor VII (rFVIIa) has been increasingly used to stop life-threatening bleeding following cardiac operations. Nonetheless, the issue of dosing, given the expense and potential for thrombotic complications, is still of major concern. We report our experience with small-dose rFVIIa in patients with refractory bleeding after cardiac surgery. From September 2005 to June 2007, 40 patients (mean age 70.1+/-9.2 years, 52.5 males) received a low dose of rFVIIa (median: 18 microg/kg, interquartile range: 9-16 microg/kg) for refractory bleeding after cardiac surgery. Forty propensity score-based greedy matched controls were compared to the study group. Low dose of rFVIIa significantly reduced the 24-h blood loss: 1610 ml [ 1285-1800 ml] versus 3171 ml [2725-3760 ml] in the study and control groups, respectively (p<0.001). Thus, hourly bleeding was 51.1 ml [34.7-65.4 ml] in patients receiving rFVIIa and 196.2 ml/h [142.1-202.9 ml] in controls (p<0.001). Furthermore, patients receiving rFVIIa showed a lower length of stay in the intensive care unit (p<0.001) and shorter mechanical ventilation time (p<0.001). In addition, the use of rFVIIa was associated with reduction of transfusion requirements of red blood cells, fresh frozen plasma and platelets (all, p<0.001). Finally, treated patients showed improved hemostasis with rapid normalization of coagulation variables (partial thromboplastin time, international normalized ratio, platelet count, p<0.001). In contrast, activated prothrombin time and fibrinogen did not differ between groups (p=ns). No thromboembolic-related event was detected in our cohort. In our experience low-dose rFVIIa was associated with reduced blood loss, improvement of coagulation variables and decreased need for transfusions. Our findings need to be confirmed by further larger studies.

  13. Cost-effectiveness of using recombinant activated factor VII as an off-label rescue treatment for critical bleeding requiring massive transfusion.

    PubMed

    Ho, Kwok M; Litton, Edward

    2012-08-01

    Recombinant activated factor VII (rFVIIa) is widely used as an off-label rescue treatment for patients with nonhemophilic critical bleeding. Using data from the intensive care unit, transfusion service, and death registry, the long-term survival after using rFVIIa and the associated cost per life-year gained in a consecutive cohort of patients with critical bleeding requiring massive transfusion (≥ 10 red blood cell [RBC] units in 24 hr) were assessed. rFVIIa was only used as a lifesaving treatment when conventional measures had failed. Of the 353 patients with critical bleeding requiring massive transfusion, 81 (23%) required rFVIIa as a lifesaving rescue treatment. The patients requiring rFVIIa received a greater number of transfusions (number of units: RBCs, 18 vs. 12; fresh-frozen plasma, 16 vs. 10; platelets, 4 vs. 2; p < 0.001) and had a shorter survival time (24 months vs. 33 months; p = 0.002) than those who did not require rFVIIa. The total cost per life-year gained of massive transfusion and incremental cost of rFVIIa as a lifesaving treatment were US$1,148,000 (£711,760; 95% confidence interval [CI], US$825,000-US$1,471,000) and US$736,000 (£456,320; 95% CI, US$527,000-US$945,000), respectively. The incremental costs of rFVIIa increased with severity of illness and transfusion requirement and were greater than the usual acceptable cost-effective limit (

  14. Electron impact collision strengths in Ne VII

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Di, L.; Shi, J.R.; Zhao, G., E-mail: gzhao@bao.ac.cn

    2012-07-15

    The lines of Ne VII have been observed in many astronomical objects, and some transitions from high energy levels were observed both in Seyfert galaxies and stellar coronae. Thus, the atomic data for these transitions are important for modeling. Using the code FAC we calculated the collision strengths based on the distorted-wave method with large configuration interactions included. The Maxwellian averaged effective collision strengths covering the typical temperature range of astronomical and laboratory hot plasmas are presented. We extend the calculation of the energy levels to n=4 and 5. The energy levels, wavelengths, spontaneous transition rates, weighted oscillator strengths, andmore » effective collision strengths were reported. Compared with the results from experiment or previous theoretical calculations a general agreement is found. It is found that the resonance effects are important in calculating the effective collision strengths.« less

  15. Identification of 5g and 6g terms and revised ionization energies in the Yb II 4f/sup 14/nl isoelectronic sequence

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Sugar, J.; Kaufman, V.

