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

PubMed

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

2016-10-01

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

Identification of a His54Gln substitution in von Willebrand factor from a patient with defective binding of factor VIII.

PubMed

Rick, M E; Krizek, D M

1996-04-01

A patient with type 2N ("Normandy" variant) von Willebrand's disease is described. Her von Willebrand factor level was borderline low, while her factor VIII was markedly decreased to 7%. Her plasma von Willebrand factor demonstrated a decreased ability to complex with factor VIII in vitro, binding less than 10% when compared to normal plasma von Willebrand factor. The factor VIII released into the circulation after the patient received DDAVP had a shortened survival in vivo. Nucleotide sequence analysis revealed a T-to-A transition at nucleotide 2451 on both alleles. This transition results in a substitution of Gln for His at amino acid 54 in the mature subunit of von Willebrand factor.

Factor VIII-associated antigen in human lymphatic endothelium.

PubMed

Nagle, R B; Witte, M H; Martinez, A P; Witte, C L; Hendrix, M J; Way, D; Reed, K

1987-03-01

Lymphatic vascular endothelium both on tissue section and in culture exhibits positivity for Factor VIII-associated antigen although staining is generally less intense and more spotty than in comparable blood vascular endothelium. Lymphatic endothelium also exhibits Weibel-Palade bodies. Neither marker, therefore, reliably distinguishes blood vascular endothelium from lymphatic endothelium.

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.

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

PubMed

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

2016-09-01

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

Population pharmacokinetics of recombinant coagulation factor VIII-SingleChain in patients with severe hemophilia A.

PubMed

Zhang, Y; Roberts, J; Tortorici, M; Veldman, A; St Ledger, K; Feussner, A; Sidhu, J

2017-06-01

Essentials rVIII-SingleChain is a unique recombinant factor VIII (FVIII) molecule. A population pharmacokinetic model was based on FVIII activity of severe hemophilia A patients. The model was used to simulate factor VIII activity-time profiles for various dosing scenarios. The model supports prolonged dosing of rVIII-SingleChain with intervals of up to twice per week. Background Single-chain recombinant coagulation factor VIII (rVIII-SingleChain) is a unique recombinant coagulation factor VIII molecule. Objectives To: (i) characterize the population pharmacokinetics (PK) of rVIII-SingleChain in patients with severe hemophilia A; (ii) identify correlates of variability in rVIII-SingleChain PK; and (iii) simulate various dosing scenarios of rVIII-SingleChain. Patients/Methods A population PK model was developed, based on FVIII activity levels of 130 patients with severe hemophilia A (n = 91 for ≥ 12-65 years; n = 39 for < 12 years) who had participated in a single-dose PK investigation with rVIII-SingleChain 50 IU kg -1 . PK sampling was performed for up to 96 h. Results A two-compartment population PK model with first-order elimination adequately described FVIII activity. Body weight and predose level of von Willebrand factor were significant covariates on clearance, and body weight was a significant covariate on the central distribution volume. Simulations using the model with various dosing scenarios estimated that > 85% and > 93% of patients were predicted to maintain FVIII activity level above 1 IU dL -1 , at all times with three-times-weekly dosing (given on days 0, 2, and 4.5) at the lowest (20 IU kg -1 ) and highest (50 IU kg -1 ) doses, respectively. For twice weekly dosing (days 0 and 3.5) of 50 IU kg -1 rVIII-SingleChain, 62-80% of patients across all ages were predicted to maintain a FVIII activity level above 1 IU dL -1 at day 7. Conclusions The population PK model adequately characterized rVIII-SingleChain PK, and the model

Factor VIII inhibitor in a patient with mild haemophilia A and an Asn618-->Ser mutation responsive to immune tolerance induction and cyclophosphamide.

PubMed

Vlot, André J; Wittebol, Shulamiet; Strengers, Paul F W; Turenhout, Ellen A M; Voorberg, Jan; van den Berg, H Marijke; Mauser-Bunschoten, Eveline P

2002-04-01

We describe a patient with mild haemophilia A (original value of factor VIII activity 0.30 U/ml) who developed an inhibitor (36.1 Bethesda U/ml) which cross-reacted with his endogenous factor VIII. This caused a decline in basal factor VIII level (< 0.01 U/ml) and severe haemorrhagic events. Treatment to induce immune tolerance was started with factor VIII/von Willebrand factor (VWF) concentrates, but inhibitor levels increased progressively and the patient suffered serious bleeding. Cyclophosphamide was administered and, after 8 months treatment, factor VIII levels increased to 0.20 U/ml and the inhibitor could no longer be detected. Screening of his factor VIII gene revealed a missense mutation in exon 13 that predicts substitution of Asn618-->Ser in the A2 domain of factor VIII. Immunoprecipitation analysis showed that the antibodies present in the patient's plasma reacted with metabolically labelled A2 domain and, to a lesser extent, with factor VIII light chain. Inhibitory antibodies were completely neutralized by recombinant A2 domain, whereas no neutralization was observed after the addition of factor VIII light chain (A3-C1-C2) and C2 domain. More detailed analysis showed that the majority of inhibitory antibodies were directed against residues Arg484-Ile508, a previously identified binding site for factor VIII inhibitors. Our findings suggest that immune tolerance therapy and cyclophosphamide were successful in eradicating inhibitory antibodies against a common epitope on factor VIII.

Factor VIII levels and the risk of pre-eclampsia, HELLP syndrome, pregnancy related hypertension and severe intrauterine growth retardation.

PubMed

Witsenburg, C P J; Rosendaal, F R; Middeldorp, J M; Van der Meer, F J M; Scherjon, S A

2005-01-01

Recently, acquired as well as genetic prothrombotic factors are associated with thrombotic events. These factors have also been related to conditions of uteroplacental insufficiency such as pre-eclampsia, HELLP syndrome and severe intrauterine growth restriction (IUGR). The aim of this study was to determine whether elevated factor VIII levels are associated with uteroplacental insufficiency, in particular pre-eclampsia, HELLP syndrome or pregnancy-induced hypertension and intrauterine growth retardation. Plasma samples of 75 women with a history of pregnancy complicated by pre-eclampsia, HELLP syndrome, pregnancy induced hypertension or intrauterine growth restriction were tested for factor VIII:C (FVIII:C) levels at a minimum of 10 weeks post-partum. Laboratory results were compared to factor VIII:C levels found in a healthy control group of 272 women. Mean factor VIII:C levels were similar at 123 IU/dl in both the patient group and the controls. In a logistic regression model, after adjusting for age and blood group, no effect of factor VIII:C levels on the risk of pregnancy complications was observed, with the exception of IUGR with (OR 2.9, CI 1.0-8.7) or without hypertension (OR 2.0, CI 0.7-6.4). If the elevated level of factor VIII would be the sole factor responsible for the increased risk observed, one would expect to find an effect of blood group on risk as well (blood group being an important determinant of FVIII:C). While no such effect could be shown a causal relationship between elevated levels of factor VIII and conditions of uteroplacental insufficiency such as pre-eclampsia, HELLP syndrome, pregnancy-induced hypertension and IUGR is not very likely.

Studies of Factors V and VIII:C in an animal model of disseminated intravascular coagulation.

PubMed Central

Giles, A R; Nesheim, M E; Mann, K G

1984-01-01

An experimental animal model of disseminated intravascular coagulation (DIC) induced by the co-infusion of coagulant-active phospholipid and activated Factor X (Factor Xa) is described. The infusion of Factor Xa at a dose of 6.6 X 10(-12) mol/kg with phosphatidylcholine/phosphatidylserine (PCPS) lipid vesicles at a dose of 4.0 X 10(-8) mol/kg was associated with significant falls in the levels of fibrinogen and Factors V and VIII, and a bleeding diathesis developed. Assays of Factors V and VIII were performed by a one-stage prothrombin time and activated partial thrombin time system, respectively. In additional experiments, the effect of the same dose combination of Factor Xa/PCPS on Factor V kinetics was studied by preinfusing 125I-labeled Factor V. After Factor Xa/PCPS infusion, Factors VIII and V were reduced at 2 min by 90 and 50% of the preinfusion levels, respectively, and at 1 h by 80 and 75%, respectively. During the same period, there was little change in the total circulating radioactivity. Autoradiography indicated small but detectable levels of circulating proteolytic products of Factor V that comigrated with peptides obtained by the incubation of Factor V with Factor Xa and activated protein C. The majority of radioactivity remained associated with the intact single-chain precursor Factor V. These observations suggested maintenance of the precursor pool after the onset of DIC. This was confirmed by performing two-stage assays of Factors V and VIII, whereby each was completely converted to the active cofactor, i.e., Va and VIII:Ca, by preincubation of the test sample with thrombin before assaying in a one-stage system as before. The Factor V levels assayed by the two-stage procedure did not change appreciably over 1 h. The Factor VIII levels fell but corrected within 1 h at a time when the level measured by a one-stage assay remained depressed. These results indicate that in the dog, infusion of Factor Xa/PCPS induces changes characteristic of DIC, and

Differentiation of embryonic stem cells into hepatocytes that coexpress coagulation factors VIII and IX.

PubMed

Cao, Jun; Shang, Chang-zhen; Lü, Li-hong; Qiu, De-chuan; Ren, Meng; Chen, Ya-jin; Min, Jun

2010-11-01

To establish an efficient culture system to support embryonic stem (ES) cell differentiation into hepatocytes that coexpress F-VIII and F-IX. Mouse E14 ES cells were cultured in differentiation medium containing sodium butyrate (SB), basic fibroblast growth factor (bFGF), and/or bone morphogenetic protein 4 (BMP4) to induce the differentiation of endoderm cells and hepatic progenitor cells. Hepatocyte growth factor, oncostatin M, and dexamethasone were then used to induce the maturation of ES cell-derived hepatocytes. The mRNA expression levels of endoderm-specific genes and hepatocyte-specific genes, including the levels of F-VIII and F-IX, were detected by RT-PCR and real-time PCR during various stages of differentiation. Protein expression was examined by immunofluorescence and Western blot. At the final stage of differentiation, flow cytometry was performed to determine the percentage of cells coexpressing F-VIII and F-IX, and ELISA was used to detect the levels of F-VIII and F-IX protein secreted into the culture medium. The expression of endoderm-specific and hepatocyte-specific markers was upregulated to highest level in response to the combination of SB, bFGF, and BMP4. Treatment with the three inducers during hepatic progenitor differentiation significantly enhanced the mRNA and protein levels of F-VIII and F-IX in ES cell-derived hepatocytes. More importantly, F-VIII and F-IX were coexpressed with high efficiency at the final stage of differentiation, and they were also secreted into the culture medium. We have established a novel in vitro differentiation protocol for ES-derived hepatocytes that coexpress F-VIII and F-IX that may provide a foundation for stem cell replacement therapy for hemophilia.

Quantitative immunohistochemistry of factor VIII-related antigen in breast carcinoma: a comparison of computer-assisted image analysis with established counting methods.

PubMed

Kohlberger, P D; Obermair, A; Sliutz, G; Heinzl, H; Koelbl, H; Breitenecker, G; Gitsch, G; Kainz, C

1996-06-01

Microvessel density in the area of the most intense neovascularization in invasive breast carcinoma is reported to be an independent prognostic factor. The established method of enumeration of microvessel density is to count the vessels using an ocular raster (counted microvessel density [CMVD]). The vessels were detected by staining endothelial cells using Factor VIII-related antigen. The aim of the study was to compare the CMVD results with the percentage of factor VIII-related antigen-stained area using computer-assisted image analysis. A true color red-green-blue (RGB) image analyzer based on a morphologically reduced instruction set computer processor was used to evaluate the area of stained endothelial cells. Sixty invasive breast carcinomas were included in the analysis. There was no significant correlation between the CMVD and the percentage of factor VIII-related antigen-stained area (Spearman correlation coefficient = 0.24, confidence interval = 0.02-0.46). Although high CMVD was significantly correlated with poorer recurrence free survival (P = .024), percentage of factor VIII-related antigen-stained area showed no prognostic value. Counted microvessel density and percentage of factor VIII-related antigen-stained area showed a highly significant correlation with vessel invasion (P = .0001 and P = .02, respectively). There was no correlation between CMVD and percentage of factor VIII-related antigen-stained area with other prognostic factors. In contrast to the CMVD within malignant tissue, the percentage of factor VIII-related antigen-stained area is not suitable as an indicator of prognosis in breast cancer patients.

Home therapy with continuous infusion of factor VIII after minor surgery or serious haemorrhage.

PubMed

Varon, D; Schulman, S; Bashari, D; Martinowitz, U

1996-10-01

Administration of factor VIII (F VIII) concentrates by continuous infusion is now routinely used at several haemophilia centers but almost exclusively for hospitalized patients. We evaluated various aspects of home therapy with continuous infusion of an immunoaffinity purified F VIII concentrate (Monoclate P®, Armour) in patients who would normally have been treated with high doses in bolus injections or with continuous infusion as in-patients. Twenty haemophilia A patients, eight after minor surgery and 12 for serious haemorrhage, received continuous infusion with undiluted F VIII by a minipump for a mean of 0.9 days in the hospital, followed by 3.3 days at home. Infusion bags were exchanged every 2.5 days. No haemorrhagic complications occurred, and five haemorrhages that had been resistant to treatment with bolus injections responded promptly to the continuous infusion. There were no technical problems and patient compliance and acceptance was good. We find this mode of therapy safe, efficacious and convenient for the patients as well as for the staff.

Hemorrhage and blood loss-induced anemia associated with an acquired coagulation factor VIII inhibitor in a Thoroughbred mare.

PubMed

Winfield, Laramie S; Brooks, Marjory B

2014-03-15

A 23-year-old Thoroughbred mare was evaluated because of a coagulopathy causing hemoperitoneum, hematomas, and signs of blood loss-induced anemia. The mare had tachycardia, pallor, hypoperfusion, and a large mass in the right flank. The mass was further characterized ultrasonographically as an extensive hematoma in the body wall with associated hemoabdomen. Coagulation testing revealed persistent, specific prolongation of the activated partial thromboplastin time (> 100 seconds; reference interval, 24 to 44 seconds) attributable to severe factor VIII deficiency (12%; reference interval, 50% to 200%). On the basis of the horse's age, lack of previous signs of a bleeding diathesis, and subsequent quantification of plasma factor VIII inhibitory activity (Bethesda assay titer, 2.7 Bethesda units/mL), acquired hemophilia A was diagnosed. The medical history did not reveal risk factors or underlying diseases; thus, the development of inhibitory antibodies against factor VIII was considered to be idiopathic. The mare was treated with 2 transfusions of fresh whole blood and fresh-frozen plasma. Immunosuppressive treatment consisting of dexamethasone and azathioprine was initiated. Factor VIII deficiency and signs of coagulopathy resolved, and the inhibitory antibody titer decreased. The mare remained healthy with no relapse for at least 1 year after treatment. Horses may develop inhibitory antibodies against factor VIII that cause acquired hemophilia A. A treatment strategy combining transfusions of whole blood and fresh-frozen plasma and administration of immunosuppressive agents was effective and induced sustained remission for at least 1 year in the mare described here.

Prevalence of the intron 22 inversion of the factor VIII gene and inhibitor development in Polish patients with severe hemophilia A.

PubMed

Sawecka, Jadwiga; Skulimowska, Joanna; Windyga, Jerzy; Lopaciuk, Stanisław; Kościelak, Jerzy

2005-01-01

Patients with severe hemophilia A often develop inhibitors (antibodies) against transfused factor VIII. One hundred thirteen Polish patients with severe hemophilia A, who had been treated on demand with cryoprecipitate until 1992 and exclusively with factor VIII concentrates after 1995, were examined for intron 22 inversion by Southern blotting and the presence and magnitude of inhibitor activity in blood as determined by the Bethesda assay. The patients' ages ranged 4--67 years (mean: 33.7+/-12.4 years, median: 32 years). The number of patients with the inversion amounted to 57, while in 56 patients the mutation types were unknown; 47 patients had a distal and 10 patients a proximal type of inversion. Thirteen patients with inversions (22.8%) were found to have inhibitor in their blood. Most patients (14 out of 15) who developed inhibitors in the course of cryoprecipitate therapy were high responders. Conversely, 4 of 5 patients treated between 1992 and 1995 with both cryoprecipitate and intermediate-purity factor VIII concentrates were low responders. One multitransfused patient who had remained inhibitor-free on cryoprecipitate therapy developed inhibitor after receiving a large dose of factor VIII concentrate during surgery. None of these 5 patients developed inhibitors during their 12--40 years of treatment with cryoprecipitate, suggesting that it was less immunogenic than factor VIII concentrates. The prevalence of the intron 22 inversion mutation of the factor VIII gene in Polish hemophiliacs is similar to that in other European countries. Treatment regimens with either cryoprecipitate or virus-inactivated plasma-derived factor VIII concentrates may affect inhibitor formation in hemophilia A patients.

Crystal Structure of the Bovine lactadherin C2 Domain, a Membrane Binding Motif, Shows Similarity of the C2 Domains of Factor V and Factor VIII

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

Lin,L.; Huai, Q.; Huang, M.

2007-01-01

Lactadherin, a glycoprotein secreted by a variety of cell types, contains two EGF domains and two C domains with sequence homology to the C domains of blood coagulation proteins factor V and factor VIII. Like these proteins, lactadherin binds to phosphatidylserine (PS)-containing membranes with high affinity. We determined the crystal structure of the bovine lactadherin C2 domain (residues 1 to 158) at 2.4 Angstroms. The lactadherin C2 structure is similar to the C2 domains of factors V and VIII (rmsd of C? atoms of 0.9 Angstroms and 1.2 Angstroms, and sequence identities of 43% and 38%, respectively). The lactadherin C2more » domain has a discoidin-like fold containing two ?-sheets of five and three antiparallel ?-strands packed against one another. The N and C termini are linked by a disulfide bridge between Cys1 and Cys158. One ?-turn and two loops containing solvent-exposed hydrophobic residues extend from the C2 domain ?-sandwich core. In analogy with the C2 domains of factors V and VIII, some or all of these solvent-exposed hydrophobic residues, Trp26, Leu28, Phe31, and Phe81, likely participate in membrane binding. The C2 domain of lactadherin may serve as a marker of cell surface phosphatidylserine exposure and may have potential as a unique anti-thrombotic agent.« less

Structure of the human factor VIII C2 domain in complex with the 3E6 inhibitory antibody

DOE PAGES

Wuerth, Michelle E.; Cragerud, Rebecca K.; Spiegel, P. Clint

2015-11-24

Blood coagulation factor VIII is a glycoprotein cofactor that is essential for the intrinsic pathway of the blood coagulation cascade. Inhibitory antibodies arise either spontaneously or in response to therapeutic infusion of functional factor VIII into hemophilia A patients, many of which are specific to the factor VIII C2 domain. The immune response is largely parsed into “classical” and “non-classical” inhibitory antibodies, which bind to opposing faces cooperatively. In this study, the 2.61 Å resolution structure of the C2 domain in complex with the antigen-binding fragment of the 3E6 classical inhibitory antibody is reported. The binding interface is largely conservedmore » when aligned with the previously determined structure of the C2 domain in complex with two antibodies simultaneously. Further inspection of the B factors for the C2 domain in various X-ray crystal structures indicates that 3E6 antibody binding decreases the thermal motion behavior of surface loops in the C2 domain on the opposing face, thereby suggesting that cooperative antibody binding is a dynamic effect. Furthermore, understanding the structural nature of the immune response to factor VIII following hemophilia A treatment will help lead to the development of better therapeutic reagents.« less

Indirect comparisons of efficacy and weekly factor consumption during continuous prophylaxis with recombinant factor VIII Fc fusion protein and conventional recombinant factor VIII products.

PubMed

Iorio, A; Krishnan, S; Myrén, K J; Lethagen, S; McCormick, N; Yermakov, S; Karner, P

2017-05-01

Recombinant factor VIII (rFVIII) products with extended half-lives have the potential to improve adherence and outcomes in haemophilia beyond the results obtained with conventional rFVIII products. In the absence of head-to-head comparisons, annualized bleed rates (ABRs) and weekly factor consumption with rFVIII Fc fusion protein (rFVIIIFc) and conventional rFVIII products were indirectly compared using studies of continuous prophylaxis. A systematic literature review was conducted to identify studies of rFVIII products for comparison with rFVIIIFc in the continuous prophylactic treatment of previously treated adolescents and adults with moderate and severe haemophilia A. Mean ABRs were compared between rFVIIIFc and individual rFVIII studies and between rFVIIIFc and a pooled measure for rFVIII estimated by meta-analysis. Comparisons of factor consumption were based on mean or median weekly factor consumption. Results from seven studies of conventional rFVIII products (injections 2-4 times week -1 ) were compared with rFVIIIFc (injections 1.4-2.4 times week -1 ). The pooled mean ABR for rFVIII products was significantly higher compared with rFVIIIFc (difference = 2.0; P = 0.007). Compared with most rFVIII studies, the reported weekly factor consumption was lower with rFVIIIFc [mean differences = 15.5-21.8 IU kg -1 week -1 (17-26%); median differences = 12.7-29.8 IU kg -1 week -1 (16-37%)]. In one comparison, mean weekly factor consumption with rFVIII was significantly lower but mean ABR was significantly higher than rFVIIIFc. Prophylaxis with rFVIIIFc may be associated with improved bleeding rates and lower weekly factor consumption than more frequently injected rFVIII products. Relative to rFVIII products with similar bleeding rates, results indicate that rFVIIIFc is associated with reduced weekly factor consumption while requiring fewer prescribed injections. © 2017 John Wiley & Sons Ltd.

Crystal Structure of the Bovine lactadherin C2 Domain, a Membrane Binding Motif, Shows Similarity to the C2 Domains of Factor V and Factor VIII

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

Lin,L.