    1979-01-01

    The 5f-5g transitions in Lu III through Os VIII and the 5f-6g transitions in Hf IV through W VI were identified and used to redetermine the ionization energies of Yb II, Lu III, W VI, Re VII, and Os VIII. Complete line-lists and energy levels are given for the one-electron spectra Hf IV, W VI and Os VIII.

  16. Rapid and Sensitive Detection of Lymphocystis Disease Virus Genotype VII by Loop-Mediated Isothermal Amplification.

    PubMed

    Valverde, Estefanía J; Cano, Irene; Castro, Dolores; Paley, Richard K; Borrego, Juan J

    2017-03-01

    Lymphocystis disease virus (LCDV) infections have been described in gilthead seabream (Sparus aurata L.) and Senegalese sole (Solea senegalensis, Kaup), two of the most important marine fish species in the Mediterranean aquaculture. In this study, a rapid, specific, and sensitive detection method for LCDV genotype VII based on loop-mediated isothermal amplification (LAMP) was developed. The LAMP assay, performed using an apparatus with real-time amplification monitoring, was able to specifically detect LCDV genotype VII from clinically positive samples in less than 12 min. In addition, the assay allowed the detection of LCDV in all asymptomatic carrier fish analysed, identified by qPCR, showing an analytical sensitivity of ten copies of viral DNA per reaction. The LCDV LAMP assay has proven to be a promising diagnostic method that can be used easily in fish farms to detect the presence and spread of this iridovirus.

  17. Cargo Movement Operations System (CMOS) Preliminary Interface Design Document Increment II

    DTIC Science & Technology

    1991-02-28

    NO [ ] COMMENT DISPOSITION: ACCEPT [ ] REJECT [ ] COMMENT STATUS: OPEN [ ] CLOSED [ ] Cmnt Page Paragraph No. No. Number Comment 1. vii List of Figures Figure 3.24, METS II is listed twice. Delete the reference to page 51 here, and Figure 3.24 on page 51. 2. 52 3.30.2.1b Change "inceements" to "increments". 3. 56 3.33.2.1 Change Table ŗ.35.2.a" to 3.40.2a". 4. A-3 DAMMS-R Change "management" to "Managemn.it". 5. A-5 HOST Change "Syatem" to "System". ORIGINATOR CONTROL NUMBER: IDD-0002 PROGRAM OFFICE

  18. Insulin-Like Growth Factor II Targets the mTOR Pathway to Reverse Autism-Like Phenotypes in Mice.

    PubMed

    Steinmetz, Adam B; Stern, Sarah A; Kohtz, Amy S; Descalzi, Giannina; Alberini, Cristina M

    2018-01-24

    Autism spectrum disorder (ASD) is a developmental disability characterized by impairments in social interaction and repetitive behavior, and is also associated with cognitive deficits. There is no current treatment that can ameliorate most of the ASD symptomatology; thus, identifying novel therapies is urgently needed. We used male BTBR T + Itpr3 tf /J (BTBR) mice, a model that reproduces most of the core behavioral phenotypes of ASD, to test the effects of systemic administration of insulin-like growth factor II (IGF-II), a polypeptide that crosses the blood-brain barrier and acts as a cognitive enhancer. We show that systemic IGF-II treatments reverse the typical defects in social interaction, cognitive/executive functions, and repetitive behaviors reflective of ASD-like phenotypes. In BTBR mice, IGF-II, via IGF-II receptor, but not via IGF-I receptor, reverses the abnormal levels of the AMPK-mTOR-S6K pathway and of active translation at synapses. Thus, IGF-II may represent a novel potential therapy for ASD. SIGNIFICANCE STATEMENT Currently, there is no effective treatment for autism spectrum disorder (ASD), a developmental disability affecting a high number of children. Using a mouse model that expresses most of the key core as well as associated behavioral deficits of ASD, that are, social, cognitive, and repetitive behaviors, we report that a systemic administration of the polypeptide insulin-like growth factor II (IGF-II) reverses all these deficits. The effects of IGF-II occur via IGF-II receptors, and not IGF-I receptors, and target both basal and learning-dependent molecular abnormalities found in several ASD mice models, including those of identified genetic mutations. We suggest that IGF-II represents a potential novel therapeutic target for ASD. Copyright © 2018 the authors 0270-6474/18/371015-15$15.00/0.