2007-01-01

Lactadherin, a glycoprotein secreted by a variety of cell types, contains two EGF domains and two C domains with sequence homology to the C domains of blood coagulation proteins factor V and factor VIII. Like these proteins, lactadherin binds to phosphatidylserine (PS)-containing membranes with high affinity. We determined the crystal structure of the bovine lactadherin C2 domain (residues 1 to 158) at 2.4 {angstrom}. The lactadherin C2 structure is similar to the C2 domains of factors V and VIII (rmsd of C{sub {alpha}} atoms of 0.9 {angstrom} and 1.2 {angstrom}, and sequence identities of 43% and 38%, respectively). The lactadherinmore » C2 domain has a discoidin-like fold containing two {beta}-sheets of five and three antiparallel {beta}-strands packed against one another. The N and C termini are linked by a disulfide bridge between Cys1 and Cys158. One {beta}-turn and two loops containing solvent-exposed hydrophobic residues extend from the C2 domain {beta}-sandwich core. In analogy with the C2 domains of factors V and VIII, some or all of these solvent-exposed hydrophobic residues, Trp26, Leu28, Phe31, and Phe81, likely participate in membrane binding. The C2 domain of lactadherin may serve as a marker of cell surface phosphatidylserine exposure and may have potential as a unique anti-thrombotic agent.« less

The story of a unique molecule in hemophilia A: recombinant single-chain factor VIII.

PubMed

Pabinger-Fasching, Ingrid

2016-05-01

For patients with hemophilia A, replacement of deficient factor VIII (FVIII) using plasma-derived or recombinant FVIII (rFVIII) products to restore hemostatic control can reduce bleeding complications and preserve musculoskeletal function. Despite the clinical availability of several of these products, challenges remain in the treatment of hemophilia A, the most notable of which are the risk of inhibitor development and the limited half-life of existing FVIII concentrates, which can make prophylaxis burdensome for patients. The use of recombinant protein technology may lead to novel FVIII products with improved properties. This article describes the story of a unique recombinant FVIII protein, rVIII-SingleChain, which is currently in development. In contrast to native FVIII and other commercially available rFVIII preparations, rVIII-SingleChain uses a strong, covalent bond to connect the light and heavy chains, thereby creating a stable, single-chain rFVIII. It has enhanced intrinsic stability, better integrity after reconstitution, and a higher binding affinity to von Willebrand factor. The physicochemical profile of rVIII-SingleChain and preclinical data on its activity and phamacokinetics strengthened the rationale for its clinical investigation. Available data from the AFFINITY clinical trial program are promising; indicating that it has good hemostatic efficacy when used on demand, for prophylaxis, and in the surgical setting, and is also very well tolerated. A pediatric study and an extension study are ongoing as part of the AFFINITY program. © 2016 Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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

PubMed Central

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

2016-01-01

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

Clotting factor VIII (FVIII) and thrombin generation in camel plasma: A comparative study with humans

PubMed Central

Abdel Gader, Abdel Galil M.; Al Momen, Abdul Karim M.; Alhaider, Abdulqader; Brooks, Marjory B.; Catalfamo, James L.; Al Haidary, Ahmed A.; Hussain, Mansour F.

2013-01-01

The objective of this study was to characterize the highly elevated levels of clotting factor VIII (FVIII) in camel plasma. Whole blood was collected from healthy camels and factor VIII clotting activity (FVIII:C) assays were conducted using both the clotting and the chromogenic techniques. The anticoagulant citrate phosphate dextrose adenine (CPDA) produced the highest harvest of FVIII:C, the level of plasma factor VIII, compared to heparin:saline and heparin:CPDA anticoagulants. Camel FVIII can be concentrated 2 to 3 times in cryoprecipitate. There was a significant loss of camel FVIII when comparing levels of FVIII in camel plasma after 1 h of incubation at 37°C (533%), 40°C (364%), and 50°C (223%). Thrombin generation of camel plasma is comparable to that of human plasma. It was concluded that camel plasma contains very elevated levels of FVIII:C, approaching 8 times the levels in human plasma, and that these elevated levels could not be attributed to excessive thrombin generation. Unlike human FVIII:C, camel FVIII:C is remarkably heat stable. Taken together, these unique features of camel FVIII could be part of the physiological adaptation of hemostasis of the Arabian camel in order to survive in the hot desert environment. PMID:24082408

Variation in baseline factor VIII concentration in a retrospective cohort of mild/moderate hemophilia A patients carrying identical F8 mutations.

PubMed

Loomans, J I; van Velzen, A S; Eckhardt, C L; Peters, M; Mäkipernaa, A; Holmstrom, M; Brons, P P; Dors, N; Haya, S; Voorberg, J; van der Bom, J G; Fijnvandraat, K

2017-02-01

Essentials Factor VIII levels vary in mild and moderate hemophilia A (MHA) patients with the same mutation. We aimed to estimate the variation and determinants of factor VIII levels among MHA patients. Age and genotype explain 59% of the observed inter-individual variation in factor VIII levels. Intra-individual variation accounted for 45% of the variation in the three largest mutation groups. Background The bleeding phenotype in patients with mild/moderate hemophilia A (MHA) is inversely associated with the residual plasma concentration of factor VIII (FVIII:C). Within a group of patients with the same F8 missense mutation, baseline FVIII:C may vary, because, in healthy individuals, von Willebrand factor (VWF) levels, ABO blood group and age are also known to influence baseline FVIII:C. Our understanding of the pathophysiologic process of the causative genetic event leading to reduced baseline FVIII:C in MHA patients is still limited. Objectives To estimate the variation and determinants of baseline FVIII:C among MHA patients with the same F8 missense mutation. Methods Three hundred and forty-six patients carrying mutations that were present in at least 10 patients in the cohort were selected from the INSIGHT and the RISE studies, which are cohort studies including data of 3534 MHA patients from Europe, Canada, and Australia. Baseline FVIII:C was measured with a one-stage clotting assay. We used Levene's test, univariate and multivariate linear regression, and mixed-model analyses. Results For 59% of patients, the observed variation in baseline FVIII:C was explained by age and genotype. Compared to FVIII:C in patients with Arg612Cys, FVIII:C was significantly different in patients with eight other F8 missense mutations. Intra-individual variation explained 45% of the observed variance in baseline FVIII:C among patients with the same mutation. Conclusion Our results indicate that baseline FVIII:C levels are not exclusively determined by F8 genotype in MHA patients

The new albumin-free recombinant factor VIII concentrates for treatment of hemophilia: do they represent an actual incremental improvement?

PubMed

Josephson, Cassandra D; Abshire, Thomas

2004-07-01

The goal of eliminating the low levels of infectious disease risk from hemophilia treatment has resulted in the development of multiple generations of recombinant factor VIII (rFVIII) products. The ideal product should be devoid of human and animal proteins, which may transmit infectious agents. These products should also maintain molecular integrity, hemostatic efficacy, similar immunogenicity, and acceptable side effect profiles as compared to plasma-derived factor VIII. Currently available first-, second-, and third-generation rFVIII products include Recombinate; Kogenate FS/Helixate FS and ReFacto; and Advate, respectively. During the evolution of rFVIII products, either full-length or B-domain-deleted factor VIII were transfected into immortalized cell lines. The B-domain-deleted product, ReFacto, has resulted in an additional method to monitor factor VIII levels. The third-generation products offer the theoretical advantage of being produced without human and/or animal proteins. Upon initial introduction into the marketplace, the newer products have a higher cost. However, when analyzing historical trends, the prices of these products are almost equivalent to first-generation products within 3 years of licensure. Thus, the initial cost of the product may be a minimal issue in the medical decision process when selecting rFVIII replacement therapy.

Establishment of the 2nd Korean national biological reference standard for blood coagulation factor VIII:C concentrate.

PubMed

Lee, Naery; Seo, Ji Suk; Kim, Jae Ok; Ban, Sang Ja

2017-05-01

Since the 1st Korean national biological reference standard for factor (F)VIII concentrate, established in 2001, has shown declining potency, we conducted this study to replace this standard with a 2nd Korean national biological reference standard for blood coagulation FVIII concentrate. The candidate materials for the 2nd standard were prepared in 8000 vials with 10 IU/ml of target potency, according to the approved manufacturing process of blood coagulation Factor VIII:C Monoclonal Antibody-purified, Freeze-dried Human Blood Coagulation Factor VIII:C. Potency was evaluated by one-stage clotting and chromogenic methods and the stability was confirmed to meet the specifications during a period of 73 months. Since the potencies obtained by the two methods differed significantly (P < 0.015), the values were determined separately according to the geometric means (8.9 and 7.4 IU/vial, respectively). The geometric coefficients of interlaboratory variability were 3.4% and 7.6% by the one-stage clotting and chromogenic assays, respectively. Copyright © 2017 International Alliance for Biological Standardization. Published by Elsevier Ltd. All rights reserved.

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

PubMed Central

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

2012-01-01

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

von Willebrand factor and factor VIII are independently required to form stable occlusive thrombi in injured veins

PubMed Central

Chauhan, Anil K.; Kisucka, Janka; Lamb, Colin B.; Bergmeier, Wolfgang

2007-01-01

von Willebrand factor (VWF) protects factor VIII (FVIII) from proteolysis and mediates the initial contact of platelets with the injured vessel wall, thus playing an important role in hemostasis and thrombosis. VWF is crucial for the formation of occlusive thrombi at arterial shear rates. However, with only a few conflicting studies published, the role of VWF in venous thrombosis is still unclear. Using gene-targeted mice, we show that in ferric chloride–injured veins platelet adhesion to subendothelium is decreased and thrombus growth is impaired in VWF−/− mice when compared with wild type (WT). We also observed increased embolization in the VWF−/− mice, which was due to lower FVIII levels in these mice as recombinant factor VIII (r-FVIII) restored thrombus stability. Despite normalization of blood clotting time and thrombus stability after r-FVIII infusion, the VWF−/− venules did not occlude. Transgenic platelets lacking the VWF receptor GPIbα extracellular domain showed decreased adhesion to injured veins. But, after a delay, all the injured venules occluded in these transgenic mice. Thus, VWF likely uses other adhesion receptors besides GPIbα in thrombus growth under venous shear conditions. Our studies document crucial roles for VWF and FVIII in experimental thrombosis under venous flow conditions in vivo. PMID:17119108

Possible Pasts: Historiography and Legitimation in "Henry VIII."

ERIC Educational Resources Information Center

Kamps, Ivo

1996-01-01

Aims to rehabilitate the reputation of Shakespeare's "Henry VIII" and emphasizes its potential usefulness in the classroom by reconsidering it in the context of Renaissance history writing. Shows how "Henry VIII" can be taught as a commentary on or seen as a continuation of incipient themes in "The Tempest" and…

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

PubMed Central

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

2017-01-01

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

Safety and efficacy of BAY 94-9027, a prolonged-half-life factor VIII.

PubMed

Reding, M T; Ng, H J; Poulsen, L H; Eyster, M E; Pabinger, I; Shin, H-J; Walsch, R; Lederman, M; Wang, M; Hardtke, M; Michaels, L A

2017-03-01

Essentials Recombinant factor VIII BAY 94-9027 conjugates in a site-specific manner with polyethylene glycol. BAY 94-9027 was given to patients with severe hemophilia A as prophylaxis and to treat bleeds. BAY 94-9027 prevented bleeds at dose intervals up to every 7 days and effectively treated bleeds. BAY 94-9027 treatment was mainly well tolerated and no patient developed factor VIII inhibitors. Click to hear Dr Tiede's perspective on half-life extended factor VIII for the treatment of hemophilia A SUMMARY: Background BAY 94-9027 is a B-domain-deleted prolonged-half-life recombinant factor VIII (FVIII) that conjugates in a site-specific manner with polyethylene glycol. Objective Assess efficacy and safety of BAY 94-9027 for prophylaxis and treatment of bleeds in patients with severe hemophilia A. Patients/methods In this multinational, phase 2/3, partially randomized, open-label trial, men aged 12-65 years with FVIII < 1% and ≥ 150 exposure days to FVIII received BAY 94-9027 for 36 weeks on demand or prophylactically at intervals determined following a 10-week run-in period on 25 IU kg -1 body weight two times per week. Patients with > 1 bleed during the run-in subsequently received 30-40 IU kg -1 two times per week; patients with ≤ 1 bleed were eligible for randomization to every-5-days (45-60 IU kg -1 ) or every-7-days (60 IU kg -1 ) prophylaxis (1 : 1) for 26 additional weeks until randomization arms were filled. Patients who were eligible but not randomized continued twice-weekly prophylaxis. The primary efficacy outcome was annualized bleeding rate (ABR). Results The intent-to-treat population included 132 patients (prophylaxis, n = 112; on demand, n = 20). Median ABR (quartile [Q1; Q3]) for patients treated two times per week who were not eligible for randomization (n = 13) improved after dose increase (17.4 [14.3; 26.0] to 4.1 [2.0; 10.6]). Median ABR for patients randomized to every-5-days treatment (n = 43) was 1.9 (0; 4.2), similar to patients

Evaluation of B&W UO2/ThO2 VIII experimental core: criticality and thermal disadvantage factor analysis

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

Carlo Parisi; Emanuele Negrenti

2017-02-01

In the framework of the OECD/NEA International Reactor Physics Experiment (IRPHE) Project, an evaluation of core VIII of the Babcock & Wilcox (B&W) Spectral Shift Control Reactor (SSCR) critical experiment program was performed. The SSCR concept, moderated and cooled by a variable mixture of heavy and light water, envisaged changing of the thermal neutron spectrum during the operation to encourage breeding and to sustain the core criticality. Core VIII contained 2188 fuel rods with 93% enriched UO2-ThO2 fuel in a moderator mixture of heavy and light water. The criticality experiment and measurements of the thermal disadvantage factor were evaluated.

Characterization of factor VIII pharmaceutical preparations by means of MudPIT proteomic approach.

PubMed

Basilico, Fabrizio; Nardini, Ilaria; Mori, Filippo; Brambilla, Elena; Benazzi, Louise; De Palma, Antonella; Rosti, Enrico; Farina, Claudio; Mauri, PierLuigi

2010-09-21

For a good clinical outcome of Haemophilia A substitutive therapy a detailed characterization of factor VIII (FVIII) concentrates is required, in order to disclose the eventual relations between differently composed concentrates and their biological effects. This preliminary work could be a first step towards a deep structural characterization of FVIII concentrates, using the fast and simply manageable MudPIT technology, which enables the identification and characterization of protein mixtures taking advantage of both the high separation capacity of two-dimensional chromatography and the powerful peptide characterization ability of tandem mass spectrometry. The aim of this study was to evaluate the suitability of for the characterization of FVIII molecule in complex mixtures such its commercial concentrates, both plasma-derived and recombinant, and for the determination of the protein composition of different FVIII preparations. By means of Multidimensional Protein Identification Technology (MudPIT) it was possible to assess the presence of factor VIII in its preparations and to identify most of the contaminant proteins without gel separation. In particular, 125 and 42 proteins were identified in plasma-derived and recombinant concentrates, respectively. Concerning investigation of FVIII, 24 different peptides were identified in plasma-derived corresponding to 7, 29, 27, 19 and 67 of percentage coverage for A1, A2, A3, C1 and C2 domains, respectively. About its multimeric carrier von Willebrand factor (VWF), we have sequenced 42% of domain interacting with A3 and C2 domains of FVIII. Finally, it has been observed that normalized parameters, such as total peptide hits obtained by SEQUEST may be used for evaluation of the relative abundance of FVIII in different preparations. Copyright 2010 Elsevier B.V. All rights reserved.

[Case of cerebral venous thrombosis due to graves' disease with increased factor VIII activity].

PubMed

Kasuga, Kensaku; Naruse, Satoshi; Umeda, Maiko; Tanaka, Midori; Fujita, Nobuya

2006-04-01

A 39 year-old man was admitted to our hospital because of severe headache with fever continuing over two weeks. Three days after admission he developed aphasia and right hemiparesis, when his CT revealed subarachnoid hemorrhage at the left sylvian fissure. He was diagnosed as suffering from cerebral venous thrombosis because empty delta sign was positive on the enhanced brain CT. Suprasagittal sinus and bilateral transverse sinuses were not detected on the cerebral angiography. He was also diagnosed as having Graves' disease for the first time on the basis of free T3 13.56 pg/ml, free T4 4.65 ng/dl, TSH < 0.01 IU/ml, anti-TSH receptor antibody 4.3 IU/l, and thyroid stimulating antibody 224%. On the examination, homocystine and activities of antithrombin III, protein C, and protein S were normal. Antinculear, anti-DNA, anti-Sm, anticardiolipin beta2GP-I antibodies, and PR3ANCA were negative. Factor VIII activity, however, markedly increased over 300%, which has been known to increase in the cases of hyperthyroidism. He recovered well after the treatment with thiamazole in addition to warfarin followed by intravenous heparin. There are only six cases of cerebral venous thrombosis due to hyperthyroidism with increased factor VIII level. All of those cases were female, and 5 of them were taking oral contraceptives. This is a first Japanese male case.

Cerebral venous thrombosis associated with thyrotoxicosis, the use of desmopressin and elevated factor VIII/von Willebrand factor.

PubMed

Waheed, Waqar; Aljerdi, Salman; Decker, Barbara; Cushman, Mary; Hamill, Robert W

2016-08-08

Cerebral venous thrombosis (CVT) is an uncommon disorder associated with diverse processes. We report a patient who, while receiving desmopressin and contraceptive pills (OCP), developed straight sinus thrombosis. Clinical assessment and laboratory investigations revealed untreated hyperthyroidism and a hypercoagulable state, characterised by high levels of von Willebrand factor, factor VIII coagulant activity and IgM cardiolipin antibody. The clinical picture improved with anticoagulation, treatment of hyperthyroidism and discontinuation of OCP and desmopressin. To the best of our knowledge, the association between the use of oral desmopressin and CVT has not been described. The multiple risk factors present in our case were probably additive in increasing the risk of CVT. Although this case represents a rare occurrence, practitioners should be alerted to the possible associations of desmopressin, oral contraceptives and Graves' disease with venous thrombosis. 2016 BMJ Publishing Group Ltd.

Recombinant to modified factor VIII and factor IX - chromogenic and one-stage assays issues.

PubMed

Kitchen, S; Kershaw, G; Tiefenbacher, S

2016-07-01

The recent development of modified recombinant factor VIII (FVIII) and factor IX (FIX) therapeutic products with extended half-lives will create challenges for the haemostasis laboratory in obtaining recovery estimates of these products in clinical samples using existing assays. The new long-acting therapeutic concentrates contain molecular modifications of Fc fusion, site-specific of polyethylene glycol or albumin fusion. The optimum methods for monitoring each new product will need to be assessed individually and laboratories should select an assay which gives similar results to the assay used to assign potency to the product in question. For some extended half-life FVIII and FIX products some one stage assays are entirely unsuitable for monitoring purposes. For most products and assay reagents studied so far, and reviewed in this manuscript, chromogenic FVIII or FIX assays can be safely used with conventional plasma standards. If one stage assays are used then they should be performed using carefully selected reagents/methods which have been shown to recover activity close to the labelled potency for the specific product being monitored. © 2016 John Wiley & Sons Ltd.

Low-dose factor VIII infusion in Chinese adult haemophilia A patients: pharmacokinetics evidence that daily infusion results in higher trough level than with every-other-day infusion with similar factor VIII consumption.

PubMed

Hua, B; Lee, A; Fan, L; Li, K; Zhang, Y; Poon, M-C; Zhao, Y

2017-05-01

Pharmacokinetics (PK) modelling suggests improvement of trough levels are achieved by using more frequent infusion strategy. However, no clinical study data exists to confirm or quantify improvement in trough level, particularly for low-dose prophylaxis in patients with haemophilia A. To provide evidence that low dose daily (ED) prophylaxis can increase trough levels without increasing FVIII consumption compared to every-other-day (EOD) infusion. A cross-over study on 5 IU kg -1 FVIII daily vs. 10 IU kg -1 EOD infusions, each for 14 days was conducted at the PUMCH-HTC. On the ED schedule, trough (immediate prior to infusion), and peak FVIII:C levels (30 min after infusion) were measured on days 1-5; and trough levels alone on days 7, 9, 11 and 13. For the EOD schedule, troughs, peaks and 4-h postinfusion were measured on day 1; troughs and peaks on days 3, 5, and 7; troughs alone on days 9, 11 and 13 and 24-h postinfusion on days 2, 4 and 6. FVIII inhibitors were assessed on days 0 and 14 during both infusion schedules. Six patients were enrolled. PK evidence showed that daily prophylaxis achieved higher (~2 times) steady-state FVIII trough levels compared to EOD with the same total factor consumption. The daily prophylaxis had good acceptability among patients and reduced chronic pain in the joints in some patients. Our PK study shows low-dose factor VIII daily infusion results in higher trough level than with EOD infusion with similar factor VIII consumption in Chinese adult haemophilia A patients. © 2017 John Wiley & Sons Ltd.

Factor VIII organisation on nanodiscs with different lipid composition.

PubMed

Grushin, Kirill; Miller, Jaimy; Dalm, Daniela; Stoilova-McPhie, Svetla

2015-04-01

Nanodiscs (ND) are lipid bilayer membrane patches held by amphiphilic scaffolding proteins (MSP) of ~10 nm in diameter. Nanodiscs have been developed as lipid nanoplatforms for structural and functional studies of membrane and membrane associated proteins. Their size and monodispersity have rendered them unique for electron microscopy (EM) and single particle analysis studies of proteins and complexes either spanning or associated to the ND membrane. Binding of blood coagulation factors and complexes, such as the Factor VIII (FVIII) and the Factor VIIIa - Factor IXa (intrinsic tenase) complex to the negatively charged activated platelet membrane is required for normal haemostasis. In this study we present our work on optimising ND, specifically designed to bind FVIII at close to physiological conditions. The binding of FVIII to the negatively charged ND rich in phosphatidylserine (PS) was followed by electron microscopy at three different PS compositions and two different membrane scaffolding protein (MSP1D1) to lipid ratios. Our results show that the ND with highest PS content (80 %) and lowest MSP1D1 to lipid ratio (1:47) are the most suitable for structure determination of the membrane-bound FVIII by single particle EM. Our preliminary FVIII 3D reconstruction as bound to PS containing ND demonstrates the suitability of the optimised ND for structural studies by EM. Further assembly of the activated FVIII form (FVIIIa) and the whole FVIIIa-FIXa complex on ND, followed by EM and single particle reconstruction will help to identify the protein-protein and protein-membrane interfaces critical for the intrinsic tenase complex assembly and function.

Manufacturing process used to produce long-acting recombinant factor VIII Fc fusion protein.

PubMed

McCue, Justin; Kshirsagar, Rashmi; Selvitelli, Keith; Lu, Qi; Zhang, Mingxuan; Mei, Baisong; Peters, Robert; Pierce, Glenn F; Dumont, Jennifer; Raso, Stephen; Reichert, Heidi

2015-07-01

Recombinant factor VIII Fc fusion protein (rFVIIIFc) is a long-acting coagulation factor approved for the treatment of hemophilia A. Here, the rFVIIIFc manufacturing process and results of studies evaluating product quality and the capacity of the process to remove potential impurities and viruses are described. This manufacturing process utilized readily transferable and scalable unit operations and employed multi-step purification and viral clearance processing, including a novel affinity chromatography adsorbent and a 15 nm pore size virus removal nanofilter. A cell line derived from human embryonic kidney (HEK) 293H cells was used to produce rFVIIIFc. Validation studies evaluated identity, purity, activity, and safety. Process-related impurity clearance and viral clearance spiking studies demonstrate robust and reproducible removal of impurities and viruses, with total viral clearance >8-15 log10 for four model viruses (xenotropic murine leukemia virus, mice minute virus, reovirus type 3, and suid herpes virus 1). Terminal galactose-α-1,3-galactose and N-glycolylneuraminic acid, two non-human glycans, were undetectable in rFVIIIFc. Biochemical and in vitro biological analyses confirmed the purity, activity, and consistency of rFVIIIFc. In conclusion, this manufacturing process produces a highly pure product free of viruses, impurities, and non-human glycan structures, with scale capabilities to ensure a consistent and adequate supply of rFVIIIFc. Copyright © 2015 Biogen. Published by Elsevier Ltd.. All rights reserved.

Cyclophosphamide Treatment for Acquired Factor VIII Inhibitor in a Patient with AIDS-Associated Progressive Multifocal Leukoencephalopathy.

PubMed

Malhotra, Uma; Aboulafia, David M

2016-01-01

Acquired hemophilia A (AHA) is a severe bleeding disorder with high mortality rates resulting from the development of autoantibodies to factor VIII (FVIII). Patients typically present with hemorrhages in the skin, subcutaneous tissues, and muscles, which are frequently severe. They can also develop life-threatening retroperitoneal hematomas and compartment syndromes. We describe the case of a man with a long history of AIDS complicated by progressive multifocal leukoencephalopathy (PML), who developed AHA while on stable antiretroviral therapy and then presented with new onset bleeding and hypotension. We treated our patient with incrementally increasing doses of cyclophosphamide resulting in resolution of coagulopathy. We review the medical literature for additional cases of HIV-associated AHA and discuss the challenges in the care of our patient, since the immunosuppression needed to eradicate the FVIII inhibitor had the potential to cause recrudescence of his PML. © The Author(s) 2015.

Correction of murine hemophilia A following nonmyeloablative transplantation of hematopoietic stem cells engineered to encode an enhanced human factor VIII variant using a safety-augmented retroviral vector

PubMed Central

Ramezani, Ali

2009-01-01

Insertional mutagenesis by retroviral vectors is a major impediment to the clinical application of hematopoietic stem cell gene transfer for the treatment of hematologic disorders. We recently developed an insulated self-inactivating gammaretroviral vector, RMSinOFB, which uses a novel enhancer-blocking element that significantly decreases genotoxicity of retroviral integration. In this study, we used the RMSinOFB vector to evaluate the efficacy of a newly bioengineered factor VIII (fVIII) variant (efVIII)—containing a combination of A1 domain point mutations (L303E/F309S) and an extended partial B domain for improved secretion plus A2 domain mutations (R484A/R489A/P492A) for reduced immunogenicity—toward successful treatment of murine hemophilia A. In cell lines, efVIII was secreted at up to 6-fold higher levels than an L303E/F309S A1 domain–only fVIII variant (sfVIIIΔB). Most important, when compared with a conventional gammaretroviral vector expressing sfVIIIΔB, lower doses of RMSin-efVIII-OFB–transduced hematopoietic stem cells were needed to generate comparable curative fVIII levels in hemophilia A BALB/c mice after reduced-intensity total body irradiation or nonmyeloablative chemotherapy conditioning regimens. These data suggest that the safety-augmented RMSin-efVIII-OFB platform represents an encouraging step in the development of a clinically appropriate gene addition therapy for hemophilia A. PMID:19470695

Measurements of Sheath Currents and Equilibrium Potential on the Explorer VIII Satellite (1960 xi)

NASA Technical Reports Server (NTRS)

Bourdeau, R. E.; Donley, J. L.; Serbu, G. P.; Whipple, E. C., Jr.

1961-01-01

Experimental data were obtained from the Explorer VIII satellite on five parameters pertinent to the problem of the interaction of space vehicles with an ionized atmosphere. The five parameters are: photoemission current due to electrons emitted from the satellite surfaces as a result of solar radiation; electron and positive ion currents due to the diffusion of charged particles from the medium to the spacecraft; the vehicle potential relative to the medium, and the ambient electron temperature. Included in the experimental data is the aspect dependence of the photoemission and diffusion currents. On the basis of the observations, certain characteristics of the satellite's plasma sheath are postulated.

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

USDA-ARS?s Scientific Manuscript database

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

12 CFR 611.1137 - Title VIII service corporations.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 12 Banks and Banking 7 2014-01-01 2014-01-01 false Title VIII service corporations. 611.1137... Corporations § 611.1137 Title VIII service corporations. (a) What is a title VIII service corporation? A title VIII service corporation is a service corporation organized for the purpose of exercising the...

12 CFR 611.1137 - Title VIII service corporations.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 12 Banks and Banking 6 2011-01-01 2011-01-01 false Title VIII service corporations. 611.1137... Organizations § 611.1137 Title VIII service corporations. (a) What is a title VIII service corporation? A title VIII service corporation is a service corporation organized for the purpose of exercising the...

12 CFR 611.1137 - Title VIII service corporations.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 12 Banks and Banking 7 2012-01-01 2012-01-01 false Title VIII service corporations. 611.1137... Organizations § 611.1137 Title VIII service corporations. (a) What is a title VIII service corporation? A title VIII service corporation is a service corporation organized for the purpose of exercising the...

12 CFR 611.1137 - Title VIII service corporations.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 12 Banks and Banking 7 2013-01-01 2013-01-01 false Title VIII service corporations. 611.1137... Organizations § 611.1137 Title VIII service corporations. (a) What is a title VIII service corporation? A title VIII service corporation is a service corporation organized for the purpose of exercising the...

A new method to determine wound age in early vital skin injuries: a probability scoring system using expression levels of Fibronectin, CD62p and Factor VIII in wound hemorrhage.

PubMed

van de Goot, Franklin R W; Korkmaz, H Ibrahim; Fronczek, Judith; Witte, Birgit I; Visser, Rob; Ulrich, Magda M W; Begieneman, Mark P V; Rozendaal, Lawrence; Krijnen, Paul A J; Niessen, Hans W M

2014-11-01

In forensic autopsies it is important to determine the age of early vital skin wounds as accurate as possible. In addition to inflammation, coagulation is also induced in vital wounds. Analysis of blood coagulation markers in wound hemorrhage could therefore be an important additional discriminating factor in wound age determination. The aim of this study was to develop a wound age probability scoring system, based on the immunohistochemical expression levels of Fibronectin, CD62p and Factor VIII in wound hemorrhage. Tissue samples of (A) non injured control skin (n=383), and samples of mechanically induced skin injuries of known wound age, (B) injuries inflicted shortly before death (up to a few minutes old) (n=382), and (C) injuries inflicted 15-30 min before death (n=42) were obtained at autopsy in order to validate wound age estimation. Tissue slides were stained for Fibronectin, CD62p and Factor VIII and were subsequently scored for staining intensity (IHC score) in wound hemorrhage (1=minor, 2=moderate, 3=strong positive). Finally, probability scores of these markers were calculated. In at most 14% of the non-injured control samples, hemorrhage was found, with mean±standard deviation IHC scores of 0.1±0.4, 0.2±0.4 and 0.2±0.5 for Fibronectin, CD62p, and Factor VIII, respectively. Expression of these markers significantly increased to mean IHC scores 1.4±0.8 (Fibronectin), 1.2±0.6 (CD62p), and 1.6±0.8 (Factor VIII) in wounds inflicted shortly before death (few minutes old) and to 2.6±0.5 (Fibronectin), 2.5±0.6 (CD62p), and 2.8±0.4 (Factor VIII) in 15-30 min old wounds. The probabilities that a wound was non vital in case of an IH score 0 were 87%, 88% and 90% for Fibronectin, CD62p, and Factor VIII, respectively. In case of an IHC score 1 or 2, the probabilities that a wound was a few minutes old were 82/90%, 82/83% and 72/93%. Finally, in case of an IHC score 3, the probabilities that a wound was 15-30 min old were 65%, 76% and 55%. Based on the

Agnostic stacking of intergalactic doublet absorption: measuring the Ne VIII population

NASA Astrophysics Data System (ADS)

Frank, Stephan; Pieri, Matthew M.; Mathur, Smita; Danforth, Charles W.; Shull, J. Michael

2018-05-01

We present a blind search for doublet intergalactic metal absorption with a method dubbed `agnostic stacking'. Using a forward-modelling framework, we combine this with direct detections in the literature to measure the overall metal population. We apply this novel approach to the search for Ne VIII absorption in a set of 26 high-quality COS spectra. We probe to an unprecedented low limit of log N>12.3 at 0.47≤z ≤1.34 over a path-length Δz = 7.36. This method selects apparent absorption without requiring knowledge of its source. Stacking this mixed population dilutes doublet features in composite spectra in a deterministic manner, allowing us to measure the proportion corresponding to Ne VIII absorption. We stack potential Ne VIII absorption in two regimes: absorption too weak to be significant in direct line studies (12.3 < log N < 13.7), and strong absorbers (log N > 13.7). We do not detect Ne VIII absorption in either regime. Combining our measurements with direct detections, we find that the Ne VIII population is reproduced with a power-law column density distribution function with slope β = -1.86 ^{+0.18 }_{ -0.26} and normalization log f_{13.7} = -13.99 ^{+0.20 }_{ -0.23}, leading to an incidence rate of strong Ne VIII absorbers dn/dz =1.38 ^{+0.97 }_{ -0.82}. We infer a cosmic mass density for Ne VIII gas with 12.3 < log N < 15.0 of Ω _{{{Ne {VIII}}}} = 2.2 ^{+1.6 }_{ _-1.2} × 10^{-8}, a value significantly lower that than predicted by recent simulations. We translate this density into an estimate of the baryon density Ωb ≈ 1.8 × 10-3, constituting 4 per cent of the total baryonic mass.

Human parvovirus B19 infection in hemophiliacs first infused with two high-purity, virally attenuated factor VIII concentrates.

PubMed

Azzi, A; Ciappi, S; Zakvrzewska, K; Morfini, M; Mariani, G; Mannucci, P M

1992-03-01

Human parvovirus B19 can be transmitted by coagulation factor concentrates and is highly resistant to virucidal methods. To evaluate whether the additional removal of virus by chromatographic methods during the manufacture of high-purity concentrates reduces the risk of B19 transmission, we have prospectively evaluated the rate of anti-B19 seroconversion in two groups of susceptible (anti-B19 negative) hemophiliacs infused with high-purity, heated (pasteurized) or solvent-detergent-treated factor VIII concentrates. Both products infected a relatively high proportion of patients (nine of 20).

[Detection of factor VIII intron 1 inversion in severe haemophilia A].

PubMed

Liang, Yan; Yan, Zhen-yu; Yan, Mei; Hua, Bao-lai; Xiao, Bai; Zhao, Yong-qiang; Liu, Jing-zhong

2009-06-01

Screening the intron 1 inversion of factor VIII (FVIII) in the population of severe haemophilia A(HA) in China and performing carrier detection and prenatal diagnosis. Using LD-PCR to detect intron 22 inversions and multiple-PCR within two tubes to intron 1 inversions in severe HA patients. Carrier detection and prenatal diagnosis were performed in affected families. Linkage analysis and DNA sequencing were used to verify these tests. One hundred and eighteen patients were seven diagnosed as intron 22 inversions and 7 were intron 1 inversions out of 247 severe HA patients. The prevalence of the intron 1 inversion in Chinese severe haemophilia A patients was 2.8% (7/247). Six women from family A and 2 from family B were diagnosed as carriers. One fetus from family A was affected fetus. Intron 1 inversion could be detected directly by multiple-PCR within two tubes. This method made the strategy more perfective in carrier and prenatal diagnosis of haemophilia A.

Elevated plasma factor VIII enhances venous thrombus formation in rabbits: contribution of factor XI, von Willebrand factor and tissue factor.

PubMed

Sugita, Chihiro; Yamashita, Atsushi; Matsuura, Yunosuke; Iwakiri, Takashi; Okuyama, Nozomi; Matsuda, Shuntaro; Matsumoto, Tomoko; Inoue, Osamu; Harada, Aya; Kitazawa, Takehisa; Hattori, Kunihiro; Shima, Midori; Asada, Yujiro

2013-07-01

Elevated plasma levels of factor VIII (FVIII) are associated with increased risk of deep venous thrombosis. The aim of this study is to elucidate how elevated FVIII levels affect venous thrombus formation and propagation in vivo. We examined rabbit plasma FVIII activity, plasma thrombin generation, whole blood coagulation, platelet aggregation and venous wall thrombogenicity before and one hour after an intravenous infusion of recombinant human FVIII (rFVIII). Venous thrombus induced by the endothelial denudation of rabbit jugular veins was histologically assessed. Thrombus propagation was evaluated as indocyanine green fluorescence intensity. Argatroban, a thrombin inhibitor, and neutralised antibodies for tissue factor (TF), factor XI (FXI), and von Willebrand factor (VWF) were infused before or after thrombus induction to investigate their effects on venous thrombus formation or propagation. Recombinant FVIII (100 IU/kg) increased rabbit plasma FVIII activity two-fold and significantly enhanced whole blood coagulation and total plasma thrombin generation, but did not affect initial thrombin generation time, platelet aggregation and venous wall thrombogenicity. The rFVIII infusion also increased the size of venous thrombus 1 hour after thrombus induction. Argatroban and the antibodies for TF, FXI or VWF inhibited such enhanced thrombus formation and all except TF suppressed thrombus propagation. In conclusion, elevated plasma FVIII levels enhance venous thrombus formation and propagation. Excess thrombin generation by FXI and VWF-mediated FVIII recruitment appear to contribute to the growth of FVIII-driven venous thrombus.

Staining for factor VIII related antigen and Ulex europaeus agglutinin I (UEA-I) in 230 tumours. An assessment of their specificity for angiosarcoma and Kaposi's sarcoma.

PubMed

Leader, M; Collins, M; Patel, J; Henry, K

1986-11-01

In this study we examined the staining reactivity of commercially available antisera to factor VIII related antigen (F VIII RAg) and Ulex europaeus agglutinin I (UEA-I) on sections from 230 formalin fixed paraffin embedded tumours. These included 196 sarcomas, 20 carcinomas and 14 angiomas. All angiomas showed positive staining for F VIII RAg; all carcinomas showed negative staining; the vasoformative areas of all angiosarcomas stained positively but only four of six angiosarcomas showed positive staining of their solid areas; of seven Kaposi's sarcomas, all showed positive staining of vessels and six showed positive staining of the spindle cell component. In the remaining 181 non-vascular sarcomas there was a false positive result in four tumours (2.2%), three of which had a history of irradiation. Pre-radiotherapy biopsies of these three tumours stained negatively with anti-F VIII RAg. UEA-I was demonstrated in all the angiomas studied, in all angiosarcomas (including the solid components) and in well-formed vessels of all Kaposi's sarcomas, but only in the spindle cell component of 3/6. However, there was an unacceptably high rate of false positive staining amongst the carcinomas and non-vascular sarcomas. In conclusion, F VIII RAg is a specific but not a sensitive marker of angiosarcomas; UEA-I is a sensitive but not a specific marker of angiosarcomas.

Storage and regulated secretion of factor VIII in blood outgrowth endothelial cells

PubMed Central

van den Biggelaar, Maartje; Bouwens, Eveline A.M.; Kootstra, Neeltje A.; Hebbel, Robert P.; Voorberg, Jan; Mertens, Koen

2009-01-01

Background Gene therapy provides an attractive alternative for protein replacement therapy in hemophilia A patients. Recent studies have shown the potential benefit of directing factor (F)VIII gene delivery to cells that also express its natural carrier protein von Willebrand factor (VWF). In this study, we explored the feasibility of blood outgrowth endothelial cells as a cellular FVIII delivery device with particular reference to long-term production levels, intracellular storage in Weibel-Palade bodies and agonist-induced regulated secretion. Design and Methods Human blood outgrowth endothelial cells were isolated from peripheral blood collected from healthy donors, transduced at passage 5 using a lentiviral vector encoding human B-domain deleted FVIII-GFP and characterized by flow cytometry and confocal microscopy. Results Blood outgrowth endothelial cells displayed typical endothelial morphology and expressed the endothelial-specific marker VWF. Following transduction with a lentivirus encoding FVIII-GFP, 80% of transduced blood outgrowth endothelial cells expressed FVIII-GFP. Levels of FVIII-GFP positive cells declined slowly upon prolonged culturing. Transduced blood outgrowth endothelial cells expressed 1.6±1.0 pmol/1×106 cells/24h FVIII. Morphological analysis demonstrated that FVIII-GFP was stored in Weibel-Palade bodies together with VWF and P-selectin. FVIII levels were only slightly increased following agonist-induced stimulation, whereas a 6- to 8-fold increase of VWF levels was observed. Subcellular fractionation revealed that 15–22% of FVIII antigen was present within the dense fraction containing Weibel-Palade bodies. Conclusions We conclude that blood outgrowth endothelial cells, by virtue of their ability to store a significant portion of synthesized FVIII-GFP in Weibel-Palade bodies, provide an attractive cellular on-demand delivery device for gene therapy of hemophilia A. PMID:19336741

Recombinant factor VIII Fc fusion protein for immune tolerance induction in patients with severe haemophilia A with inhibitors-A retrospective analysis.

PubMed

Carcao, M; Shapiro, A; Staber, J M; Hwang, N; Druzgal, C; Lieuw, K; Belletrutti, M; Thornburg, C D; Ahuja, S P; Morales-Arias, J; Dumont, J; Miyasato, G; Tsao, E; Jain, N; Pipe, S W

2018-03-01

Immune tolerance induction (ITI) is the gold standard for eradication of factor VIII inhibitors in severe haemophilia A; however, it usually requires treatment for extended periods with associated high burden on patients and healthcare resources. Review outcomes of ITI with recombinant factor VIII Fc fusion protein (rFVIIIFc) in patients with severe haemophilia A and high-titre inhibitors. Multicentre retrospective chart review of severe haemophilia A patients treated with rFVIIIFc for ITI. Of 19 patients, 7 were first-time ITI and 12 were rescue ITI. Of 7 first-time patients, 6 had at least 1 high-risk feature for ITI failure. Four of 7 first-time patients were tolerized in a median of 7.8 months. The remaining 3 patients continue on rFVIIIFc ITI. Of 12 rescue patients, 7 initially achieved a negative Bethesda titre (≤0.6) in a median of 3.3 months, 1 had a decrease in Bethesda titre and continues on rFVIIIFc ITI and 4 have not demonstrated a decrease in Bethesda titre. Of these 4, 3 continue on rFVIIIFc ITI and 1 switched to bypass therapy alone. Two initially responsive patients transitioned to other factors due to recurrence. Overall, 16 of 19 patients remain on rFVIIIFc (prophylaxis or ITI). For those still undergoing ITI, longer follow-up is needed to determine final outcomes. No adverse events reported. Recombinant factor VIII Fc fusion protein demonstrated rapid time to tolerization in high-risk first-time ITI patients. For rescue ITI, rFVIIIFc showed therapeutic benefit in some patients who previously failed ITI with other products. These findings highlight the need to further evaluate the use of rFVIIIFc for ITI. © 2018 The Authors. Haemophilia Published by John Wiley & Sons Ltd.

Thermodynamic analysis of the interaction of factor VIII with von Willebrand factor.

PubMed

Dimitrov, Jordan D; Christophe, Olivier D; Kang, Jonghoon; Repessé, Yohann; Delignat, Sandrine; Kaveri, Srinivas V; Lacroix-Desmazes, Sébastien

2012-05-22

Factor VIII (FVIII) is a glycoprotein that plays an important role in the intrinsic pathway of coagulation. In circulation, FVIII is protected upon binding to von Willebrand factor (VWF), a chaperone molecule that regulates its half-life, distribution, and activity. Despite the biological significance of this interaction, its molecular mechanisms are not fully characterized. We determined the equilibrium and activation thermodynamics of the interaction between FVIII and VWF. The equilibrium affinity determined by surface plasmon resonance was temperature-dependent with a value of 0.8 nM at 35 °C. The FVIII-VWF interaction was characterized by very fast association (8.56 × 10(6) M(-1) s(-1)) and fast dissociation (6.89 × 10(-3) s(-1)) rates. Both the equilibrium association and association rate constants, but not the dissociation rate constant, were dependent on temperature. Binding of FVIII to VWF was characterized by favorable changes in the equilibrium and activation entropy (TΔS° = 89.4 kJ/mol, and -TΔS(++) = -8.9 kJ/mol) and unfavorable changes in the equilibrium and activation enthalpy (ΔH° = 39.1 kJ/mol, and ΔH(++) = 44.1 kJ/mol), yielding a negative change in the equilibrium Gibbs energy. Binding of FVIII to VWF in solid-phase assays demonstrated a high sensitivity to acidic pH and a sensitivity to ionic strength. Our data indicate that the interaction between FVIII and VWF is mediated mainly by electrostatic forces, and that it is not accompanied by entropic constraints, suggesting the absence of conformational adaptation but the presence of rigid "pre-optimized" binding surfaces.

12 CFR 611.1137 - Title VIII service corporations.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 12 Banks and Banking 6 2010-01-01 2010-01-01 false Title VIII service corporations. 611.1137 Section 611.1137 Banks and Banking FARM CREDIT ADMINISTRATION FARM CREDIT SYSTEM ORGANIZATION Service Organizations § 611.1137 Title VIII service corporations. (a) What is a title VIII service corporation? A title...

Von Willebrand factor-containing factor VIII concentrates and inhibitors in haemophilia A. A critical literature review.