  19. Differential regulation and impact of fucosyltransferase VII and core 2 β1,6-N-acetyl-glycosaminyltransferase for generation of E-selectin and P-selectin ligands in murine CD4+ T cells

    PubMed Central

    Schroeter, Micha F; Ratsch, Boris A; Lehmann, Jeanette; Baumgrass, Ria; Hamann, Alf; Syrbe, Uta

    2012-01-01

    Ligands for E-selectin and P-selectin (E-lig and P-lig) are induced on CD4+ T cells upon differentiation into effector T cells. Glycosyltransferases, especially α 1,3-fucosyltransferase VII (FucT-VII) and core 2 β1,6-N-acetyl-glycosaminyltransferase I (C2GlcNAcT-I), are critical for their synthesis. We here analysed the signals that control the expression of E-lig, P-lig and mRNA coding for FucT-VII and C2GlcNAcT-I. In line with previous reports, we found that P-lig expression correlates with the regulation of C2GlcNAcT-I, whereas E-lig expression can occur at low levels of C2GlcNAcT-I mRNA but requires high FucT-VII mRNA expression. Interestingly, the two enzymes are regulated by different signals. Activation-induced C2GlcNAcT-I up-regulation under permissive (T helper type 1) conditions was strongly reduced by cyclosporin A (CsA), suggesting the involvement of T-cell receptor-dependent, calcineurin/NFAT-dependent signals in combination with interleukin-12 (IL-12) -mediated signals in the regulation of C2GlcNAcT-I. In contrast, expression of FucT-VII mRNA was not significantly inhibited by CsA. Interleukin-4 inhibited the expression of FucT-VII but IL-2 and IL-7 were found to support induction of FucT-VII and E-lig. E-selectin, P-selectin and their ligands initially appeared to have rather overlapping functions. These findings however, unravel striking differences in the regulation of E-lig and P-lig expression, dictated by the dominance of FucT-VII and C2GlcNAcT-I, respectively, and their dependency on signals from either promiscuous or homeostatic cytokines (FucT-VII) or a strong T-cell receptor signal in combination with inflammatory cytokines in case of C2GlcNAcT-I. PMID:23039181

  20. Industrial production of clotting factors: Challenges of expression, and choice of host cells.

    PubMed

    Kumar, Sampath R

    2015-07-01

    The development of recombinant forms of blood coagulation factors as safer alternatives to plasma derived factors marked a major advance in the treatment of common coagulation disorders. These are complex proteins, mostly enzymes or co-enzymes, involving multiple post-translational modifications, and therefore are difficult to express. This article reviews the nature of the expression challenges for the industrial production of these factors, vis-à-vis the translational and post-translational bottlenecks, as well as the choice of host cell lines for high-fidelity production. For achieving high productivities of vitamin K dependent proteins, which include factors II (prothrombin), VII, IX and X, and protein C, host cell limitation of γ-glutamyl carboxylation is a major bottleneck. Despite progress in addressing this, involvement of yet unidentified protein(s) impedes a complete cell engineering solution. Human factor VIII expresses at very low levels due to limitations at several steps in the protein secretion pathway. Protein and cell engineering, vector improvement and alternate host cells promise improvement in the productivity. Production of Von Willebrand factor is constrained by its large size, complex structure, and the need for extensive glycosylation and disulfide-bonded oligomerization. All the licensed therapeutic factors are produced in CHO, BHK or HEK293 cells. While HEK293 is a recent adoption, BHK cells appear to be disfavored. Copyright © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. Recombinant Activated Factor VII (Eptacog Alfa Activated, NovoSeven®) in Patients with Rare Congenital Bleeding Disorders. A Systematic Review on its Use in Surgical Procedures.

    PubMed

    Di Minno, Matteo Nicola Dario; Ambrosino, Pasquale; Myasoedova, Veronika; Amato, Manuela; Ventre, Itala; Tremoli, Elena; Minno, Alessandro Di

    2017-01-01

    In the absence of definite guidelines in the area, we have carried a systemic review to provide a thorough overview concerning the efficacy and safety of recombinant activated factor VII (rFVIIa, NovoSeven®, Novo Nordisk A/S, Bagsværd, Denmark) in patients with Glanzmann's thrombasthenia (GT) and FVII deficiency, undergoing surgical procedures. PubMed, Web of Science, Scopus and EMBASE databases was employed for the search. Three multicenter registries were identified: the Glanzmann's Thrombasthenia Registry (GTR), the Seven Treatment Evaluation Registry (STER), and a German post-marketing surveillance registry (the WIRK study). In addition, data from 10 case-series and/or single-center experiences have been summarized. We have found that the following; perioperatively, the hemostatic effectiveness of rFVIIa was high in GT patients and in those with FVII deficiency undergoing both minor and major surgical procedures. Moreover, in all studies, rFVIIa was well tolerated. Thus, the current evidence shows an optimal perioperative safety/efficacy profile of rFVIIa in the setting of these rare bleeding disorders, and provides the rationale for further studies aimed at evaluating the optimal perioperative anti-hemorrhagic prophylaxis with rFVIIa in GT and in FVII deficient patients. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  2. In Vivo Bleeding Time and In Vitro Thrombelastography Measurements are Better Indicators of Dilutional Hypothermic Coagulopathy Than Prothrombin Time

    DTIC Science & Technology

    2007-06-01

    of increased bruising, hematomas, and oozing from the recent surgical sites, or in massive hemorrhage from silent, pre-existing lesions such as peptic ... ulcers . Severe reduction of the vitamin K-dependent coagulation factors II, VII, IX, and X prolongs both PT and aPTT tests. Treatment with sodium

  3. Stellar laboratories . VIII. New Zr iv-vii, Xe iv-v, and Xe vii oscillator strengths and the Al, Zr, and Xe abundances in the hot white dwarfs G191-B2B and RE 0503-289

    NASA Astrophysics Data System (ADS)

    Rauch, T.; Gamrath, S.; Quinet, P.; Löbling, L.; Hoyer, D.; Werner, K.; Kruk, J. W.; Demleitner, M.

    2017-03-01

    Context. For the spectral analysis of high-resolution and high-signal-to-noise spectra of hot stars, state-of-the-art non-local thermodynamic equilibrium (NLTE) model atmospheres are mandatory. These are strongly dependent on the reliability of the atomic data that is used for their calculation. Aims: To search for zirconium and xenon lines in the ultraviolet (UV) spectra of G191-B2B and RE 0503-289, new Zr iv-vii, Xe iv-v, and Xe vii oscillator strengths were calculated. This allows, for the first time, determination of the Zr abundance in white dwarf (WD) stars and improvement of the Xe abundance determinations. Methods: We calculated Zr iv-vii, Xe iv-v, and Xe vii oscillator strengths to consider radiative and collisional bound-bound transitions of Zr and Xe in our NLTE stellar-atmosphere models for the analysis of their lines exhibited in UV observations of the hot WDs G191-B2B and RE 0503-289. Results: We identified one new Zr iv, 14 new Zr v, and ten new Zr vi lines in the spectrum of RE 0503-289. Zr was detected for the first time in a WD. We measured a Zr abundance of -3.5 ± 0.2 (logarithmic mass fraction, approx. 11 500 times solar). We identified five new Xe vi lines and determined a Xe abundance of -3.9 ± 0.2 (approx. 7500 times solar). We determined a preliminary photospheric Al abundance of -4.3 ± 0.2 (solar) in RE 0503-289. In the spectra of G191-B2B, no Zr line was identified. The strongest Zr iv line (1598.948 Å) in our model gave an upper limit of -5.6 ± 0.3 (approx. 100 times solar). No Xe line was identified in the UV spectrum of G191-B2B and we confirmed the previously determined upper limit of -6.8 ± 0.3 (ten times solar). Conclusions: Precise measurements and calculations of atomic data are a prerequisite for advanced NLTE stellar-atmosphere modeling. Observed Zr iv-vi and Xe vi-vii line profiles in the UV spectrum of RE 0503-289 were simultaneously well reproduced with our newly calculated oscillator strengths. Based on observations

  4. Biological and phylogenetic characterization of a genotype VII Newcastle disease virus from Venezuela: Efficacy of vaccination

    USDA-ARS?s Scientific Manuscript database

    Here we describe the characterization a virulent genotype VII Newcastle disease virus (NDV) from Venezuela and evaluate the efficacy of heterologous genotype commercial vaccination under field and controlled rearing conditions. Biological pathotyping and molecular analysis were applied. Results sh...