PubMed

Franchini, Massimo; Lippi, Giuseppe

2010-11-01

The development of inhibitors that neutralise the function of factor VIII (FVIII) is currently not only the most challenging complication associated with the treatment of haemophilia A but it also increases the disease-related morbidity as bleeding episodes do not respond to standard therapy. The main short-term goal of the treatment of inhibitor patients is to control bleeding episodes while the long-term one is to permanently eradicate the inhibitor by immune tolerance induction, particularly in the case of high-titer antibodies. Due to some in vitro studies and clinical observations, some investigators have suggested that FVIII concentrates containing von Willebrand factor (VWF) may be less immunogenic than high-purity or recombinant FVIII products. It has also been suggested that success rates for immune tolerance induction are higher when plasma-derived FVIII products are used. The currently available data from laboratory and clinical studies on the role of VWF in inhibitor development and eradication in haemophilia A is critically analysed in this review. As a result, we have not found definitive evidence supporting a role for product type on inhibitor incidence and inhibitor eradication in haemophilia A patients.

Development, Validation, and Application of a Novel Ligand-Binding Assay to Selectively Measure PEGylated Recombinant Human Coagulation Factor VIII (BAX 855).

PubMed

Weber, Alfred; Engelmaier, Andrea; Hainzelmayer, Sandra; Minibeck, Eva; Anderle, Heinz; Schwarz, Hans Peter; Turecek, Peter L

2015-10-21

BAX 855 is a PEGylated recombinant factor VIII preparation that showed prolonged circulatory half-life in nonclinical and clinical studies. This paper describes the development, validation, and application of a novel ligand-binding assay (LBA) to selectively measure BAX 855 in plasma. The LBA is based on PEG-specific capture of BAX 855, followed by immunological factor VIII (FVIII)-specific detection of the antibody-bound BAX 855. This assay principle enabled sensitive measurement of BAX 855 down to the low nanomolar range without interference from non-PEGylated FVIII as demonstrated by validation data for plasma from animals typically used for nonclinical characterization of FVIII. The selectivity of an in-house-developed anti-PEG and a commercially available preparation, shown by competition studies to primarily target the terminating methoxy group of PEG, also allowed assessment of the intactness of the attached PEG chains. Altogether, this new LBA adds to the group of methods to selectively, accurately, and precisely measure a PEGylated drug in complex biological matrices. The feasibility and convenience of using this method was demonstrated during extensive nonclinical characterization of BAX 855.

Components in Plasma-Derived Factor VIII, But Not in Recombinant Factor VIII Downregulate Anti-Inflammatory Surface Marker CD163 in Human Macrophages through Release of CXCL4 (Platelet Factor 4)

PubMed Central

Bertling, Anne; Brodde, Martin F.; Visser, Mayken; Treffon, Janina; Fennen, Michelle; Fender, Anke C.; Kelsch, Reinhard; Kehrel, Beate E.

2017-01-01

Background Hemarthrosis, or bleeding into the joints, is a hallmark of hemophilia. Heme triggers oxidative stress, inflammation, and destruction of cartilage and bone. The haptoglobin-CD163-heme oxygenase-1 (HO-1) pathway circumvents heme toxicity through enzymatic degradation of heme and transcription of antioxidant genes. Plasma-derived factor concentrates contain many proteins that might impact on cellular pathways in joints, blood, and vessels. Methods Activation of platelets from healthy volunteers was assessed by flow cytometry analysis of fibrinogen binding and CD62P expression. Platelet CXCL4 release was measured by ELISA. Human peripheral blood mononuclear cells were exposed to CXCL4 or platelet supernatants (untreated or pre-stimulated with factor VIII (FVIII) products) during their differentiation to macrophages and analyzed for CD163 expression. Some macrophage cultures were additionally incubated with autologous hemoglobin for 18 h for analysis of HO-1 expression. Results Platelet CXCL4 release was increased by all 8 tested plasma-derived FVIII products but not the 3 recombinant products. Macrophages exposed to supernatant from platelets treated with some plasma-derived FVIII products downregulated CD163 surface expression and failed to upregulate the athero- and joint protective enzyme HO-1 in response to hemoglobin. Conclusion Plasma-derived FVIII products might promote bleeding-induced joint injury via generation of macrophages that are unable to counteract redox stress. PMID:29070980

Components in Plasma-Derived Factor VIII, But Not in Recombinant Factor VIII Downregulate Anti-Inflammatory Surface Marker CD163 in Human Macrophages through Release of CXCL4 (Platelet Factor 4).

PubMed

Bertling, Anne; Brodde, Martin F; Visser, Mayken; Treffon, Janina; Fennen, Michelle; Fender, Anke C; Kelsch, Reinhard; Kehrel, Beate E

2017-09-01

Hemarthrosis, or bleeding into the joints, is a hallmark of hemophilia. Heme triggers oxidative stress, inflammation, and destruction of cartilage and bone. The haptoglobin-CD163-heme oxygenase-1 (HO-1) pathway circumvents heme toxicity through enzymatic degradation of heme and transcription of antioxidant genes. Plasma-derived factor concentrates contain many proteins that might impact on cellular pathways in joints, blood, and vessels. Activation of platelets from healthy volunteers was assessed by flow cytometry analysis of fibrinogen binding and CD62P expression. Platelet CXCL4 release was measured by ELISA. Human peripheral blood mononuclear cells were exposed to CXCL4 or platelet supernatants (untreated or pre-stimulated with factor VIII (FVIII) products) during their differentiation to macrophages and analyzed for CD163 expression. Some macrophage cultures were additionally incubated with autologous hemoglobin for 18 h for analysis of HO-1 expression. Platelet CXCL4 release was increased by all 8 tested plasma-derived FVIII products but not the 3 recombinant products. Macrophages exposed to supernatant from platelets treated with some plasma-derived FVIII products downregulated CD163 surface expression and failed to upregulate the athero- and joint protective enzyme HO-1 in response to hemoglobin. Plasma-derived FVIII products might promote bleeding-induced joint injury via generation of macrophages that are unable to counteract redox stress.

Endothelial cell markers in vascular neoplasms: an immunohistochemical study comparing factor VIII-related antigen, blood group specific antigens, 6-keto-PGF1 alpha, and Ulex europaeus 1 lectin.

PubMed

Little, D; Said, J W; Siegel, R J; Fealy, M; Fishbein, M C

1986-06-01

Markers for endothelial cells including Ulex europaeus 1 lectin, blood group A, B, and H, and the prostaglandin metabolite 6-keto-PGF1 alpha were evaluated in paraffin secretions from formalin-fixed benign and malignant vascular neoplasms using a variety of immunohistochemical techniques, and results compared with staining for factor VIII-related antigen. Staining for Ulex appeared more sensitive than factor VIII-related antigen in identifying poorly differentiated neoplasms including haemangiosarcomas and spindle cell proliferations in Kaposi's sarcoma. Staining for blood group related antigens correlated with blood group in all cases. Ulex europaeus 1 lectin was the only marker for endothelial cells in lymphangiomas.

Factor VIII brand and the incidence of factor VIII inhibitors in previously untreated UK children with severe hemophilia A, 2000-2011

PubMed Central

Palmer, Benedict P.; Chalmers, Elizabeth A.; Hart, Daniel P.; Liesner, Ri; Rangarajan, Savita; Talks, Katherine; Williams, Michael; Hay, Charles R. M.

2014-01-01

The effect of recombinant factor VIII (rFVIII) brand on inhibitor development was investigated in all 407 severe hemophilia A previously untreated patients born in the United Kingdom (UK) between 1 January 2000 and 31 December 2011. Eighty-eight (22%) had been in the RODIN study. Information was extracted from the National Haemophilia Database. Because exposure days (EDs) were not known for some patients, time from first treatment was used as a surrogate for rFVIII exposure. An inhibitor developed in 118 (29%) patients, 60 high and 58 low titer, after a median (interquartile range) of 7.8 (3.3-13.5) months from first exposure and 16 (9-30) EDs. Of 128 patients treated with Kogenate Bayer/Helixate NexGen, 45 (35.2%, 95% confidence interval [CI] 27.4-43.8) developed an inhibitor compared with 42/172 (24.4%, 95% CI 18.6% to 31.4%) with Advate (P = .04). The adjusted hazard ratio (HR) (95% CI) for Kogenate Bayer/Helixate NexGen compared with Advate was 2.14 (1.12-4.10) (P = .02) for high titer and 1.75 (1.11-2.76) (P = .02) for all inhibitors. When excluding UK-RODIN patients, the adjusted HR (95% CI) for high-titer inhibitors was 2.00 (0.93-4.34) (P = .08). ReFacto AF was associated with a higher incidence of all, but not high-titer, inhibitors than Advate. These results will help inform debate around the relative immunogenicity and use of rFVIII brands. PMID:25339360

Inhibitors in haemophilia A: a perspective on clotting factor products as a potential contributing factor.

PubMed

Mathew, P; Dinter, H; Church, N; Humphries, T J; Kulkarni, R

2016-05-01

The occurrence of a neutralizing antibody in previously untreated patients (PUPs) with haemophilia A appears to be the result of an intricate interplay of both genetic and environmental factors. Recently, the type of factor VIII (FVIII) product used in the PUPs population has been implicated as a risk factor for inhibitor development. The aim of this review was to explore in a systematic manner potential hypotheses for the product-related findings in these studies (i.e. differences in the expression system of the cell lines used to produce recombinant FVIII [rFVIII], differences in the administered antigen load or changes in clinical practice over time). Review of the available clinical studies illustrates the high degree of variability for the risk of inhibitor development for the same products across different studies. Differences in cell lines or antigen load were not found to provide a reasonable explanation. The possibility of changes in clinical practice over time and patient selection bias (i.e. the preferential use of one product over another in patients at higher risk for inhibitors) offers a potential explanation and should be carefully considered when evaluating the studies. © 2016 The Authors. Haemophilia Published by John Wiley & Sons Ltd.

The effect of V/III ratio on the morphology and structure of GaAs nanowires by MOCVD

NASA Astrophysics Data System (ADS)

Liu, Yan; Peng, Yan; Guo, Jingwei; La, Dongsheng; Xu, Zhaopeng

2018-05-01

In this paper, GaAs nanowires with different V/III ratios (70, 140, 280 and 560) were vertically grown from bottom to top on GaAs substrates by using metal organic chemical vapor deposition based on gold assisted vapor-liquid-solid mechanism. It is found that the growth rate of nanowires is inversely proportional to their V/III ratio. And the V/III ratio can also change nanowire growth type. For the nanowire with small V/III ratios (≤280), the reactants are most from those atoms merged in the catalyst. But, for the nanowire with V/III ratio 560, the contribution mainly comes from the diffusions of atoms pyrolyzed on the surface of the nanowire and the substrate. A shrunken neck under the catalyst is observed in TEM characterizations. These results will provide a theoretical basis for potential practical applications of nanowire-based devices.

Population pharmacokinetic characterization of BAY 81-8973, a full-length recombinant factor VIII: lessons learned - importance of including samples with factor VIII levels below the quantitation limit.

PubMed

Garmann, D; McLeay, S; Shah, A; Vis, P; Maas Enriquez, M; Ploeger, B A

2017-07-01

The pharmacokinetics (PK), safety and efficacy of BAY 81-8973, a full-length, unmodified, recombinant human factor VIII (FVIII), were evaluated in the LEOPOLD trials. The aim of this study was to develop a population PK model based on pooled data from the LEOPOLD trials and to investigate the importance of including samples with FVIII levels below the limit of quantitation (BLQ) to estimate half-life. The analysis included 1535 PK observations (measured by the chromogenic assay) from 183 male patients with haemophilia A aged 1-61 years from the 3 LEOPOLD trials. The limit of quantitation was 1.5 IU dL -1 for the majority of samples. Population PK models that included or excluded BLQ samples were used for FVIII half-life estimations, and simulations were performed using both estimates to explore the influence on the time below a determined FVIII threshold. In the data set used, approximately 16.5% of samples were BLQ, which is not uncommon for FVIII PK data sets. The structural model to describe the PK of BAY 81-8973 was a two-compartment model similar to that seen for other FVIII products. If BLQ samples were excluded from the model, FVIII half-life estimations were longer compared with a model that included BLQ samples. It is essential to assess the importance of BLQ samples when performing population PK estimates of half-life for any FVIII product. Exclusion of BLQ data from half-life estimations based on population PK models may result in an overestimation of half-life and underestimation of time under a predetermined FVIII threshold, resulting in potential underdosing of patients. © 2017 Bayer AG. Haemophilia Published by John Wiley & Sons Ltd.

NE VIII lambda 774 and time variable associated absorption in the QSO UM 675

NASA Astrophysics Data System (ADS)

Hamann, Fred; Barlow, Thomas A.; Beaver, E. A.; Burbidge, E. M.; Cohen, Ross D.; Junkkarinen, Vesa; Lyons, R.

1995-04-01

We discuss measurements of Ne VIII lambda 774 absorption and the time variability of other lines in the za approximately equal ze absorption system of the ze = 2.15 QSO UM 675 (0150-203). The C IV lambda 1549 and N V 1240 doublets at za = 2.1340 (shifted approximately 1500 km/s from ze strengthened by a factor of approximately 3 between observations by Sargent, Boksenberg and Steidel (1981 November) and our earliest measurements (1990 November and December). We have no information on changes in other za approximately equal ze absorption lines. Continued monitoring since 1990 November shows no clear changes in any of the absorptions between approximately 1100 and 1640 A rest. The short timescale of the variability (less than or approximately equal to 2.9 yr rest) strongly suggests that the clouds are dense, compact, close to the QSO, and photoionized by the QSO continuum. If the line variability is caused by changes in the ionization, the timescale requires densities greater than approximately 4000/cu cm. Photoionization calculations place the absorbing clouds within approximately 200 pc of the continuum source. The full range of line ionizations (from Ne VIII lambda 774 to C III lambda 977) in optically thin gas (no Lyman limit) implies that the absorbing regions span a factor of more than approximately 10 in distance or approximately 100 in density. Across these regions, the total hydrogen (H I + H II) column ranges from a few times 1018/sq cm in the low-ionization gas to approximately 1020/sq cm where the Ne VIII doublet forms. The metallicity is roughly solar or higher, with nitrogen possibly more enhanced by factors of a few. The clouds might contribute significant line emission if they nearly envelop the QSO. The presence of highly ionized Ne VIII lambda 774 absorption near the QSO supports recent studies that link za approximately equal to ze systems with X-ray 'wamr absorbers. We show that the Ne VIII absorbing gas would itself produce measurable warm

32 CFR 2003.8 - Records (Article VIII).

Code of Federal Regulations, 2013 CFR

2013-07-01

... 32 National Defense 6 2013-07-01 2013-07-01 false Records (Article VIII). 2003.8 Section 2003.8 National Defense Other Regulations Relating to National Defense INFORMATION SECURITY OVERSIGHT OFFICE...) BYLAWS, RULES, AND APPEAL PROCEDURES Bylaws § 2003.8 Records (Article VIII). (a) Integrity of ISCAP...

32 CFR 2003.8 - Records (Article VIII).

Code of Federal Regulations, 2014 CFR

2014-07-01

... 32 National Defense 6 2014-07-01 2014-07-01 false Records (Article VIII). 2003.8 Section 2003.8 National Defense Other Regulations Relating to National Defense INFORMATION SECURITY OVERSIGHT OFFICE...) BYLAWS, RULES, AND APPEAL PROCEDURES Bylaws § 2003.8 Records (Article VIII). (a) Integrity of ISCAP...

The structural basis for the functional comparability of Factor VIII and the long-acting variant recombinant Factor VIII Fc fusion protein

PubMed Central

Leksa, N.C.; Chiu, P.-L.; Bou-Assaf, G.M.; Quan, C.; Liu, Z.; Goodman, A.B.; Chambers, M.G.; Tsutakawa, S.E.; Hammel, M.; Peters, R.T.; Walz, T.; Kulman, J.D.

2017-01-01

SUMMARY Background Fusion of the human IgG1 Fc domain to the C-terminal C2 domain of B domain-deleted (BDD) factor VIII (FVIII) results in the rFVIIIFc fusion protein that has a 1.5-fold longer half-life in humans. Objective To assess the structural properties of rFVIIIFc by comparing its constituent FVIII and Fc elements with their respective isolated components and evaluating their structural independence within rFVIIIFc. Methods rFVIIIFc and its isolated FVIII and Fc components were compared by hydrogen-deuterium exchange mass spectrometry (HDX-MS). The structure of rFVIIIFc was also evaluated by X-ray crystallography, small-angle X-ray scattering (SAXS), and electron microscopy (EM). The degree of steric interference by the appended Fc domain was assessed by EM and surface plasmon resonance (SPR). Results HDX-MS analysis of rFVIIIFc revealed that fusion caused no structural perturbations in FVIII or Fc. The rFVIIIFc crystal structure showed that the FVIII component is indistinguishable from published BDD FVIII structures. The Fc domain was not observed, indicating high mobility. SAXS analysis was consistent with an ensemble of rigid-body models in which the Fc domain exists in a largely extended orientation relative to FVIII. Binding of Fab fragments of anti-C2 domain antibodies to BDD FVIII was visualized by EM, and the affinities of the corresponding intact antibodies for BDD FVIII and rFVIIIFc were comparable by SPR analysis. Conclusions The FVIII and Fc components of rFVIIIFc are structurally indistinguishable from their isolated constituents and exhibit a high degree of structural independence, consistent with the functional comparability of rFVIIIFc and unmodified FVIII. PMID:28397397

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

PubMed Central

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

2016-01-01

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

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

PubMed

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

2016-08-04

Recombinant VIII (rVIII)-SingleChain is a novel B-domain-truncated recombinant factor VIII (rFVIII), comprised of covalently bonded factor VIII (FVIII) heavy and light chains. It was designed to have a higher binding affinity for von Willebrand factor (VWF). This phase 1/3 study investigated the efficacy and safety of rVIII-SingleChain in the treatment of bleeding episodes, routine prophylaxis, and surgical prophylaxis. Participants were ≥12 years of age, with severe hemophilia A (endogenous FVIII <1%). The participants were allocated by the investigator to receive rVIII-SingleChain in either an on-demand or prophylaxis regimen. Of the 175 patients meeting study eligibility criteria, 173 were treated with rVIII-SingleChain, prophylactically (N = 146) or on-demand (N = 27). The total cumulative exposure was 14 306 exposure days (EDs), with 120 participants reaching ≥50 EDs and 52 participants having ≥100 EDs. Hemostatic efficacy was rated by the investigator as excellent or good in 93.8% of the 835 bleeds treated and assessed. Across all prophylaxis regimens, the median annualized spontaneous bleeding rate was 0.00 (Q1, Q3: 0.0, 2.4) and the median overall annualized bleeding rate (ABR) was 1.14 (Q1, Q3: 0.0, 4.2). Surgical hemostasis was rated as excellent/good in 100% of major surgeries by the investigator. No participant developed FVIII inhibitors. In conclusion, rVIII-SingleChain is a novel rFVIII molecule showing excellent hemostatic efficacy in surgery and in the control of bleeding events, low ABR in patients on prophylaxis, and a favorable safety profile in this large clinical study. This trial was registered at www.clinicaltrials.gov as #NCT01486927. © 2016 by The American Society of Hematology.

40 CFR Appendix Viii to Part 600 - Fuel Economy Label Formats

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 29 2010-07-01 2010-07-01 false Fuel Economy Label Formats VIII Appendix VIII to Part 600 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) ENERGY POLICY FUEL ECONOMY AND CARBON-RELATED EXHAUST EMISSIONS OF MOTOR VEHICLES Pt. 600, App. VIII Appendix VIII to Part 600—Fuel Economy Label Formats...

[Ehler-Danlos syndrome type VIII].

PubMed

Ciarloni, L; Perrigouard, C; Lipsker, D; Cribier, B

2010-03-01

Ehlers-Danlos syndrome (EDS) comprises a heterogeneous group of diseases involving genetic collagen fibre impairment. We describe a case of a patient presenting the rare type VIII, in which dermatitis ocre was associated with parodontal disease, and which was diagnosed late. A 29-year-old man consulted for a pretibial ulcer present for seven years, resulting from a post-traumatic haematoma that had failed to heal. In view of the longiliner morphology, it had previously been diagnosed as Marfan syndrome. Subsequently, edentation was observed as well as "alveolar bone fragility". Examination revealed a marfanoid morphotype, a pretibial ulcer set within long-standing bilateral dermatitis ocre and papyraceous scars, but no joint hyperlaxity or cutaneous hyperelasticity. The diagnosis was consequently corrected to EDS type VIII. Type VIII is a rare form of EDS, and the molecular mechanism is poorly understood. The involvement of parodontal connective tissue suggests impairment of collagen I and III proteins. It is important to identify this type of the disease since it involves parodontal disease for which early treatment is required in order to try to prevent edentation. The present case demonstrates the importance of diagnosis, which may be based upon appearance of bilateral dermatitis ocre from the age of 15 years associated with skin fragility. This sign is not part of the classical picture of Marfan syndrome, with which EDS type VIII is often confounded. Copyright 2009 Elsevier Masson SAS. All rights reserved.

Factor VIII Interacts with the Endocytic Receptor Low-density Lipoprotein Receptor-related Protein 1 via an Extended Surface Comprising "Hot-Spot" Lysine Residues.

PubMed

van den Biggelaar, Maartje; Madsen, Jesper J; Faber, Johan H; Zuurveld, Marleen G; van der Zwaan, Carmen; Olsen, Ole H; Stennicke, Henning R; Mertens, Koen; Meijer, Alexander B

2015-07-03

Lysine residues are implicated in driving the ligand binding to the LDL receptor family. However, it has remained unclear how specificity is regulated. Using coagulation factor VIII as a model ligand, we now study the contribution of individual lysine residues in the interaction with the largest member of the LDL receptor family, low-density lipoprotein receptor-related protein (LRP1). Using hydrogen-deuterium exchange mass spectrometry (HDX-MS) and SPR interaction analysis on a library of lysine replacement variants as two independent approaches, we demonstrate that the interaction between factor VIII (FVIII) and LRP1 occurs over an extended surface containing multiple lysine residues. None of the individual lysine residues account completely for LRP1 binding, suggesting an additive binding model. Together with structural docking studies, our data suggest that FVIII interacts with LRP1 via an extended surface of multiple lysine residues that starts at the bottom of the C1 domain and winds around the FVIII molecule. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Prevalence of IgG antibodies to human parvovirus B19 in haemophilia children treated with recombinant factor (F)VIII only or with at least one plasma-derived FVIII or FIX concentrate: results from the French haemophilia cohort.