  5. Divergent mechanisms of insulin-like growth factor I and II on rat hepatocyte proliferation.

    PubMed

    Raper, S; Kothary, P; Ishoo, E; Dikin, M; Kokudo, N; Hashimoto, M; DeMatteo, R P

    1995-07-21

    Insulin-like growth factors I and II are peptides with a structural homology for proinsulin, and are involved in hepatocyte proliferation. IGF-I and IGF-II, however, have different metabolic roles, and their mechanisms of action are incompletely known. We hypothesized that IGF-I and IGF-II act by different signal transduction pathways. To test this hypothesis, hepatocytes from 200 g male Sprague-Dawley rats were isolated by a two-step collagenase perfusion technique and plated at a density of 10(5) cells/16 mm Primaria plate. Proliferation was measured by [3H]thymidine ([3H]thy) incorporation into DNA, and an autoradiographic nuclear labeling index (LI). To analyze signal transduction, cyclic AMP (cAMP) levels were measured 5 min after addition of reagents by a radioimmunoassay. Reagents (doses) used were: IGF-I (2 nM), IGF-II (2 nM), the inhibitory peptide somatostatin-14 (SS14) (10 nM), and the adenylyl cyclase antagonist dideoxyadenosine (DDA) (10 microM). A summary of the findings is as follows: (1) IGF-I stimulates [3H]thy, LI and cAMP accumulation. (2) IGF-II stimulates [3H]thy and LI but not cAMP; (3) IGF-I but not IGF-II effects are inhibited by SS14 and DDA. We conclude that the hepatotrophic effects of IGF-I and IGF-II occur by different mechanisms: IGF-I is cAMP-dependent, IGF-II is cAMP-independent.

  6. Phase transitions of antibiotic clarithromycin forms I, IV and new form VII crystals.

    PubMed

    Ito, Masataka; Shiba, Rika; Watanabe, Miteki; Iwao, Yasunori; Itai, Shigeru; Noguchi, Shuji

    2018-06-01

    Metastable crystal form I of the antibiotic clarithromycin has a pharmaceutically valuable characteristic that its crystalline phase transition can be applied for its sustained release from tablets. The phase transition of form I was investigated in detail by single crystal and powder X-ray analyses, dynamic vapor sorption analysis and thermal analysis. The single crystal structure of form I revealed that form I was not an anhydrate crystal but contained a partially occupied water molecule in the channel-like void space. Dynamic vapor sorption (DVS) analysis demonstrated that form I crystals reversibly sorbed water molecules in two steps when the relative humidity (RH) increased and finally transited to hydrate form IV at 95% RH. DVS analysis also showed that when the RH decreased form IV crystals lost water molecules at 40% RH and transited to the newly identified anhydrate crystal form VII. Form VII reversibly transited to form IV at lower RH than form I, suggesting that form I is more suitable for manufacturing a sustained-release tablet of CAM utilizing the crystalline phase transition. Copyright © 2018 Elsevier B.V. All rights reserved.

  7. Edgewood Independent School District, Title VII Bilingual Education Program. Final Evaluation Report, 1970-71.

    ERIC Educational Resources Information Center

    Edgewood Independent School District, San Antonio, TX.

    The 1970-71 evaluation of the Title VII bilingual education program in the Edgewood Independent School District in San Antonio, Texas, is presented in this report. The report discusses the program with regard to (1) curriculum development, (2) staff development, (3) community involvement, and (4) the pre- and post-tests given to the students. The…

  8. ENDF/B-VII.1 Nuclear Data for Science and Technology: Cross Sections, Covariances, Fission Product Yields and Decay Data

    NASA Astrophysics Data System (ADS)

    Chadwick, M. B.; Herman, M.; Obložinský, P.; Dunn, M. E.; Danon, Y.; Kahler, A. C.; Smith, D. L.; Pritychenko, B.; Arbanas, G.; Arcilla, R.; Brewer, R.; Brown, D. A.; Capote, R.; Carlson, A. D.; Cho, Y. S.; Derrien, H.; Guber, K.; Hale, G. M.; Hoblit, S.; Holloway, S.; Johnson, T. D.; Kawano, T.; Kiedrowski, B. C.; Kim, H.; Kunieda, S.; Larson, N. M.; Leal, L.; Lestone, J. P.; Little, R. C.; McCutchan, E. A.; MacFarlane, R. E.; MacInnes, M.; Mattoon, C. M.; McKnight, R. D.; Mughabghab, S. F.; Nobre, G. P. A.; Palmiotti, G.; Palumbo, A.; Pigni, M. T.; Pronyaev, V. G.; Sayer, R. O.; Sonzogni, A. A.; Summers, N. C.; Talou, P.; Thompson, I. J.; Trkov, A.; Vogt, R. L.; van der Marck, S. C.; Wallner, A.; White, M. C.; Wiarda, D.; Young, P. G.