PubMed

Gaboulaud, Valérie; Parquet, Armelle; Tahiri, Cedric; Claeyssens, Ségolène; Potard, Valérie; Faradji, Albert; Peynet, Jocelyne; Costagliola, Dominique

2002-02-01

Human parvovirus B19 (B19) has been transmitted by some brands of virally attenuated plasma-derived factor VIII (FVIII) or IX (FIX) concentrates. To quantify the differences of human parvovirus B19 risk transmission between albumin-stabilized recombinant factor and plasma-derived factor, we studied the prevalence of IgG antibodies to B19 (anti-B19) in 193 haemophiliac children between 1 and 6-years of age who had previously been treated with albumin-stabilized recombinant FVIII only (n = 104), and in children previously treated with solvent/detergent high-purity non-immunopurified and non-nanofiltered FVIII or IX concentrates (n = 89). Association between the prevalence of anti-B19 and the treatment group was analysed using multivariate logistic regression. Age, severity and type of haemophilia, number of cumulative days of exposure to factor VIII or IX, previous history of red blood cells or plasma transfusion were considered as potential confounding variables. A higher prevalence of anti-B19 was found in children previously treated with solvent/detergent high-purity non-immunopurified and non-nanofiltered FVIII or IX concentrates than in children treated with albumin- stabilized recombinant FVIII only (OR: 22.3; CI: 7.9-62.8), independently of the other factors studied.

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

PubMed Central

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

2016-01-01

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

Native-like aggregates of Factor VIII (FVIII) are immunogenic von Willebrand Factor deficient and hemophilia A mice

PubMed Central

Pisal, Dipak S.; Kosloski, Matthew P.; Middaugh, C. Russell; Bankert, Richard B.; Balu-Iyer, Sathy V.

2013-01-01

The administration of recombinant Factor VIII (FVIII) is the first line therapy for Hemophilia A (HA), but 25–35% of patients develop an inhibitory antibody response. In general, the presence of aggregates contributes to unwanted immunogenic responses against therapeutic proteins. FVIII has been shown to form both native-like and non-native aggregates. Previously, we showed that non-native aggregates of FVIII are less immunogenic compared to the native protein. Here we investigated the effect of native-like aggregates of FVIII on immunogenicity in HA and von Willebrand Factor knockout (vWF−/−) mice. Mice immunized with native-like aggregates showed significantly higher inhibitory antibody titers compared to animals that received native FVIII. Following re-stimulation in vitro with native FVIII, the activation of CD4+ T cells isolated from mice immunized with native-like aggregates is ~4 fold higher than mice immunized with the native protein. Furthermore, this is associated with increases in the secretion of pro-inflammatory cytokines IL-6 and IL-17 in the native-like aggregate treatment group. The results indicate that the native-like aggregates of FVIII are more immunogenic than native FVIII for both the B cell and T cell responses. PMID:22388918

The structural basis for the functional comparability of factor VIII and the long-acting variant recombinant factor VIII Fc fusion protein

DOE PAGES

Leksa, N. C.; Chiu, P. -L.; Bou-Assaf, G. M.; ...

2017-05-03

Fusion of the human IgG 1 Fc domain to the C-terminal C2 domain of B-domain-deleted (BDD) factor VIII (FVIII) results in the recombinant FVIII Fc (rFVIIIFc) fusion protein, which has a 1.5-fold longer half-life in humans. To assess the structural properties of rFVIIIFc by comparing its constituent FVIII and Fc elements with their respective isolated components, and evaluating their structural independence within rFVIIIFc. rFVIIIFc and its isolated FVIII and Fc components were compared by the use of hydrogen–deuterium exchange mass spectrometry (HDX-MS). The structure of rFVIIIFc was also evaluated by the use of X-ray crystallography, small-angle X-ray scattering (SAXS), andmore » electron microscopy (EM). The degree of steric interference by the appended Fc domain was assessed by EM and surface plasmon resonance (SPR). HDX-MS analysis of rFVIIIFc revealed that fusion caused no structural perturbations in FVIII or Fc. The rFVIIIFc crystal structure showed that the FVIII component is indistinguishable from published BDD FVIII structures. The Fc domain was not observed, indicating high mobility. SAXS analysis was consistent with an ensemble of rigid-body models in which the Fc domain exists in a largely extended orientation relative to FVIII. Binding of Fab fragments of anti-C2 domain antibodies to BDD FVIII was visualized by EM, and the affinities of the corresponding intact antibodies for BDD FVIII and rFVIIIFc were comparable by SPR analysis. Thus, the FVIII and Fc components of rFVIIIFc are structurally indistinguishable from their isolated constituents, and show a high degree of structural independence, consistent with the functional comparability of rFVIIIFc and unmodified FVIII.« less

The structural basis for the functional comparability of factor VIII and the long-acting variant recombinant factor VIII Fc fusion protein

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

Leksa, N. C.; Chiu, P. -L.; Bou-Assaf, G. M.

Fusion of the human IgG 1 Fc domain to the C-terminal C2 domain of B-domain-deleted (BDD) factor VIII (FVIII) results in the recombinant FVIII Fc (rFVIIIFc) fusion protein, which has a 1.5-fold longer half-life in humans. To assess the structural properties of rFVIIIFc by comparing its constituent FVIII and Fc elements with their respective isolated components, and evaluating their structural independence within rFVIIIFc. rFVIIIFc and its isolated FVIII and Fc components were compared by the use of hydrogen–deuterium exchange mass spectrometry (HDX-MS). The structure of rFVIIIFc was also evaluated by the use of X-ray crystallography, small-angle X-ray scattering (SAXS), andmore » electron microscopy (EM). The degree of steric interference by the appended Fc domain was assessed by EM and surface plasmon resonance (SPR). HDX-MS analysis of rFVIIIFc revealed that fusion caused no structural perturbations in FVIII or Fc. The rFVIIIFc crystal structure showed that the FVIII component is indistinguishable from published BDD FVIII structures. The Fc domain was not observed, indicating high mobility. SAXS analysis was consistent with an ensemble of rigid-body models in which the Fc domain exists in a largely extended orientation relative to FVIII. Binding of Fab fragments of anti-C2 domain antibodies to BDD FVIII was visualized by EM, and the affinities of the corresponding intact antibodies for BDD FVIII and rFVIIIFc were comparable by SPR analysis. Thus, the FVIII and Fc components of rFVIIIFc are structurally indistinguishable from their isolated constituents, and show a high degree of structural independence, consistent with the functional comparability of rFVIIIFc and unmodified FVIII.« less

NE VIII lambda 774 and time variable associated absorption in the QSO UM 675

NASA Technical Reports Server (NTRS)

Hamann, Fred; Barlow, Thomas A.; Beaver, E. A.; Burbidge, E. M.; Cohen, Ross D.; Junkkarinen, Vesa; Lyons, R.

1995-01-01

We discuss measurements of Ne VIII lambda 774 absorption and the time variability of other lines in the z(sub a) approximately equal z(sub e) absorption system of the z(sub e) = 2.15 QSO UM 675 (0150-203). The C IV lambda 1549 and N V 1240 doublets at z(sub a) = 2.1340 (shifted approximately 1500 km/s from z(sub e) strengthened by a factor of approximately 3 between observations by Sargent, Boksenberg and Steidel (1981 November) and our earliest measurements (1990 November and December). We have no information on changes in other z(sub a) approximately equal z(sub e) absorption lines. Continued monitoring since 1990 November shows no clear changes in any of the absorptions between approximately 1100 and 1640 A rest. The short timescale of the variability (less than or approximately equal to 2.9 yr rest) strongly suggests that the clouds are dense, compact, close to the QSO, and photoionized by the QSO continuum. If the line variability is caused by changes in the ionization, the timescale requires densities greater than approximately 4000/cu cm. Photoionization calculations place the absorbing clouds within approximately 200 pc of the continuum source. The full range of line ionizations (from Ne VIII lambda 774 to C III lambda 977) in optically thin gas (no Lyman limit) implies that the absorbing regions span a factor of more than approximately 10 in distance or approximately 100 in density. Across these regions, the total hydrogen (H I + H II) column ranges from a few times 10(exp 18)/sq cm in the low-ionization gas to approximately 10(exp 20)/sq cm where the Ne VIII doublet forms. The metallicity is roughly solar or higher, with nitrogen possibly more enhanced by factors of a few. The clouds might contribute significant line emission if they nearly envelop the QSO. The presence of highly ionized Ne VIII lambda 774 absorption near the QSO supports recent studies that link z(sub a) approximately equal to z(sub e) systems with X-ray 'wamr absorbers. We show that the

Platelet-targeted gene therapy with human factor VIII establishes haemostasis in dogs with haemophilia A.

PubMed

Du, Lily M; Nurden, Paquita; Nurden, Alan T; Nichols, Timothy C; Bellinger, Dwight A; Jensen, Eric S; Haberichter, Sandra L; Merricks, Elizabeth; Raymer, Robin A; Fang, Juan; Koukouritaki, Sevasti B; Jacobi, Paula M; Hawkins, Troy B; Cornetta, Kenneth; Shi, Qizhen; Wilcox, David A

2013-01-01

It is essential to improve therapies for controlling excessive bleeding in patients with haemorrhagic disorders. As activated blood platelets mediate the primary response to vascular injury, we hypothesize that storage of coagulation Factor VIII within platelets may provide a locally inducible treatment to maintain haemostasis for haemophilia A. Here we show that haematopoietic stem cell gene therapy can prevent the occurrence of severe bleeding episodes in dogs with haemophilia A for at least 2.5 years after transplantation. We employ a clinically relevant strategy based on a lentiviral vector encoding the ITGA2B gene promoter, which drives platelet-specific expression of human FVIII permitting storage and release of FVIII from activated platelets. One animal receives a hybrid molecule of FVIII fused to the von Willebrand Factor propeptide-D2 domain that traffics FVIII more effectively into α-granules. The absence of inhibitory antibodies to platelet-derived FVIII indicates that this approach may have benefit in patients who reject FVIII replacement therapies. Thus, platelet FVIII may provide effective long-term control of bleeding in patients with haemophilia A.

Platelet-targeted gene therapy with human factor VIII establishes haemostasis in dogs with haemophilia A

PubMed Central

Du, Lily M.; Nurden, Paquita; Nurden, Alan T.; Nichols, Timothy C.; Bellinger, Dwight A.; Jensen, Eric S.; Haberichter, Sandra L.; Merricks, Elizabeth; Raymer, Robin A.; Fang, Juan; Koukouritaki, Sevasti B.; Jacobi, Paula M.; Hawkins, Troy B.; Cornetta, Kenneth; Shi, Qizhen; Wilcox, David A.

2013-01-01

It is essential to improve therapies for controlling excessive bleeding in patients with haemorrhagic disorders. As activated blood platelets mediate the primary response to vascular injury, we hypothesize that storage of coagulation Factor VIII within platelets may provide a locally inducible treatment to maintain haemostasis for haemophilia A. Here we show that haematopoietic stem cell gene therapy can prevent the occurrence of severe bleeding episodes in dogs with haemophilia A for at least 2.5 years after transplantation. We employ a clinically relevant strategy based on a lentiviral vector encoding the ITGA2B gene promoter, which drives platelet-specific expression of human FVIII permitting storage and release of FVIII from activated platelets. One animal receives a hybrid molecule of FVIII fused to the von Willebrand Factor propeptide-D2 domain that traffics FVIII more effectively into α-granules. The absence of inhibitory antibodies to platelet-derived FVIII indicates that this approach may have benefit in patients who reject FVIII replacement therapies. Thus, platelet FVIII may provide effective long-term control of bleeding in patients with haemophilia A. PMID:24253479

19 CFR Annex Viii-B to Part 351 - Schedule for Expedited Sunset Reviews

Code of Federal Regulations, 2010 CFR

2010-04-01

... 19 Customs Duties 3 2010-04-01 2010-04-01 false Schedule for Expedited Sunset Reviews VIII Annex VIII-B to Part 351 Customs Duties INTERNATIONAL TRADE ADMINISTRATION, DEPARTMENT OF COMMERCE ANTIDUMPING AND COUNTERVAILING DUTIES Pt. 351, Annex VIII-B Annex VIII-B to Part 351—Schedule for Expedited...

19 CFR Annex Viii-B to Part 351 - Schedule for Expedited Sunset Reviews

Code of Federal Regulations, 2011 CFR

2011-04-01

... 19 Customs Duties 3 2011-04-01 2011-04-01 false Schedule for Expedited Sunset Reviews VIII Annex VIII-B to Part 351 Customs Duties INTERNATIONAL TRADE ADMINISTRATION, DEPARTMENT OF COMMERCE ANTIDUMPING AND COUNTERVAILING DUTIES Pt. 351, Annex VIII-B Annex VIII-B to Part 351—Schedule for Expedited...

19 CFR Annex Viii-B to Part 351 - Schedule for Expedited Sunset Reviews

Code of Federal Regulations, 2013 CFR

2013-04-01

... 19 Customs Duties 3 2013-04-01 2013-04-01 false Schedule for Expedited Sunset Reviews VIII Annex VIII-B to Part 351 Customs Duties INTERNATIONAL TRADE ADMINISTRATION, DEPARTMENT OF COMMERCE ANTIDUMPING AND COUNTERVAILING DUTIES Pt. 351, Annex VIII-B Annex VIII-B to Part 351—Schedule for Expedited...

19 CFR Annex Viii-B to Part 351 - Schedule for Expedited Sunset Reviews

Code of Federal Regulations, 2014 CFR

2014-04-01

... 19 Customs Duties 3 2014-04-01 2014-04-01 false Schedule for Expedited Sunset Reviews VIII Annex VIII-B to Part 351 Customs Duties INTERNATIONAL TRADE ADMINISTRATION, DEPARTMENT OF COMMERCE ANTIDUMPING AND COUNTERVAILING DUTIES Pt. 351, Annex VIII-B Annex VIII-B to Part 351—Schedule for Expedited...

19 CFR Annex Viii-B to Part 351 - Schedule for Expedited Sunset Reviews

Code of Federal Regulations, 2012 CFR

2012-04-01

... 19 Customs Duties 3 2012-04-01 2012-04-01 false Schedule for Expedited Sunset Reviews VIII Annex VIII-B to Part 351 Customs Duties INTERNATIONAL TRADE ADMINISTRATION, DEPARTMENT OF COMMERCE ANTIDUMPING AND COUNTERVAILING DUTIES Pt. 351, Annex VIII-B Annex VIII-B to Part 351—Schedule for Expedited...

19 CFR Annex Viii-C to Part 351 - Schedule for Full Sunset Reviews

Code of Federal Regulations, 2010 CFR

2010-04-01

... 19 Customs Duties 3 2010-04-01 2010-04-01 false Schedule for Full Sunset Reviews VIII Annex VIII-C to Part 351 Customs Duties INTERNATIONAL TRADE ADMINISTRATION, DEPARTMENT OF COMMERCE ANTIDUMPING AND COUNTERVAILING DUTIES Pt. 351, Annex VIII-C Annex VIII-C to Part 351—Schedule for Full Sunset Reviews Day 1 Event...

19 CFR Annex Viii-C to Part 351 - Schedule for Full Sunset Reviews

Code of Federal Regulations, 2014 CFR

2014-04-01

... 19 Customs Duties 3 2014-04-01 2014-04-01 false Schedule for Full Sunset Reviews VIII Annex VIII-C to Part 351 Customs Duties INTERNATIONAL TRADE ADMINISTRATION, DEPARTMENT OF COMMERCE ANTIDUMPING AND COUNTERVAILING DUTIES Pt. 351, Annex VIII-C Annex VIII-C to Part 351—Schedule for Full Sunset Reviews Day 1 Event...

19 CFR Annex Viii-C to Part 351 - Schedule for Full Sunset Reviews

Code of Federal Regulations, 2011 CFR

2011-04-01

... 19 Customs Duties 3 2011-04-01 2011-04-01 false Schedule for Full Sunset Reviews VIII Annex VIII-C to Part 351 Customs Duties INTERNATIONAL TRADE ADMINISTRATION, DEPARTMENT OF COMMERCE ANTIDUMPING AND COUNTERVAILING DUTIES Pt. 351, Annex VIII-C Annex VIII-C to Part 351—Schedule for Full Sunset Reviews Day 1 Event...

19 CFR Annex Viii-C to Part 351 - Schedule for Full Sunset Reviews

Code of Federal Regulations, 2013 CFR

2013-04-01

... 19 Customs Duties 3 2013-04-01 2013-04-01 false Schedule for Full Sunset Reviews VIII Annex VIII-C to Part 351 Customs Duties INTERNATIONAL TRADE ADMINISTRATION, DEPARTMENT OF COMMERCE ANTIDUMPING AND COUNTERVAILING DUTIES Pt. 351, Annex VIII-C Annex VIII-C to Part 351—Schedule for Full Sunset Reviews Day 1 Event...

19 CFR Annex Viii-C to Part 351 - Schedule for Full Sunset Reviews

Code of Federal Regulations, 2012 CFR

2012-04-01

... 19 Customs Duties 3 2012-04-01 2012-04-01 false Schedule for Full Sunset Reviews VIII Annex VIII-C to Part 351 Customs Duties INTERNATIONAL TRADE ADMINISTRATION, DEPARTMENT OF COMMERCE ANTIDUMPING AND COUNTERVAILING DUTIES Pt. 351, Annex VIII-C Annex VIII-C to Part 351—Schedule for Full Sunset Reviews Day 1 Event...

40 CFR Appendix Viii to Part 600 - Fuel Economy Label Formats

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 30 2011-07-01 2011-07-01 false Fuel Economy Label Formats VIII... POLICY FUEL ECONOMY AND CARBON-RELATED EXHAUST EMISSIONS OF MOTOR VEHICLES Pt. 600, App. VIII Appendix VIII to Part 600—Fuel Economy Label Formats EC01MY92.117 EC01MY92.118 EC01MY92.119 EC01MY92.120...

Abnormal cerebellar development and ataxia in CARP VIII morphant zebrafish.

PubMed

Aspatwar, Ashok; Tolvanen, Martti E E; Jokitalo, Eija; Parikka, Mataleena; Ortutay, Csaba; Harjula, Sanna-Kaisa E; Rämet, Mika; Vihinen, Mauno; Parkkila, Seppo

2013-02-01

Congenital ataxia and mental retardation are mainly caused by variations in the genes that affect brain development. Recent reports have shown that mutations in the CA8 gene are associated with mental retardation and ataxia in humans and ataxia in mice. The gene product, carbonic anhydrase-related protein VIII (CARP VIII), is predominantly present in cerebellar Purkinje cells, where it interacts with the inositol 1,4,5-trisphosphate receptor type 1, a calcium channel. In this study, we investigated the effects of the loss of function of CARP VIII during embryonic development in zebrafish using antisense morpholino oligonucleotides against the CA8 gene. Knockdown of CA8 in zebrafish larvae resulted in a curved body axis, pericardial edema and abnormal movement patterns. Histologic examination revealed gross morphologic defects in the cerebellar region and in the muscle. Electron microscopy studies showed increased neuronal cell death in developing larvae injected with CA8 antisense morpholinos. These data suggest a pivotal role for CARP VIII during embryonic development. Furthermore, suppression of CA8 expression leads to defects in motor and coordination functions, mimicking the ataxic human phenotype. This work reveals an evolutionarily conserved function of CARP VIII in brain development and introduces a novel zebrafish model in which to investigate the mechanisms of CARP VIII-related ataxia and mental retardation in humans.

Detection of two intervening Ne viii absorbers probing warm gas at z ˜ 0.6

NASA Astrophysics Data System (ADS)

Pachat, Sachin; Narayanan, Anand; Khaire, Vikram; Savage, Blair D.; Muzahid, Sowgat; Wakker, Bart P.

2017-10-01

We report on the detection of two Ne viii absorbers, at z = 0.619 07 and 0.570 52 in the Hubble Space Telescope/Cosmic Origins Spectrograph spectrum of background quasars SDSS J080908.13 + 461925.6 and SBS 1122 + 594, respectively. The Ne viii 770 line is at ˜3σ significance. In both instances, the Ne viii is found to be tracing gas with T ≳ 105 K, predominantly collisionally ionized, with moderate densities of n_{H} ≲ 10^{-4} cm-3, sub-solar metallicities and total hydrogen column densities of N(H) ≳ 1019 cm-2. In the z = 0.619 07 absorber, the low, intermediate ions and O VI are consistent with origin in photoionized gas, with the O VI potentially having some contribution from the warm collisional phase traced by Ne viii. The z = 0.570 52 system has H I absorption in at least three kinematically distinct components, with one of them having b({H I}) = 49 {± } 11 km s-1. The intermediate-ionization lines, O VI and Ne viii, are coincident in velocity with this component. Their different line widths suggest warm temperatures of T = (0.5-1.5) × 105 K. Both absorbers are residing in regions where there are several luminous (≳L★) galaxies. The absorber at z = 0.570 52 is within the virial radius of a 2.6L★ galaxy, possibly associated with shock-heated circumgalactic material.

Physician preferences for medication attributes for the prophylactic treatment of patients with severe haemophilia A with inhibitors to factor VIII.

PubMed

Gelhorn, H; Merikle, E; Krishnan, S; Nemes, L; Leissinger, C; Valentino, L

2013-01-01

Prophylaxis may be beneficial for patients with severe haemophilia A who have developed inhibitors to factor VIII. The aim of this study was to determine physicians' preferences for medication attributes in the prophylactic treatment of this patient population. Haematologists from Europe (EU) and the United States (US) participated in a discrete choice exercise to explore their preferences for medication attributes (efficacy, cost, scientific evidence, dosing frequency and administration time) associated with prophylaxis for severe haemophilia A in patients with inhibitors to factor VIII. Physicians' preferences for medication attributes were assessed through completion of 25 trade-off tasks that included a choice between two hypothetical medications each comprised of one randomized level of each medication attribute. Participants also completed a sociodemographic questionnaire. Data were analysed using a random effects logit model. Participants (N = 36: US = 19; EU = 17) were 80.6% men, had a mean of 19.8 years (SD ± 8.1) [range 6-35] of practice experience. The physicians treated an average of 5.7 (± 5.5) patients with severe haemophilia A and inhibitors per month and reported treating 36.2% of these patients prophylactically. The most important medication attributes for prophylactic treatment were efficacy [Relative Importance (RI) = 35.0%] and scientific evidence (RI = 34.1%), whereas treatment cost (12.0%), dosing frequency (10.8%) and administration time (8.2%) were less important. Results were similar across the EU and US. Efficacy and scientific evidence are the primary considerations for physicians' choice of prophylactic medications for use in this patient population. © 2012 Blackwell Publishing Ltd.