    2011-12-01

    The ENDF/B-VII.1 library is our latest recommended evaluated nuclear data file for use in nuclear science and technology applications, and incorporates advances made in the five years since the release of ENDF/B-VII.0. These advances focus on neutron cross sections, covariances, fission product yields and decay data, and represent work by the US Cross Section Evaluation Working Group (CSEWG) in nuclear data evaluation that utilizes developments in nuclear theory, modeling, simulation, and experiment. The principal advances in the new library are: (1) An increase in the breadth of neutron reaction cross section coverage, extending from 393 nuclides to 423 nuclides; (2) Covariance uncertainty data for 190 of the most important nuclides, as documented in companion papers in this edition; (3) R-matrix analyses of neutron reactions on light nuclei, including isotopes of He, Li, and Be; (4) Resonance parameter analyses at lower energies and statistical high energy reactions for isotopes of Cl, K, Ti, V, Mn, Cr, Ni, Zr and W; (5) Modifications to thermal neutron reactions on fission products (isotopes of Mo, Tc, Rh, Ag, Cs, Nd, Sm, Eu) and neutron absorber materials (Cd, Gd); (6) Improved minor actinide evaluations for isotopes of U, Np, Pu, and Am (we are not making changes to the major actinides 235,238U and 239Pu at this point, except for delayed neutron data and covariances, and instead we intend to update them after a further period of research in experiment and theory), and our adoption of JENDL-4.0 evaluations for isotopes of Cm, Bk, Cf, Es, Fm, and some other minor actinides; (7) Fission energy release evaluations; (8) Fission product yield advances for fission-spectrum neutrons and 14 MeV neutrons incident on 239Pu; and (9) A new decay data sublibrary. Integral validation testing of the ENDF/B-VII.1 library is provided for a variety of quantities: For nuclear criticality, the VII.1 library maintains the generally-good performance seen for VII.0 for a wide range

  9. Biological and analytical variations of 16 parameters related to coagulation screening tests and the activity of coagulation factors.

    PubMed

    Chen, Qian; Shou, Weiling; Wu, Wei; Guo, Ye; Zhang, Yujuan; Huang, Chunmei; Cui, Wei

    2015-04-01

    To accurately estimate longitudinal changes in individuals, it is important to take into consideration the biological variability of the measurement. The few studies available on the biological variations of coagulation parameters are mostly outdated. We confirmed the published results using modern, fully automated methods. Furthermore, we added data for additional coagulation parameters. At 8:00 am, 12:00 pm, and 4:00 pm on days 1, 3, and 5, venous blood was collected from 31 healthy volunteers. A total of 16 parameters related to coagulation screening tests as well as the activity of coagulation factors were analyzed; these included prothrombin time, fibrinogen (Fbg), activated partial thromboplastin time, thrombin time, international normalized ratio, prothrombin time activity, activated partial thromboplastin time ratio, fibrin(-ogen) degradation products, as well as the activity of factor II, factor V, factor VII, factor VIII, factor IX, and factor X. All intraindividual coefficients of variation (CVI) values for the parameters of the screening tests (except Fbg) were less than 5%. Conversely, the CVI values for the activity of coagulation factors were all greater than 5%. In addition, we calculated the reference change value to determine whether a significant difference exists between two test results from the same individual. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  10. The Tenth Circuit View of Title VII Discovery--EEOC v. University of New Mexico, 504 F. 2d 1296 (10th Cir. 1974); Rich v. Martin Marietta Corp., 522 F. 2d 353 (10th Cir. 1975)

    ERIC Educational Resources Information Center

    Hoeltgen, Kristine A.

    1976-01-01

    In both these cases the Tenth Circuit continued the trend begun in earlier Title VII cases of giving a liberal interpretation to the scope of discovery. In these decisions the court began to speak more particularly of the factors to be considered in acting on motions to compel discovery. (Author/LBH)

  11. Class II ADP-ribosylation factors are required for efficient secretion of dengue viruses.

    PubMed

    Kudelko, Mateusz; Brault, Jean-Baptiste; Kwok, Kevin; Li, Ming Yuan; Pardigon, Nathalie; Peiris, J S Malik; Bruzzone, Roberto; Desprès, Philippe; Nal, Béatrice; Wang, Pei Gang