Preparing for ENDF/B-VIII

NASA Astrophysics Data System (ADS)

Brown, David

2017-09-01

Although the next major release of the ENDF/B library is not due until the 2017-2018 time frame, ENDF/B-VIII is already positioned to become the most important release of the library in some time. ENDF/B-VIII will be built around the Neutron Reaction Standards as well as the 1H, 16O, 56Fe, 235U, 238U and 239Pu evaluations developed as part of the Coordinated International Evaluation Library Organization (CIELO) pilot project. In this contribution, we summarize these improvements as well as the many other improvements to ENDF that have already been made or are scheduled to be made in the next year. Improvements already included in the ENDF/B-VIII beta releases: • Aggressive use of the flexible and physically correct LRF=7 resolved resonance format in 12 updated evaluations (35,37Cl, 40Ca, 54,56,57Fe, 63,65Cu and 182,183,184,186W) • Thermal capture gammas from the EGAF project (6,7Li, 11B, 19F, 23Na, 27Al, 28Si, 35,37Cl) • Thermal Scattering Law evaluations from NCSU (α and β phase SiO2, SiC, lucite, BeO, and polyethylene) and from the CAB-CNL collaboration (heavy and light water) • Many new evaluations in the neutron sublibrary (n, 12,13C, 40Ar, 54,57,58Fe, 58,59,60,61,62,64Ni, 63,65Cu, 73As, 120Sn, 236m1Np) Inclusion of Red Cullen's EPICS2014 library, updating the photo-atomic, electron and atomic-relaxation sublibraries. Many improvements are planned in the next year including new evaluations such as charged particle evaluations translated from LLNL's ECPL. In addition to these major changes, ENDF/B-VIII will be the first official library released simultaneously in the legacy ENDF-6 and the newly developed Generalized Nuclear Data (GND) formats.

19 CFR Annex Viii-A to Part 351 - Schedule for 90-Day Sunset Reviews

Code of Federal Regulations, 2010 CFR

2010-04-01

... 19 Customs Duties 3 2010-04-01 2010-04-01 false Schedule for 90-Day Sunset Reviews VIII Annex VIII-A to Part 351 Customs Duties INTERNATIONAL TRADE ADMINISTRATION, DEPARTMENT OF COMMERCE ANTIDUMPING AND COUNTERVAILING DUTIES Pt. 351, Annex VIII-A Annex VIII-A to Part 351—Schedule for 90-Day Sunset...

19 CFR Annex Viii-A to Part 351 - Schedule for 90-Day Sunset Reviews

Code of Federal Regulations, 2014 CFR

2014-04-01

... 19 Customs Duties 3 2014-04-01 2014-04-01 false Schedule for 90-Day Sunset Reviews VIII Annex VIII-A to Part 351 Customs Duties INTERNATIONAL TRADE ADMINISTRATION, DEPARTMENT OF COMMERCE ANTIDUMPING AND COUNTERVAILING DUTIES Pt. 351, Annex VIII-A Annex VIII-A to Part 351—Schedule for 90-Day Sunset...

19 CFR Annex Viii-A to Part 351 - Schedule for 90-Day Sunset Reviews

Code of Federal Regulations, 2012 CFR

2012-04-01

... 19 Customs Duties 3 2012-04-01 2012-04-01 false Schedule for 90-Day Sunset Reviews VIII Annex VIII-A to Part 351 Customs Duties INTERNATIONAL TRADE ADMINISTRATION, DEPARTMENT OF COMMERCE ANTIDUMPING AND COUNTERVAILING DUTIES Pt. 351, Annex VIII-A Annex VIII-A to Part 351—Schedule for 90-Day Sunset...

19 CFR Annex Viii-A to Part 351 - Schedule for 90-Day Sunset Reviews

Code of Federal Regulations, 2013 CFR

2013-04-01

... 19 Customs Duties 3 2013-04-01 2013-04-01 false Schedule for 90-Day Sunset Reviews VIII Annex VIII-A to Part 351 Customs Duties INTERNATIONAL TRADE ADMINISTRATION, DEPARTMENT OF COMMERCE ANTIDUMPING AND COUNTERVAILING DUTIES Pt. 351, Annex VIII-A Annex VIII-A to Part 351—Schedule for 90-Day Sunset...

19 CFR Annex Viii-A to Part 351 - Schedule for 90-Day Sunset Reviews

Code of Federal Regulations, 2011 CFR

2011-04-01

... 19 Customs Duties 3 2011-04-01 2011-04-01 false Schedule for 90-Day Sunset Reviews VIII Annex VIII-A to Part 351 Customs Duties INTERNATIONAL TRADE ADMINISTRATION, DEPARTMENT OF COMMERCE ANTIDUMPING AND COUNTERVAILING DUTIES Pt. 351, Annex VIII-A Annex VIII-A to Part 351—Schedule for 90-Day Sunset...

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

PubMed

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

2017-07-01

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

40 CFR Appendix Viii to Part 268 - LDR Effective Dates of Injected Prohibited Hazardous Wastes

Code of Federal Regulations, 2014 CFR

2014-07-01

... Prohibited Hazardous Wastes VIII Appendix VIII to Part 268 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) SOLID WASTES (CONTINUED) LAND DISPOSAL RESTRICTIONS Pt. 268, App. VIII Appendix VIII to Part 268—LDR Effective Dates of Injected Prohibited Hazardous Wastes National Capacity LDR...

40 CFR Appendix Viii to Part 268 - LDR Effective Dates of Injected Prohibited Hazardous Wastes

Code of Federal Regulations, 2012 CFR

2012-07-01

... Prohibited Hazardous Wastes VIII Appendix VIII to Part 268 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) SOLID WASTES (CONTINUED) LAND DISPOSAL RESTRICTIONS Pt. 268, App. VIII Appendix VIII to Part 268—LDR Effective Dates of Injected Prohibited Hazardous Wastes National Capacity LDR...

40 CFR Appendix Viii to Part 268 - LDR Effective Dates of Injected Prohibited Hazardous Wastes

Code of Federal Regulations, 2011 CFR

2011-07-01

... Prohibited Hazardous Wastes VIII Appendix VIII to Part 268 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) SOLID WASTES (CONTINUED) LAND DISPOSAL RESTRICTIONS Pt. 268, App. VIII Appendix VIII to Part 268—LDR Effective Dates of Injected Prohibited Hazardous Wastes National Capacity LDR...

40 CFR Appendix Viii to Part 268 - LDR Effective Dates of Injected Prohibited Hazardous Wastes

Code of Federal Regulations, 2013 CFR

2013-07-01

... Prohibited Hazardous Wastes VIII Appendix VIII to Part 268 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) SOLID WASTES (CONTINUED) LAND DISPOSAL RESTRICTIONS Pt. 268, App. VIII Appendix VIII to Part 268—LDR Effective Dates of Injected Prohibited Hazardous Wastes National Capacity LDR...

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

PubMed

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

2017-04-01

Essentials rVIII-SingleChain is a novel recombinant factor VIII with covalently bonded heavy and light chains. Efficacy, safety and pharmacokinetics were studied in pediatric patients with severe hemophilia A. Across all prophylaxis regimens, the median annualized spontaneous bleeding rate was 0.00. rVIII-SingleChain showed excellent hemostatic efficacy and a favorable safety profile. Background rVIII-SingleChain is a novel B-domain truncated recombinant factor VIII (rFVIII) comprised of covalently bonded FVIII heavy and light chains, demonstrating a high binding affinity to von Willebrand factor. Objectives This phase III study investigated the safety, efficacy and pharmacokinetics of rVIII-SingleChain in previously treated pediatric patients < 12 years of age with severe hemophilia A. Patients/Methods Patients could be assigned to prophylaxis or on-demand therapy by the investigator. For patients assigned to prophylaxis, the treatment regimen and dose were based on the bleeding phenotype. For patients receiving on-demand therapy, dosing was guided by World Federation of Hemophilia recommendations. The primary endpoint was treatment success, defined as a rating of 'excellent' or 'good' on the investigator's clinical assessment of hemostatic efficacy for all treated bleeding events. Results The study enrolled 84 patients (0 to < 6 years, n = 35; ≥ 6 to < 12 years, n = 49); 81 were assigned to prophylaxis and three to an on-demand regimen. Patients accumulated a total of 5239 exposure days (EDs), with 65 participants reaching > 50 EDs. In the 347 bleeds treated and evaluated by the investigator, hemostatic efficacy was rated as excellent or good in 96.3%. The median annualized spontaneous bleeding rate was 0.00 (Q1, Q3: 0.00, 2.20), and the median annualized bleeding rate was 3.69 (Q1, Q3: 0.00, 7.20) across all prophylaxis regimens. No participant developed an inhibitor. Conclusions rVIII-SingleChain is a novel rFVIII molecule showing excellent hemostatic

Chromosome VIII disomy influences the nonsense suppression efficiency and transition metal tolerance of the yeast Saccharomyces cerevisiae.

PubMed

Zadorsky, S P; Sopova, Y V; Andreichuk, D Y; Startsev, V A; Medvedeva, V P; Inge-Vechtomov, S G

2015-06-01

The SUP35 gene of the yeast Saccharomyces cerevisiae encodes the translation termination factor eRF3. Mutations in this gene lead to the suppression of nonsense mutations and a number of other pleiotropic phenotypes, one of which is impaired chromosome segregation during cell division. Similar effects result from replacing the S. cerevisiae SUP35 gene with its orthologues. A number of genetic and epigenetic changes that occur in the sup35 background result in partial compensation for this suppressor effect. In this study we showed that in S. cerevisiae strains in which the SUP35 orthologue from the yeast Pichia methanolica replaces the S. cerevisiae SUP35 gene, chromosome VIII disomy results in decreased efficiency of nonsense suppression. This antisuppressor effect is not associated with decreased stop codon read-through. We identified SBP1, a gene that localizes to chromosome VIII, as a dosage-dependent antisuppressor that strongly contributes to the overall antisuppressor effect of chromosome VIII disomy. Disomy of chromosome VIII also leads to a change in the yeast strains' tolerance of a number of transition metal salts. Copyright © 2015 John Wiley & Sons, Ltd.

In vivo recovery of factor VIII and factor IX: intra- and interindividual variance in a clinical setting.

PubMed

Björkman, S; Folkesson, A; Berntorp, E

2007-01-01

In vivo recovery (IVR) is traditionally used as a parameter to characterize the pharmacokinetic properties of coagulation factors. It has also been suggested that dosing of factor VIII (FVIII) and factor IX (FIX) can be adjusted according to the need of the individual patient, based on an individually determined IVR value. This approach, however, requires that the individual IVR value is more reliably representative for the patient than the mean value in the population, i.e. that there is less variance within than between the individuals. The aim of this investigation was to compare intra- and interindividual variance in IVR (as U dL1 per U kg1) for FVIII and plasma-derived FIX in a cohort of non-bleeding patients with haemophilia. The data were collected retrospectively from six clinical studies, yielding 297 IVR determinations in 50 patients with haemophilia A and 93 determinations in 13 patients with haemophilia B. For FVIII, the mean variance within patients exceeded the between-patient variance. Thus, an individually determined IVR value is apparently no more informative than an average, or population, value for the dosing of FVIII. There was no apparent relationship between IVR and age of the patient (1.5-67 years). For FIX, the mean variance within patients was lower than the between-patient variance, and there was a significant positive relationship between IVR and age (13-69 years). From these data, it seems probable that using an individual IVR confers little advantage in comparison to using an age-specific population mean value. Dose tailoring of coagulation factor treatment has been applied successfully after determination of the entire single-dose curve of FVIII:C or FIX:C in the patient and calculation of the relevant pharmacokinetic parameters. However, the findings presented here do not support the assumption that dosing of FVIII or FIX can be individualized on the basis of a clinically determined IVR value.

Genotyping the factor VIII intron 22 inversion locus using fluorescent in situ hybridization.

PubMed

Sheen, Campbell R; McDonald, Margaret A; George, Peter M; Smith, Mark P; Morris, Christine M

2011-02-15

The factor VIII intron 22 inversion is the most common cause of hemophilia A, accounting for approximately 40% of all severe cases of the disease. Southern hybridization and multiplex long distance PCR are the most commonly used techniques to detect the inversion in a diagnostic setting, although both have significant limitations. Here we describe our experience establishing a multicolor fluorescent in situ hybridization (FISH) based assay as an alternative to existing methods for genetic diagnosis of the inversion. Our assay was designed to apply three differentially labelled BAC DNA probes that when hybridized to interphase nuclei would exhibit signal patterns that are consistent with the normal or the inversion locus. When the FISH assay was applied to five normal and five inversion male samples, the correct genotype was assignable with p<0.001 for all samples. When applied to carrier female samples the assay could not assign a genotype to all female samples, probably due to a lower proportion of informative nuclei in female samples caused by the added complexity of a second X chromosome. Despite this complication, these pilot findings show that the assay performs favourably compared to the commonly used methods. Copyright © 2010 Elsevier Inc. All rights reserved.

Association of ABO blood groups with von Willebrand factor, factor VIII and ADAMTS-13 in patients with lung cancer.

PubMed

Liu, Xia; Chen, Xiaogang; Yang, Jiezuan; Guo, Renyong

2017-09-01

Coagulative and fibrinolytic disorders appear to be associated with the development of lung cancer. The aim of the present study was to determine plasma levels of von Willebrand factor (VWF) and a disintegrin and metalloproteinase with a thrombospondin type 1 motif 13 (ADAMTS-13), and factor VIII (FVIII) activity, in association with O and non-O blood groups in patients with lung cancer. Plasma levels of VWF and ADAMTS-13, and FVIII activity were measured in 115 patients with lung cancer and 98 healthy subjects. Phenotyping of the ABO blood groups was also performed for the two groups. Significantly increased VWF levels and FVIII activity, as well as significantly decreased ADAMTS-13 levels, were observed in patients with distant metastasis as compared with those without distant metastasis and the healthy controls. Plasma VWF levels and FVIII activity were significantly increased in subjects with non-O type blood compared with those with type O blood in the two groups. However, a significant decrease in ADAMTS-13 levels was observed only in the control group among those with non-O type blood, compared with those with type O blood. The results of the present study indicate that increased VWF and decreased ADAMTS-13 levels facilitate the invasiveness and metastasis of lung cancer. Non-O blood groups constitute a risk factor for increased VWF and FVIII in plasma. Continued monitoring of VWF and ADAMTS-13 levels, and of FVIII activity in patients with lung cancer with distinct blood groups may help to minimize the incidence of thrombotic events and improve assessment of disease progression.

Manufacturing challenges in the commercial production of recombinant coagulation factor VIII.

PubMed

Jiang, R; Monroe, T; McRogers, R; Larson, P J

2002-03-01

Advances in gene technology have led to the development of a method to manufacture recombinant coagulation Factor VIII (rFVIII) for haemophilia A. Because rFVIII is a large and complex protein, its commercialization has required that many challenges in manufacturing, purification and processing be overcome. In order to license the first generation of rFVIII (Kogenate) in 1993, Bayer Corporation invested over 10 years in research and manufacturing development. Seven additional years were subsequently devoted to research and manufacturing improvements in order to accomplish the recent licensing of a second rFVIII product (KOGENATE Bayer or Kogenate FS). This product differs from its predecessor, in that human albumin is removed from the purification and the formulation steps. In addition, fewer chromatography steps are involved resulting in greater yields per mL of conditioned medium, and a solvent-detergent viral inactivation step replaces the heat-processing step used for the previous product. Despite these changes in the manufacturing, the protein backbone and carbohydrate structure of the final rFVIII molecule are identical. The complexity of the production processes is reflected by over 100 000 manufacturing data entries and by 600 quality control tests for each batch of rFVIII. Manufacturers are continuing to develop the next generation of rFVIII, which will be produced without the addition of any human or animal proteins or byproducts. Investments in research, development and manufacturing technology are expected to result in the development of new products with enhanced safety profiles, and in an increase in the production capacity for products that are chronically in short supply.

[Detection of intron 22 inversion of factor VIII gene in severe hemophilia A patients].

PubMed

Guo, Zhi-ping; Chen, Jian-fang; Qin, Xiu-yu; Zhang, Yao-fang; Yang, Lin-hua

2013-11-01

To investigate the incidence of intron 22 inversion (INV22) of factor VIII (FVIII) gene in severe hemophilia A (HA) patients, clarify its pathological mechanism, and identify INV22 carrier in the female family members. One-stage method was used to assay the FVIII activity (FVIII:C)in 126 severe HA patients with a median age of 14 years old (range: 4 months-63 years). INV22 was analyzed by long-distance polymerase chain reaction (LD-PCR) and pulsed field gel electrophoresis (PFGE), and pedigree were conducted in 3 involved HA families. Of all the 126 severe HA, 52 (41.3%) cases had the INV22. Four females including 3 mothers and 1 sister of probands were diagnosed as INV22 carriers among 11 suspected carrier mosaicisms from 3 INV22 positive HA families. In 8 females from one family without HA history, the patient's mother was a INV22 carrier, but her maternal grandmother, 2 maternal aunts, 2 female siblings and 1 elder female cousin were negative. LD-PCR and PFGE could be used to diagnose severe HA patients with INV22 and identify the carriers.

Relationship between ABO blood groups and von Willebrand factor, ADAMTS13 and factor VIII in patients undergoing hemodialysis.

PubMed

Rios, Danyelle R A; Fernandes, Ana Paula; Figueiredo, Roberta C; Guimarães, Daniela A M; Ferreira, Cláudia N; Simões E Silva, Ana C; Carvalho, Maria G; Gomes, Karina B; Dusse, Luci Maria Sant' Ana

2012-05-01

Several studies have demonstrated that non-O blood groups subjects present an increased VTE risk as compared to those carrying O blood group. The aim of this study was to investigate the ABO blood groups influence on factor VIII (FVIII) activity, von Willebrand factor (VWF), and ADAMTS13 plasma levels in patients undergoing hemodialysis (HD). Patients undergoing HD (N=195) and 80 healthy subjects (control group) were eligible for this cross-sectional study. The ABO blood group phenotyping was performed by the reverse technique. FVIII activity was measured through coagulometric method, and VWF and ADAMTS13 antigens were assessed by ELISA. FVIII activity and VWF levels were significantly higher and ADAMTS13 levels was decreased in HD patients, as compared to healthy subjects (P < 0.001, in three cases). HD patients carrying non-O blood groups showed a significant increase in FVIII activity (P = 0.001) and VWF levels (P < 0.001) when compared to carriers of O blood group. However, no significant difference was observed in ADAMTS13 levels (P = 0.767). In the control group, increased in FVIII activity (P = 0.001) and VWF levels (P = 0.002) and decreased in ADAMTS13 levels (P = 0.005) were observed in subjects carrying non-O blood groups as compared to carriers of O blood group.Our data confirmed that ABO blood group is an important risk factor for increased procoagulant factors in plasma, as FVIII and VWF. Admitting the possible role of kidneys in ADAMTS13 synthesis or on its metabolism, HD patients were not able to increase ADAMTS13 levels in order to compensate the increase of VWF levels mediated by ABO blood groups. Considering that non-O blood groups constitute a risk factor for thrombosis, it is reasonable to admit that A, B and AB HD patients need a careful and continuous follow-up in order to minimize thrombotic events.

Factor VIII in Acute Cerebral Ischemia Pilot Study: Biomarker in Patients With Large Vessel Occlusion?

PubMed

Navalkele, Digvijaya; Boehme, Amelia; Albright, Karen; Leissinger, Cindy; Schluter, Laurie; Freeman, Melissa; Drury, Stacy; Khoury, Ramy El; Beasley, T Mark; Martin-Schild, Sheryl

2018-01-01

We conducted a prospective serial laboratory cohort study to assess the correlation of factor VIII (FVIII) levels in response to thrombolysis in patients with large vessel occlusion (LVO) and acute ischemic stroke (AIS). Patients with AIS with anterior circulation LVO were eligible for enrollment if treated within 4.5 hours from last seen normal with intravenous tissue plasminogen activator (tPA). Patients (n = 29) had a mean age of 71 years and median National Institute of Health Stroke Scale of 14. Baseline pre-tPA FVIII was not significantly correlated with clot burden score (-0.147, P = .447) or vessel recanalization (-0.133, P = .499). Median FVIII decreased significantly from baseline to 6 hours post-tPA (282% to 161%, P = .002), but delta in FVIII level did not correlate with vessel recanalization (0.013, P = .948). There was no difference between median FVIII level at baseline and 90 days post-AIS. FVIII level decreased significantly after tPA, but baseline FVIII level and early change in FVIII level were not significant predictors of clot burden, vessel recanalization after thrombolysis, or symptomatic hemorrhage.

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

PubMed

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

2017-01-01

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

Thrombomodulin as a marker for vascular tumors. Comparative study with factor VIII and Ulex europaeus I lectin.

PubMed

Yonezawa, S; Maruyama, I; Sakae, K; Igata, A; Majerus, P W; Sato, E

1987-10-01

Thrombomodulin (TM) is a newly described endothelial cell-associated protein that functions as a potent natural anticoagulant by converting thrombin from a procoagulant protease to an anticoagulant. Various vascular tumors were characterized with immunoperoxidase staining with the use of a polyclonal anti-TM serum. The staining patterns of TM were compared with those of Factor VIII-related antigen (FVIII-RAG) and Ulex europaeus agglutinin-I (UEA-I), which have been used as markers for endothelial cells. The results showed that TM is a specific and a highly sensitive marker for angiosarcomas in comparison with FVIII-RAG or UEA-I. In contrast, UEA-I is more sensitive for benign vascular tumors than TM or FVIII-RAG. The other mesenchymal tumors of nonvascular origin showed negative staining for three endothelial markers. These results indicate that TM is a new specific and sensitive tool for the diagnosis of angiosarcomas.

Novel factor VIII variants with a modified furin cleavage site improve the efficacy of gene therapy for hemophilia A.