    2012-01-02

    Identification and characterization of virus-host interactions are very important steps toward a better understanding of the molecular mechanisms responsible for disease progression and pathogenesis. To date, very few cellular factors involved in the life cycle of flaviviruses, which are important human pathogens, have been described. In this study, we demonstrate a crucial role for class II Arf proteins (Arf4 and Arf5) in the dengue flavivirus life cycle. We show that simultaneous depletion of Arf4 and Arf5 blocks recombinant subviral particle secretion for all four dengue serotypes. Immunostaining analysis suggests that class II Arf proteins are required at an early pre-Golgi step for dengue virus secretion. Using a horseradish peroxidase protein fused to a signal peptide, we show that class II Arfs act specifically on dengue virus secretion without altering the secretion of proteins through the constitutive secretory pathway. Co-immunoprecipitation data demonstrate that the dengue prM glycoprotein interacts with class II Arf proteins but not through its C-terminal VXPX motif. Finally, experiments performed with replication-competent dengue and yellow fever viruses demonstrate that the depletion of class II Arfs inhibits virus secretion, thus confirming their implication in the virus life cycle, although data obtained with West Nile virus pointed out the differences in virus-host interactions among flaviviruses. Our findings shed new light on a molecular mechanism used by dengue viruses during the late stages of the life cycle and demonstrate a novel function for class II Arf proteins.

  12. Estimation of the Dose and Dose Rate Effectiveness Factor

    NASA Technical Reports Server (NTRS)

    Chappell, L.; Cucinotta, F. A.

    2013-01-01

    Current models to estimate radiation risk use the Life Span Study (LSS) cohort that received high doses and high dose rates of radiation. Transferring risks from these high dose rates to the low doses and dose rates received by astronauts in space is a source of uncertainty in our risk calculations. The solid cancer models recommended by BEIR VII [1], UNSCEAR [2], and Preston et al [3] is fitted adequately by a linear dose response model, which implies that low doses and dose rates would be estimated the same as high doses and dose rates. However animal and cell experiments imply there should be curvature in the dose response curve for tumor induction. Furthermore animal experiments that directly compare acute to chronic exposures show lower increases in tumor induction than acute exposures. A dose and dose rate effectiveness factor (DDREF) has been estimated and applied to transfer risks from the high doses and dose rates of the LSS cohort to low doses and dose rates such as from missions in space. The BEIR VII committee [1] combined DDREF estimates using the LSS cohort and animal experiments using Bayesian methods for their recommendation for a DDREF value of 1.5 with uncertainty. We reexamined the animal data considered by BEIR VII and included more animal data and human chromosome aberration data to improve the estimate for DDREF. Several experiments chosen by BEIR VII were deemed inappropriate for application to human risk models of solid cancer risk. Animal tumor experiments performed by Ullrich et al [4], Alpen et al [5], and Grahn et al [6] were analyzed to estimate the DDREF. Human chromosome aberration experiments performed on a sample of astronauts within NASA were also available to estimate the DDREF. The LSS cohort results reported by BEIR VII were combined with the new radiobiology results using Bayesian methods.

  13. Multiple-Purpose Project, Osage River Basin, Osage River, Missouri. Harry S. Truman Dam & Reservoir Operation and Maintenance Manual. Appendix VII. Volume 1. Construction Foundation Report.

    DTIC Science & Technology

    1984-01-01

    RIVER MISSOURI Report from September 1966 HARRY S. TROMAN DAM & RESERVOIR November 1979 OPERATION AND MAINTENANCE MANUAL 6 PERFORMING DRG. REPORT N4040E...Two of this report ) VII- I- xxiv ............................. .... ... .... ... . .2. . . OPERATION AND MAINTENANCE MANUAL HARRY S. TRUMAN DAM AND...RESERVOIR OSAGE RIVER, MISSOURI APPENDIX VII CONSTRUCTION FOUNDATION REPORT CHAPTER 1 INTRODUCTION 1-01. Location and Description of Project: Harry S

  14. Dos Idiomas, Un Mundo. Dual Language Project. Title VII Biennial Evaluation Report, 1995-97.

    ERIC Educational Resources Information Center

    Ernest, Harishini M.; Gonzalez, Rosa M.