PubMed

Nguyen, G N; George, L A; Siner, J I; Davidson, R J; Zander, C B; Zheng, X L; Arruda, V R; Camire, R M; Sabatino, D E

2017-01-01

Essentials Factor (F) VIII is an inefficiently expressed protein. Furin deletion FVIII variants were purified and characterized using in vitro and in vivo assays. These minimally modified novel FVIII variants have enhanced function. These variants provide a strategy for increasing FVIII expression in hemophilia A gene therapy. Background The major challenge for developing gene-based therapies for hemophilia A is that human factor VIII (hFVIII) has intrinsic properties that result in inefficient biosynthesis. During intracellular processing, hFVIII is predominantly cleaved at a paired basic amino acid cleaving enzyme (PACE) or furin cleavage site to yield a heterodimer that is the major form of secreted protein. Previous studies with B-domain-deleted (BDD) canine FVIII and hFVIII-R1645H, both differing from hFVIII by a single amino acid at this site, suggested that these proteins are secreted mainly in a single polypeptide chain (SC) form and exhibit enhanced function. Objective We hypothesized that deletion(s) of the furin site modulates FVIII biology and may enhance its function. Methods A series of recombinant hFVIII-furin deletion variants were introduced into hFVIII-BDD [Δ1645, 1645-46(Δ2), 1645-47(Δ3), 1645-48(Δ4), or Δ1648] and characterized. Results In vitro, recombinant purified Δ3 and Δ4 were primarily SC and, interestingly, had 2-fold higher procoagulant activity compared with FVIII-BDD. In vivo, the variants also have improved hemostatic function. After adeno-associated viral (AAV) vector delivery, the expression of these variants is 2-4-fold higher than hFVIII-BDD. Protein challenges of each variant in mice tolerant to hFVIII-BDD showed no anti-FVIII immune response. Conclusions These data suggest that the furin deletion hFVIII variants are superior to hFVIII-BDD without increased immunogenicity. In the setting of gene-based therapeutics, these novel variants provide a unique strategy to increase FVIII expression, thus lowering the vector dose, a

Potency determination of factor VIII and factor IX for new product labelling and postinfusion testing: challenges for caregivers and regulators.

PubMed

Dodt, J; Hubbard, A R; Wicks, S J; Gray, E; Neugebauer, B; Charton, E; Silvester, G

2015-07-01

A workshop organized by the European Medicines Agency and the European Directorate for the Quality of Medicines and HealthCare was held in London, UK on November 28-29, 2013, to provide an overview of the current knowledge of the characterization of new factor VIII (FVIII) and factor IX (FIX) concentrates with respect to potency assays and testing of postinfusion material. The objective was to set the basis for regulatory authorities' discussion on the most appropriate potency assay for the individual products, and European Pharmacopoeia (Ph. Eur.) discussion on whether to propose revision of the Ph. Eur. monographs with respect to potency assays in the light of information on new FVIII and FIX concentrates. The workshop showed that for all products valid assays vs. the international concentrate standards were obtained and potency could be expressed in International Units. The Ph. Eur. chromogenic potency assay gave valid assay results which correlate with in vivo functionality of rFVIII products. For some modified rFVIII products and all modified rFIX products, one-stage clotting assay methods result in different potencies depending on the activated partial thromboplastin time reagent. As a consequence, monitoring of patients' postinfusion levels is challenging but it was pointed out that manufacturers are responsible for providing the users with appropriate information for use and laboratory testing of their product. Strategies to avoid misleading determination of patents' plasma levels, e.g. information on suitable assays, laboratory standards or correction factors were discussed. © 2015 John Wiley & Sons Ltd.

Extracorporeal adsorption of anti-factor VIII allo-antibodies on randomly functionalized polystyrene resins.

PubMed

Huguet, Hélène-Céline; Lasne, Dominique; Rothschild, Chantal; Siali, Rosa; Jozefonvicz, Jacqueline

2004-02-01

The occurrence of anti-factor VIII (FVIII) allo-antibodies is a severe complication of the treatment of haemophilia A patients, leading to the inhibition of transfused FVIII activity. The effective elimination of these inhibitory antibodies plays a decisive role in the management of affected patients. To achieve this, immunoadsorption devices employing synthetic adsorbers, which selectively eliminate inhibitors, are of interest in the treatment strategy of haemophilia A patients with inhibitors. Adsorbers consisting of polystyrene-based beads substituted with sulphonate and L-tyrosyl methylester groups, which mimic part of epitope of FVIII molecule recognized by inhibitors, exhibit selective binding capacities towards anti-FVIII antibodies. The adsorption of FVIII inhibitors was investigated by simulating an extracorporeal circulation of haemophilic plasma over these functionalized resins. These innovative adsorbers are able to remove around 25% of anti-FVIII antibodies in 15 minutes depending on the plasma tested. Furthermore, they do not modify the amount of essential plasmatic proteins or residual immunoglobulins G. Experiments which were carried out using different plasmas with various inhibitor titres demonstrate a good reproducibility regarding the adsorption capacity of the synthetic resin. The characteristics of adsorption are similar on either native or regenerated resins. Both the purely synthetic nature of the resin and its easy processability demonstrate the real advantages over currently available protocols. This synthetic adsorber is a major technological advance in selective removal of FVIII inhibitory antibodies.

Detection of Ne VIII in an Intervening Multiphase Absorption System Toward 3C 263

NASA Astrophysics Data System (ADS)

Narayanan, Anand; Wakker, Bart P.; Savage, Blair D.

2009-09-01

We report the detection of Ne VIII in an intervening multiphase absorption line system at z = 0.32566 in the Far Ultraviolet Spectroscopic Explorer spectrum of the quasar 3C 263 (zem = 0.646). The Ne VIII λ770 Å detection has a 3.9σ significance. At the same velocity, we also find absorption lines from C IV, O III, O IV, and N IV. The line parameter measurements yield log [N(Ne VIII) cm-2] = 13.98+0.10 -0.13 and b = 49.8 ± 5.5 km s-1. We find that the ionization mechanism in the gas phase giving rise to the Ne VIII absorption is inconsistent with photoionization. The absorber has a multiphase structure, with the intermediate ions produced in cool photoionized gas and the Ne VIII most likely in a warm collisionally ionized medium in the temperature range (0.5-1.0) × 106 K. This is the second ever detection of an intervening Ne VIII absorption system. Its properties resemble the previous Ne VIII absorber reported by Savage and colleagues. Direct observations of H I and O VI are needed to better constrain the physical conditions in the collisionally ionized gas phase of this absorber. Based on observations with the NASA-CNES-CSA Far Ultraviolet Spectroscopic Explorer operated by Johns Hopkins University, supported by NASA contract NAS5-32985.

Effectiveness of Mind Mapping in English Teaching among VIII Standard Students

ERIC Educational Resources Information Center

Hallen, D.; Sangeetha, N.

2015-01-01

The aim of the study is to find out the effectiveness of mind mapping technique over conventional method in teaching English at high school level (VIII), in terms of Control and Experimental group. The sample of the study comprised, 60 VIII Standard students in Tiruchendur Taluk. Mind Maps and Achievement Test (Pretest & Posttest) were…

Use of routine histopathology and factor VIII-related antigen/von Willebrand factor immunohistochemistry to differentiate primary hemangiosarcoma of bone from telangiectatic osteosarcoma in 54 dogs.

PubMed

Giuffrida, M A; Bacon, N J; Kamstock, D A

2017-12-01

Hemangiosarcoma (HSA) of bone and telangiectatic osteosarcoma (tOSA) can appear similar histologically, but differ in histogenesis (malignant endothelial cells versus osteoblasts), and may warrant different treatments. Immunohistochemistry (IHC) for endothelial cell marker factor VIII-related antigen/von Willebrand factor (FVIII-RAg/vWF) is a well-documented ancillary test to confirm HSA diagnoses in soft tissues, but its use in osseous HSA is rarely described. Archived samples of 54 primary appendicular bone tumours previously diagnosed as HSA or tOSA were evaluated using combination routine histopathology (RHP) and IHC. Approximately 20% of tumours were reclassified on the basis of FVIII-RAg/vWF immunoreactivity, typically from an original diagnosis of tOSA to a reclassified diagnosis of HSA. No sample with tumour osteoid clearly identified on RHP was immunopositive for FVIII-RAg/vWF. RHP alone was specific but not sensitive for diagnosis of HSA, compared with combination RHP and IHC. Routine histopathological evaluation in combination with FVIII-RAg/vWF IHC can help differentiate canine primary appendicular HSA from tOSA. © 2016 John Wiley & Sons Ltd.

Aceroside VIII is a new natural selective HDAC6 inhibitor that synergistically enhances the anticancer activity of HDAC inhibitor in HT29 cells.

PubMed

Ryu, Hyun-Wook; Lee, Dong-Hun; Shin, Dong-Hee; Kim, Seung Hyun; Kwon, So Hee

2015-02-01

The identification of new isoform-specific histone deacetylase inhibitors is important for revealing the biological functions of individual histone deacetylase and for determining their potential use as therapeutic agents. Among the 11 zinc-dependent histone deacetylases that have been identified in humans, histone deacetylase 6 is a structurally and functionally unique enzyme. Here, we tested the inhibitory activity of diarylheptanoids isolated from Betula platyphylla against histone deacetylase 6. Aceroside VIII selectively inhibited histone deacetylase 6 catalytic activity and the combined treatment of aceroside VIII or (-)-centrolobol with A452, another selective histone deacetylase 6 inhibitor, led to a synergistic increase in levels of acetylated α-tubulin. Aceroside VIII, paltyphyllone, and (-)-centrolobol synergistically enhanced the induction of apoptosis and growth inhibition by A452. Consistent with these results, A452 in combination with aceroside VIII, paltyphyllone, or (-)-centrolobol was more potent than either drug alone for the induction of apoptosis. Together, these findings indicate that aceroside VIII is a specific histone deacetylase 6 inhibitor and points to a mechanism by which natural histone deacetylase 6-selective inhibitors may enhance the efficacy of other histone deacetylase 6 inhibitors in colon cancer cells. Georg Thieme Verlag KG Stuttgart · New York.

Potential supplementary utility of combined PFA-100 and functional von Willebrand factor testing for the laboratory assessment of desmopressin and factor concentrate therapy in von Willebrand disease.

PubMed

Favaloro, Emmanuel J; Thom, Jim; Patterson, David; Just, Sarah; Baccala, Maria; Dixon, Tracy; Meiring, Muriel; Koutts, Jerry; Rowell, John; Baker, Ross

2009-09-01

We performed a retrospective audit of cross-laboratory testing of desmopressin and factor concentrate therapy to assess the potential utility of supplementary testing using the PFA-100 with functional von Willebrand factor (VWF) activity testing. Data were evaluated for a large number of patients with von Willebrand disease of type 1, type 2A or type 2M, as well as a comparative subset of individuals with haemophilia or carriers of haemophilia. Laboratory testing comprised pre and postdesmopressin, or pre and postconcentrate, evaluation of factor VIII, VWF antigen (VWF:Ag) and VWF ristocetin cofactor activity as traditionally performed, supplemented with collagen-binding (VWF:CB) testing and PFA-100 closure times. In brief, both therapies tended to normalize VWF test parameters and closure times in individuals with type 1 von Willebrand disease, with the level of correction in closure times related to the level of normalization of VWF, particularly the VWF:CB. However, although occasional correction of closure times was observed in patients with type 2A or type 2M von Willebrand disease, these did not in general normalize PFA-100 closure times either with desmopressin or factor concentrate therapy. In these patients, improvement in closure times was more likely in those in whom VWF:CB values normalized or when VWF:CB/VWF:Ag ratios normalized. This study confirms that there is a strong relationship between the presenting levels of plasma VWF and PFA-100 closure times, and that the supplementary combination of PFA-100 and VWF:CB testing might provide added clinical utility to current broadly applied testing strategies limited primarily to VWF:Ag, VWF ristocetin cofactor and factor VIII:coagulant. Future prospective investigations are warranted to validate these relationships and to investigate their therapeutic implications.

Factors Associated with the Time of Admission among Notified Dengue Fever Cases in Region VIII Philippines from 2008 to 2014

PubMed Central

Gil Cuesta, Julita; Cerro, Boyd Roderick; Guha-Sapir, Debarati

2016-01-01

In cases of Dengue fever, late hospital admission can lead to treatment delay and even death. In order to improve early disease notification and management, it is essential to investigate the factors affecting the time of admission of Dengue cases. This study determined the factors associated with the time of admission among notified Dengue cases. The study covered the period between 2008 and 2014 in Region VIII, Philippines. The factors assessed were age, sex, hospital sector, hospital level, disease severity based on the 1997 WHO Dengue classification, and period of admission (distinguishing between the 2010 Dengue epidemic and non-epidemic time). We analysed secondary data from the surveillance of notified Dengue cases. We calculated the association through chi-square test, ordinal logistic regression and linear regression at p value < 0.05. The study included 16,357 admitted Dengue cases. The reported cases included a majority of children (70.09%), mild cases of the disease (64.00%), patients from the public sector (69.82%), and non-tertiary hospitals (62.76%). Only 1.40% of cases had a laboratory confirmation. The epidemic period in 2010 comprised 48.68% of all the admitted cases during this period. Late admission was more likely among adults than children (p<0.05). The severe type of the disease was more likely to be admitted late than the mild type (p<0.05). Late admission was also more likely in public hospitals than in private hospitals (p<0.05); and within tertiary level hospitals than non-tertiary hospitals (p<0.05). Late admission was more likely during the non-epidemic period than the 2010 epidemic period (p<0.05). A case fatality rate of 1 or greater was significantly associated with children, severe diseases, tertiary hospitals and public hospitals when admitted late (p<0.05). Data suggests that early admission among child cases was common in Region VIII. This behavior is encouraging, and should be continued. However, further study is needed on the

[Determinants of the elevated factor VIII activity in patients following venous thromboembolism].

PubMed

Lech, Monika; Kościelniak, Barbara; Bryk, Agata; Undas, Anetta

2016-01-01

Activity of factor VIII (FVIII) increased above 150% of reference range predisposes to venous thromboembolism (VTE). The aim of this study was to identify predictors of increased FVIII activity in patients following VTE. 241 (38% men) patients presented due to objectively documented VTE episode at least 3 months ago were included in this study. FVIII activity was measured using a clotting assay on the analyzer BCS XP. Among 241 patients with VTE, activity of FVIII above 150% (FVIII ≥ 150%) was observed in 96 (40%). These patients were older (p = 0.035) and their concentrations of fibrinogen and C-reactive protein (CRP) were higher by 12% and 88% (p < 0.001), respectively, compared with other patients. There was a positive correlation between FVIII and fibrinogen (r = 0.34; p < 0.001), FVIII and CRP (r = 0.30; p < 0.001). Type of treatment, time from the VTE episode and type of VTE were not associated with FVIII. Twenty patients (8%) had activity of FVIII increased above 200% (FVIII > 200%) and this group was also older (p = 0.015), more patients in that group had obesity (p = 0.015), idiopathic VTE (p = 0.043), less of them had positive family history (p = 0.010) and they were characterized by fibrinogen and CRP increased by 28% (p < 0.001) and 102% (p = 0.004), respectively, compared with patients with FVIII between 150-200%. Independent predictors of FVIII ≥ 150% were: fibrinogen (p < 0.001), bilirubin (p = 0.002), hemoglobin (p = 0.016), glucose (p = 0.040), CRP (p = 0.023), total homocysteine (p = 0.032). Fibrinogen was the only independent predictor of FVIII > 200% (p = 0.016). The activity of FVIII in patients after VTE episode is influenced by age, concentration of fibrinogen, bilirubin, hemoglobin, glucose, CRP and homocysteine. Our results suggest the role of environmental factors, mainly inflammatory response in maintaining elevated FVIII activity following VTE.

Functional assembly of intrinsic coagulation proteases on monocytes and platelets. Comparison between cofactor activities induced by thrombin and factor Xa

PubMed Central

1992-01-01

Generation of coagulation factor Xa by the intrinsic pathway protease complex is essential for normal activation of the coagulation cascade in vivo. Monocytes and platelets provide membrane sites for assembly of components of this protease complex, factors IXa and VIII. Under biologically relevant conditions, expression of functional activity by this complex is associated with activation of factor VIII to VIIIa. In the present studies, autocatalytic regulatory pathways operating on monocyte and platelet membranes were investigated by comparing the cofactor function of thrombin-activated factor VIII to that of factor Xa-activated factor VIII. Reciprocal functional titrations with purified human factor VIII and factor IXa were performed at fixed concentrations of human monocytes, CaCl2, factor X, and either factor IXa or factor VIII. Factor VIII was preactivated with either thrombin or factor Xa, and reactions were initiated by addition of factor X. Rates of factor X activation were measured using chromogenic substrate specific for factor Xa. The K1/2 values, i.e., concentration of factor VIIIa at which rates were half maximal, were 0.96 nM with thrombin- activated factor VIII and 1.1 nM with factor Xa-activated factor VIII. These values are close to factor VIII concentration in plasma. The Vsat, i.e., rates at saturating concentrations of factor VIII, were 33.3 and 13.6 nM factor Xa/min, respectively. The K1/2 and Vsat values obtained in titrations with factor IXa were not significantly different from those obtained with factor VIII. In titrations with factor X, the values of Michaelis-Menten coefficients (Km) were 31.7 nM with thrombin- activated factor VIII, and 14.2 nM with factor Xa-activated factor VIII. Maximal rates were 23.4 and 4.9 nM factor Xa/min, respectively. The apparent catalytic efficiency was similar with either form of factor VIIIa. Kinetic profiles obtained with platelets as a source of membrane were comparable to those obtained with monocytes

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.

40 CFR Appendix Viii to Part 86 - Aging Bench Equipment and Procedures

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 19 2014-07-01 2014-07-01 false Aging Bench Equipment and Procedures.... VIII Appendix VIII to Part 86—Aging Bench Equipment and Procedures This appendix provides specifications for standard aging bench equipment and aging procedures which may be used to conduct bench aging...

A post-marketing safety and efficacy assessment of a monoclonal antibody purified high-purity factor VIII concentrate.

PubMed

Hay, C R; Lee, C A; Savidge, G

1996-01-01

The identification of infrequent side-effects of clotting factor concentrates, undetected by clinical trials, is facilitated by post-marketing surveillance. We present a post-marketing surveillance study in which 97 patients with haemophilia A, attending three haemophilia centres, were treated over a median follow-up period of 284 days (range 1-1074), and a total follow-up period of 30,080 days, with a pasteurized immunoaffinity purified factor VIII concentrate (Monoclate-P, Armour, Collegeville, USA). 5216 infusions, using 10,527,000 units of Monoclate-P, were carried out, mostly for routine haemarthroses or prophylaxis. No new inhibitors were observed during the study. At the start of the study 60/97 were HIV seropositive, 67/97 HBs antibody positive, 12 HbsAb negative and the remainder HBsAb positive before the study period. 13/14 tested were HAV seropositive at the beginning of the study. One patient became HAV seropositive during the study period, an infection thought to be community acquired. No other seroconversions were observed. Only one mild transfusion reaction was observed. This study confirms the safety and efficacy of Monoclate-P. Post-marketing surveillance or nationally organized pharmaco-vigilance should be practiced more widely to enable identification of low-frequency side-effects of treatment.

40 CFR Appendix Viii to Part 86 - Aging Bench Equipment and Procedures

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 20 2013-07-01 2013-07-01 false Aging Bench Equipment and Procedures.... 86, App. VIII Appendix VIII to Part 86—Aging Bench Equipment and Procedures This appendix provides specifications for standard aging bench equipment and aging procedures which may be used to conduct bench aging...

40 CFR Appendix Viii to Part 86 - Aging Bench Equipment and Procedures

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 20 2012-07-01 2012-07-01 false Aging Bench Equipment and Procedures.... 86, App. VIII Appendix VIII to Part 86—Aging Bench Equipment and Procedures This appendix provides specifications for standard aging bench equipment and aging procedures which may be used to conduct bench aging...

Pregnancy and delivery in women with von Willebrand's disease and different von Willebrand factor mutations.

PubMed

Castaman, Giancarlo; Tosetto, Alberto; Rodeghiero, Francesco

2010-06-01

Pregnancy in von Willebrand's disease may carry a significant risk of bleeding. Information on changes in factor VIII and von Willebrand factor and pregnancy outcome in relation to von Willebrand factor gene mutations are very scanty. We examined biological response to desmopressin, changes in factor VIII and von Willebrand factor and pregnancy outcome in a cohort of 23 women with von Willebrand's disease characterized at molecular level and prospectively followed during 2000-2007. Thirty-one pregnancies occurred during the study period. Remarkably, similar changes of factor VIII and von Willebrand factor were observed after desmopressin and during pregnancy in nine women with R854Q, R1374H, V1665E, V1822G and C2362F mutations. Women with von Willebrand's disease and R1205H and C1130F mutations (17 pregnancies in 12 women) had only a slight increase of factor VIII and von Willebrand factor during pregnancy while their response to desmopressin was marked but short-lived. For these women, two to three desmopressin administrations within the first 48 hours were sufficient to successfully manage vaginal delivery. Two women with recessive von Willebrand's disease due to compound heterozygosity for different gene mutations had a spontaneous, major increase in factor VIII while von Willebrand factor remained severely reduced. Desmopressin increased factor VIII and was clinically useful in the first case, while a factor VIII/von Willebrand factor concentrate was required in the second patient not responsive to the compound. Factor VIII/von Willebrand factor concentrate was also required for two women with type 2 A von Willebrand's disease with V1665E mutations who had no von Willebrand factor activity change during pregnancy. In one of them, delayed bleeding occurred 15 days later requiring treatment with Factor VIII/von Willebrand factor concentrate. No miscarriages or stillbirths occurred. Close follow-up and detailed guidelines for the management of parturition have

Factor VIII, Protein C and Cardiovascular Disease Risk: The REasons for Geographic and Racial Differences in Stroke Study (REGARDS).