    This is an evaluation of the first 2 years of a 5-year comprehensive Bilingual Education grant funded by Title VII Part A of the Improving America's Schools Act of 1994 in the Austin Independent School District (AISD) (Texas). The grant awarded to the AISD funds a program of Developmental Bilingual Education at two elementary schools where more…

  15. Parents and Federal Education Programs. Volume 4: Title VII. The Study of Parental Involvement.

    ERIC Educational Resources Information Center

    Cadena-Munoz, Raquel; Keesling, J. Ward

    This fourth volume in a seven-volume study is part of a larger study of parental involvement in four federal programs in selected school districts across the country. Presented here are results of an intensive examination of school district programs funded by Title VII of the Elementary and Secondary Education Act. Site studies of Title VII…

  16. Atomic Structures of Minor Proteins VI and VII in the Human Adenovirus.

    PubMed

    Dai, Xinghong; Wu, Lily; Sun, Ren; Zhou, Z Hong

    2017-10-04

    Human adenoviruses (Ad) are dsDNA viruses associated with infectious diseases, yet better known as tools for gene delivery and oncolytic anti-cancer therapy. Atomic structures of Ad provide the basis for the development of antivirals and for engineering efforts towards more effective applications. Since 2010, atomic models of human Ad5 have been independently derived from photographic film cryoEM and X-ray crystallography, but discrepancies exist concerning the assignment of cement proteins IIIa, VIII and IX. To clarify these discrepancies, here we have employed the technology of direct electron-counting to obtain a cryoEM structure of human Ad5 at 3.2 Å resolution. Our improved structure unambiguously confirmed our previous cryoEM models of proteins IIIa, VIII and IX and explained the likely cause of conflict in the crystallography models. The improved structure also allows the identification of three new components in the cavities of hexons - the cleaved N-terminus of precursor protein VI (pVIn), the cleaved N-terminus of precursor protein VII (pVIIn2), and mature protein VI. The binding of pVIIn2--by extension that of genome-condensing pVII--to hexons is consistent with the previously proposed dsDNA genome-capsid co-assembly for adenoviruses, which resembles that of ssRNA viruses but differs from the well-established mechanism of pumping dsDNA into a preformed protein capsid, as exemplified by tailed bacteriophages and herpesviruses. IMPORTANCE Adenovirus is a double-edged sword to humans - as a widespread pathogen and a bioengineering tool for anti-cancer and gene therapy. Atomic structure of the virus provides the basis for antiviral and application developments, but conflicting atomic models from conventional/film cryoEM and X-ray crystallography for important cement proteins IIIa, VIII, and IX have caused confusion. Using the cutting-edge cryoEM technology with electron counting, we improved the structure of human adenovirus type 5 and confirmed our

  17. Laser plasma x-ray line spectra fitted using the Pearson VII function

    NASA Astrophysics Data System (ADS)

    Michette, A. G.; Pfauntsch, S. J.

    2000-05-01

    The Pearson VII function, which is more general than the Gaussian, Lorentzian and other profiles, is used to fit the x-ray spectral lines produced in a laser-generated plasma, instead of the more usual, but computationally expensive, Voigt function. The mean full-width half-maximum of the fitted lines is 0.102+/-0.014 nm, entirely consistent with the value expected from geometrical considerations, and the fitted line profiles are generally inconsistent with being either Lorentzian or Gaussian.

  18. Military Curricula for Vocational & Technical Education. Metals Processing Specialist, Block VII, Classroom Course 13-8.

    ERIC Educational Resources Information Center

    Ohio State Univ., Columbus. National Center for Research in Vocational Education.

    These curriculum materials are the fourth section of a four-part, secondary-postsecondary-level course in metals processing. The course is one of a number of military-developed curriculum packages selected for adaptation to vocational instruction and curriculum development in a civilian setting. Block VII deals with heat treating, hardness…

  19. Sarah J. Hale High School Project SABER. ESEA Title VII. Final Evaluation Report, 1979-80.

    ERIC Educational Resources Information Center

    New York City Board of Education, Brooklyn, NY. Office of Educational Evaluation.

    This is an evaluation of a Title VII Bilingual Program conducted at a New York City High School in 1979-80. The report contains information on the program goals and objectives, the school site, and the student characteristics. Aspects of the instructional component discussed include programming, mainstreaming, and program funding.…

  20. Optimizing the Disposition and Retrograde of United States Air Force Class VII Equipment from Afghanistan

    DTIC Science & Technology

    2014-03-27

    1959). On a linear-programming, combinatorial approach to the traveling - salesman problem . Operations Research, 58-66. Daugherty, P. J., Myers, M. B...1 Problem Statement... Problem Statement As of 01 September 2013, the USAF is tracking 12,571 individual Class VII assets valued at $213.5 million for final disposition