PubMed

Zakai, Neil A; Judd, Suzanne E; Kissela, Brett; Howard, George; Safford, Monika M; Cushman, Mary

2018-06-11

 Haemostatic balance represented by low protein C (PC) and elevated factor VIII (FVIII) has been inconsistently associated with stroke and coronary heart disease (CHD) risk.  This article assesses whether an elevated FVIII and a low PC would increase cardiovascular risk more than either individually.  REGARDS recruited 30,239 black and white U.S. participants aged ≥ 45 years between 2003 and 2007. FVIII and PC were measured in a case-cohort sample of 646 stroke, 654 CHD, and a 1,104-person random sample with follow-up for approximately 4.5 years. Hazard ratios (HRs) were estimated using Cox models adjusted for demographic and cardiovascular risk factors.  Elevated FVIII (per standard deviation [SD] increase) was associated with increased risk of both stroke (HR, 1.26; 95% confidence interval [CI], 1.08, 1.46) and CHD (HR, 1.52; 95% CI, 1.29, 1.79), while there was no association of PC per SD decrease. For PC, there was a trend towards increased cardiovascular disease risk in the lowest values (bottom 5%). For stroke, there was no interaction between FVIII and low PC ( p interaction  = 0.55). For CHD, the adjusted HR of FVIII per SD increase was significantly greater with PC in the bottom 5% (HR, 3.59; 95% CI, 1.39, 8.29) than PC in the upper 95% (HR, 1.45; 95% CI, 1.23, 1.71; p interaction  = 0.07).  Higher FVIII was associated with both CHD and stroke risk and the risk potentiated by low PC for CHD. Findings demonstrate that risks for cardiovascular diseases conferred by adverse levels of haemostasis biomarkers may be augmented by levels of other biomarkers. Schattauer GmbH Stuttgart.

Stabilization of a human recombinant factor VIII by poloxamer 188 in relation to polysorbate 80.

PubMed

Clark, Jakson; Montgomery, Jade; Squires, Ryan; McGuire, Joseph

2016-03-01

Detection of enhanced surface tension depression by surfactant in the presence of protein was recently suggested as a basis for determining whether protein stabilization by that surfactant is owing to surfactant forming a steric barrier at interfaces or surfactant association with the protein. In particular, protein interaction with surfactant aggregates may lead to an increased concentration of monomers thus enhancing surfactant adsorption, or to formation of surfactant-protein complexes having little or no effect on adsorption. We compared the initial rates of surface tension depression by poloxamer 188 and polysorbate 80 (PS 80) in the presence and absence of a human recombinant factor VIII (rFVIII). Indirect evidence had suggested poloxamer 188 enters into stable associations with rFVIII in solution but does not form a steric barrier at the interface, while PS 80 behaves in contrary fashion. In this study, we show the presence of rFVIII caused an increase in the rate (reduction in the activation energy) of PS 80 adsorption, while no such change was recorded in the case of poloxamer 188. Thus, we provide substantiation for detection of protein-mediated acceleration of surfactant adsorption as a means to compare different surfactants in relation to their favored mechanism for protein stabilization.

VIII Olimpíada Brasileira de Astronomia e Astronáutica

NASA Astrophysics Data System (ADS)

Garcia Canalle, João Batista; Villas da Rocha, Jaime Fernando; Wuensche de Souza, Carlos Alexandre; Pereira Ortiz, Roberto; Aguilera, Nuricel Villalonga; Padilha, Maria De Fátima Catta Preta; Pessoa Filho, José Bezerra; Soares Rodrigues, Ivette Maria

2007-07-01

Neste trabalho apresentamos as motivações pelas quais organizamos, em conjunto, pela primeira vez, a Olimpíada Brasileira de Astronomia incluindo a Astronáutica, em colaboração com a Agência Espacial Brasileira. Esta ampliação contribuiu para atrair ainda mais alunos, professores, escolas e patrocinadores para participarem desta Olimpíada. Em 2005 participaram da VIII Olimpíada Brasileira de Astronomia e Astronáutica (VIII OBA) 187.726 alunos distribuídos por 3.229 escolas, pertencentes a todos os estados brasileiros, incluindo o Distrito Federal. O crescimento em número de alunos participantes foi 52,4% maior do que em 2004. Em abril de 2005 organizamos, em Itapecerica da Serra, SP, um curso para os 50 alunos previamente selecionados e participantes da VII OBA e ao final selecionamos, dentre eles, uma equipe de 5 alunos, os quais representaram o Brasil na X Olimpíada Internacional de Astronomia, na China, em outubro de 2005. Ganhamos, pela primeira vez, uma medalha de ouro naquele evento. Em Agosto de 2005, organizamos a VIII Escola de Agosto para 50 alunos e respectivos professores, em Águas de Lindóia, SP, juntamente com a XXXI reunião anual da Sociedade Astronômica Brasileira (SAB). Em novembro de 2005 realizamos a I Jornada Espacial, em São José dos Campos, com 22 alunos e 22 professores selecionados dentre os participantes que melhores resultados obtiveram nas questões de Astronáutica da VIII OBA. Neste trabalho detalhamos os resultados da VIII OBA bem como as ações subseqüentes.

40 CFR Appendix Viii to Part 85 - Vehicle and Engine Parameters and Specifications

Code of Federal Regulations, 2014 CFR

2014-07-01

...) AIR PROGRAMS (CONTINUED) CONTROL OF AIR POLLUTION FROM MOBILE SOURCES Pt. 85, App. VIII Appendix VIII.... Air Inlet System. 1. Temperature control system calibration. IV. Fuel System. 1. General. a. Engine idle speed. b. Engine idle mixture. 2. Carburetion. a. Air-fuel flow calibration. b. Transient...

40 CFR Appendix Viii to Part 85 - Vehicle and Engine Parameters and Specifications

Code of Federal Regulations, 2013 CFR

2013-07-01

...) AIR PROGRAMS (CONTINUED) CONTROL OF AIR POLLUTION FROM MOBILE SOURCES Pt. 85, App. VIII Appendix VIII.... Air Inlet System. 1. Temperature control system calibration. IV. Fuel System. 1. General. a. Engine idle speed. b. Engine idle mixture. 2. Carburetion. a. Air-fuel flow calibration. b. Transient...

40 CFR Appendix Viii to Part 85 - Vehicle and Engine Parameters and Specifications

Code of Federal Regulations, 2012 CFR

2012-07-01

...) AIR PROGRAMS (CONTINUED) CONTROL OF AIR POLLUTION FROM MOBILE SOURCES Pt. 85, App. VIII Appendix VIII.... Air Inlet System. 1. Temperature control system calibration. IV. Fuel System. 1. General. a. Engine idle speed. b. Engine idle mixture. 2. Carburetion. a. Air-fuel flow calibration. b. Transient...

Cost-effectiveness analysis of alternative factor VIII products in treatment of haemophilia A.

PubMed

Hay, J W; Ernst, R L; Kessler, C M

1999-05-01

Manufactured factor VIII (FVIII) concentrates of varying purity are available for managing patients with haemophilia A. This study is a cost-effectiveness analysis of ultra-high purity and recombinant (UHP/R) FVIII products relative to intermediate and very-high purity (IP/VHP) preparations. Because the societal (including research and development) costs of FVIII products are unknown and product prices vary with market conditions, we conducted the analysis with treatment cost as a variable quantity. We estimated the largest price premium that could be paid for a UHP/R concentrate relative to an IP/VHP concentrate such that the UHP/R product is the more cost-effective preparation. In the analysis haemophilic patients were assumed to be seropositive for human immunodeficiency virus, seropositive for hepatitis C (HCV), or at risk for seroconversion of hepatitis A (HAV) or hepatitis B (HBV). The results showed that the maximum cost-effective UHP/R price premium is essentially zero if the patient is only at risk of HAV or HBV infection, positive but small for the base-case HCV+ patient, and positive and large for the base-case HIV+ patient having a short life expectancy. Thus UHP/R preparations are not uniformly more cost-effective than IP/VHP products across the spectrum of haemophilic patients' health problems, and the relative cost-effectiveness of the two classes of prepared FVIII products is sensitive to product prices. The methodology employed here can be used in other circumstances where multiple treatments exist for illnesses for which there are significant multiple comorbidities or health risks.

Clot stability as a determinant of effective factor VIII replacement in hemophilia A.

PubMed

Leong, L; Chernysh, I N; Xu, Y; Sim, D; Nagaswami, C; de Lange, Z; Kosolapova, S; Cuker, A; Kauser, K; Weisel, J W

2017-10-01

Factor VIII (FVIII) replacement is standard of care for patients with hemophilia A (HemA); however, patient response does not always correlate with FVIII levels. We hypothesize this may be in part due to the physical properties of clots and contributions of fibrin, platelets, and erythrocytes, which may be important for hemostasis. To understand how FVIII contributes to effective hemostasis in terms of clot structure and mechanical properties. In vitro HemA clots in human plasma or whole blood were analyzed using turbidity waveform analysis, confocal microscopy, and rheometry with or without added FVIII. In vivo clots from saphenous vein puncture in wild-type and HemA mice with varying FVIII levels were examined using scanning electron microscopy. FVIII profoundly affected HemA clot structure and physical properties; added FVIII converted the open and porous fibrin meshwork and low stiffness of HemA clots to a highly branched and dense meshwork with higher stiffness. Platelets and erythrocytes incorporated into clots modulated clot properties. The clots formed in the mouse saphenous vein model contained variable amounts of compressed erythrocytes (polyhedrocytes), fibrin, and platelets depending on the levels of FVIII, correlating with bleeding times. FVIII effects on clot characteristics were dose-dependent and reached a maximum at ~25% FVIII, such that HemA clots formed with this level of FVIII resembled clots from unaffected controls. Effective clot formation can be achieved in HemA by replacement therapy, which alters the architecture of the fibrin network and associated cells, thus increasing clot stiffness and decreasing clot permeability.

The vestibulocochlear nerve (VIII).

PubMed

Benoudiba, F; Toulgoat, F; Sarrazin, J-L

2013-10-01

The vestibulocochlear nerve (8th cranial nerve) is a sensory nerve. It is made up of two nerves, the cochlear, which transmits sound and the vestibular which controls balance. It is an intracranial nerve which runs from the sensory receptors in the internal ear to the brain stem nuclei and finally to the auditory areas: the post-central gyrus and superior temporal auditory cortex. The most common lesions responsible for damage to VIII are vestibular Schwannomas. This report reviews the anatomy and various investigations of the nerve. Copyright © 2013. Published by Elsevier Masson SAS.

Biochemical and functional characterization of a recombinant monomeric factor VIII-Fc fusion protein.

PubMed

Peters, R T; Toby, G; Lu, Q; Liu, T; Kulman, J D; Low, S C; Bitonti, A J; Pierce, G F

2013-01-01

Hemophilia A results from a deficiency in factor VIII activity. Current treatment regimens require frequent dosing, owing to the short half-life of FVIII. A recombinant FVIII-Fc fusion protein (rFVIIIFc) was molecularly engineered to increase the half-life of FVIII, by 1.5-2-fold, in several preclinical animal models and humans. To perform a biochemical and functional in vitro characterization of rFVIIIFc, with existing FVIII products as comparators.  rFVIIIFc was examined by utilizing a series of structural and analytic assays, including mass spectrometry following lysyl endopeptidase or thrombin digestion. rFVIIIFc activity was determined in both one-stage clotting (activated partial thromboplastin time) and chromogenic activity assays, in the context of the FXase complex with purified components, and in both in vitro and ex vivo rotational thromboelastometry (ROTEM) assays performed in whole blood.  rFVIIIFc contained the predicted primary structure and post-translational modifications, with an FVIII moiety that was similar to other recombinant FVIII products. The von Willebrand factor-binding and specific activity of rFVIIIFc were also found to be similar to those of other recombinant FVIII molecules. Both chromogenic and one-stage assays of rFVIIIFc gave similar results. Ex vivo ROTEM studies demonstrated that circulating rFVIIIFc activity was prolonged in mice with hemophilia A in comparison with B-domain-deleted or full-length FVIII. Clot parameters at early time points were similar to those for FVIII, whereas rFVIIIFc showed prolonged improvement of clot formation.  rFVIIIFc maintains normal FVIII interactions with other proteins necessary for its activity, with prolonged in vivo activity, owing to fusion with the Fc region of IgG(1) . © 2012 International Society on Thrombosis and Haemostasis.

Pharmacokinetic properties of BAY 81-8973, a full-length recombinant factor VIII.

PubMed

Shah, A; Delesen, H; Garger, S; Lalezari, S

2015-11-01

BAY 81-8973 is a full-length recombinant factor VIII (FVIII) with the same primary amino acid sequence as sucrose-formulated recombinant FVIII (rFVIII-FS) but is produced with advanced manufacturing technologies. To analyse the pharmacokinetics (PK) of BAY 81-8973 after single and multiple dosing across different age and ethnic groups in the LEOPOLD clinical trial programme. The LEOPOLD trials enrolled patients with severe haemophilia A aged 12-65 years (LEOPOLD I and II) or ≤12 years (LEOPOLD Kids) with ≥150 (LEOPOLD I and II) or ≥50 (LEOPOLD Kids) exposure days to any FVIII product and no history of FVIII inhibitors. PK were assessed using chromogenic and one-stage assays (only chromogenic assay for LEOPOLD Kids) after a single 50-IU kg(-1) dose of BAY 81-8973 and, in a subset of patients in LEOPOLD I, after repeated dosing. Pharmacokinetic analyses were also performed based on age (18 to 65, 12 to <18, 6 to <12 and <6 years) and ethnicity (Asian and non-Asian). Pharmacokinetic assessments in the LEOPOLD I trial showed non-inferiority of BAY 81-8973 vs. rFVIII-FS. The PK of BAY 81-8973 were comparable after single and multiple dosing. Age-based analysis in the three trials showed that plasma concentrations were slightly lower for children, but similar for adolescents compared with adults. Pharmacokinetic results were similar in the different ethnic groups. Results of the LEOPOLD trials show that the BAY 81-8973 pharmacokinetic profile is non-inferior to rFVIII-FS. Similar BAY 81-8973 pharmacokinetic values were observed following single and repeated dosing and across ethnic groups. © 2015 John Wiley & Sons Ltd.

Common and rare von Willebrand factor (VWF) coding variants, VWF levels, and factor VIII levels in African Americans: the NHLBI Exome Sequencing Project.

PubMed

Johnsen, Jill M; Auer, Paul L; Morrison, Alanna C; Jiao, Shuo; Wei, Peng; Haessler, Jeffrey; Fox, Keolu; McGee, Sean R; Smith, Joshua D; Carlson, Christopher S; Smith, Nicholas; Boerwinkle, Eric; Kooperberg, Charles; Nickerson, Deborah A; Rich, Stephen S; Green, David; Peters, Ulrike; Cushman, Mary; Reiner, Alex P

2013-07-25

Several rare European von Willebrand disease missense variants of VWF (including p.Arg2185Gln and p.His817Gln) were recently reported to be common in apparently healthy African Americans (AAs). Using data from the NHLBI Exome Sequencing Project, we assessed the association of these and other VWF coding variants with von Willebrand factor (VWF) and factor VIII (FVIII) levels in 4468 AAs. Of 30 nonsynonymous VWF variants, 6 were significantly and independently associated (P < .001) with levels of VWF and/or FVIII. Each additional copy of the common VWF variants encoding p.Thr789Ala or p.Asp1472His was associated with 6 to 8 IU/dL higher VWF levels. The VWF variant encoding p.Arg2185Gln was associated with 7 to 13 IU/dL lower VWF and FVIII levels. The type 2N-related VWF variant encoding p.His817Gln was associated with 17 IU/dL lower FVIII level but normal VWF level. A novel, rare missense VWF variant that predicts disruption of an O-glycosylation site (p.Ser1486Leu) and a rare variant encoding p.Arg2287Trp were each associated with 30 to 40 IU/dL lower VWF level (P < .001). In summary, several common and rare VWF missense variants contribute to phenotypic differences in VWF and FVIII among AAs.

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

PubMed Central

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

2015-01-01

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

Impact of being overweight on factor VIII dosing in children with haemophilia A.

PubMed

Henrard, S; Hermans, C

2016-05-01

Treatment of haemophilia A (HA) requires infusions of factor VIII (FVIII) concentrates. The number of FVIII units infused to obtain a specific circulating FVIII level is calculated with the formula: [body weight (BW) (kg) × desired FVIII increase (%)]/2, with the assumption that each unit of FVIII infused per kg of BW increases the circulating FVIII level by 2%. The aim of this study was to evaluate the impact of several morphometric parameters (BW, body mass index (BMI)-for-age, height), age and type of FVIII concentrate on FVIII recovery in children with HA. A total of 66 children aged between 10 and 18 with severe HA selected from six pharmacokinetic (PK) clinical trials using two recombinant FVIII concentrates were included in the analysis. Regression tree (RT) was used to identify predictors of FVIII recovery. The median age was 14.5 years with a median FVIII recovery of 2.09 for all children. The median FVIII recovery was not significantly different between age groups. Two groups were created by RT: children with a BMI-for-age percentile

Frequencies of VNTR and RFLP polymorphisms associated with factor VIII gene in Singapore

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

Fong, I.; Lai, P.S.; Ouah, T.C.

1994-09-01

The allelic frequency of any polymorphism within a population determines its usefulness for genetic counselling. This is important in populations of non-Caucasian origin as RFLPs may significantly differ among ethnic groups. We report a study of five intragenic polymorphisms in factor VIII gene carried out in Singapore. The three PCR-based RFLP markers studied were Intron 18/Bcl I, Intron 19/Hind III and Intron 22/Xba I. In an analysis of 148 unrelated normal X chromosomes, the allele frequencies were found to be A1 = 0.18, A2 = 0.82 (Bcl I RFLP), A1 = 0.80, A2 = 0.20 (Hind III RFLP) and A1more » = 0.58, and A2 = 0.42 (Xba I RFLP). The heterozygosity rates of 74 females analyzed separately were 31%, 32% and 84.2%, respectively. Linkage disequilibrium was also observed to some degree between Bcl I and Hind III polymorphism in our population. We have also analyzed a sequence polymorphism in Intron 7 using hybridization with radioactive-labelled {sup 32}P allele-specific oligonucleotide probes. This polymorphism was not very polymorphic in our population with only 2% of 117 individuals analyzed being informative. However, the use of a hypervariable dinucleotide repeat sequence (VNTR) in Intron 13 showed that 25 of our of 27 (93%) females were heterozygous. Allele frequencies ranged from 1 to 55 %. We conclude that a viable strategy for molecular analysis of Hemophilia A families in our population should include the use of Intron 18/Bcl I and Intron 22/Xba I RFLP markers and the Intron 13 VNTR marker.« less

Henry VIII, McLeod syndrome and Jacquetta's curse.

PubMed

Stride, P; Lopes Floro, K

2013-01-01

The mental decline of King Henry VIII from being a jovial, charismatic and athletic young man into an increasingly paranoid, brutal tyrant in later life, ever more concerned at his lack of one or more male heirs, has attracted many medical diagnostic theories. Previous hypotheses have included diabetes, syphilis and hypothyroidism, among others. However, these inadequately explain Henry's failure to produce a male heir, despite multiple pairings. The latest postulated diagnoses for Henry are the coexistence of both Kell blood group antigenicity (possibly inherited from Jacquetta Woodville, Henry's maternal great grandmother) causing related impaired fertility, and McLeod syndrome, causing psychotic changes. As the mutated McLeod protein of the syndrome significantly reduces the expression, effectively inactivating the Kell antigen, we critically review this theory, examining in detail the pathophysiology of these conditions and assessing the genealogy of Henry VIII and its effect in subsequent generations.

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

PubMed

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

2016-05-01

Essentials Factor VIII (FVIII) binding IgG detected by ELISA could be an alternative to the Bethesda assay. We studied the performance of anti-FVIII IgG ELISA in patients with acquired hemophilia and controls. Anti-FVIII IgG > 99th percentile of controls was highly sensitive and specific. Patients with high anti-FVIII IgG have a lower chance of achieving remission. Background Acquired hemophilia A is a severe bleeding disorder that requires fast and accurate diagnosis as it occurs often unexpectedly in previously healthy men and women of every age. The Nijmegen-modified Bethesda assay is the diagnostic reference standard for detecting neutralizing autoantibodies against factor VIII (FVIII), but is not widely available, not ideal for quantifying the complex type 2 inhibitors seen in acquired hemophilia, and suffers from high inter-laboratory variability. Objectives To assess the diagnostic and prognostic value of FVIII-binding antibodies as detected by ELISA compared with the Nijmegen Bethesda assay. Methods Samples from the time of first diagnosis and clinical data were available from 102 patients with acquired hemophilia enrolled in the prospective GTH-AH 01/2010 study. Controls (n = 102) were matched for gender and age. Diagnostic cut-offs were determined by receiver-operator curve analysis. The prognostic value was assessed in 92 of the 102 patients by Cox regression analysis of time to partial remission. Results Anti-FVIII IgG above the 99th percentile (> 15 arbitrary units per mL) revealed high sensitivity and specificity (both 0.99; 95% confidence interval, 0.95-1.0) for diagnosing acquired hemophilia. The likelihood of achieving partial remission was related to anti-FVIII IgG concentration (< 300 arbitrary units, 1.0; 300-1050, 0.65; > 1050, 0.39). The Bethesda titer was only associated with the likelihood of partial remission when analyzed in the central laboratory, but not when data from local GTH study sites were used. Conclusion Although the Nijmegen

Structural characterization of the novel aminoglycoside phosphotransferase AphVIII from Streptomyces rimosus with enzymatic activity modulated by phosphorylation

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

Boyko, Konstantin M., E-mail: kmb@inbi.ras.ru; National Research Center “Kurchatov Institute”, Kurchatov Complex of NBICS-technologies, Akad. Kurchatova sqr., 1, Moscow, 123182; Gorbacheva, Marina A.

2016-09-02

Aminoglycoside phosphotransferases represent a broad class of enzymes that promote bacterial resistance to aminoglycoside antibiotics via the phosphorylation of hydroxyl groups in the latter. Here we report the spatial structure of the 3′-aminoglycoside phosphotransferase of novel VIII class (AphVIII) solved by X-ray diffraction method with a resolution of 2.15 Å. Deep analysis of APHVIII structure and its comparison with known structures of aminoglycoside phosphotransferases of various types reveals that AphVIII has a typical two-domain fold and, however, possesses some unique characteristics that distinguish the enzyme from its known homologues. The most important difference is the presence of the activation loop withmore » unique Ser146 residue. We demonstrate that in the apo-state of the enzyme the activation loop does not interact with other parts of the enzyme and seems to adopt catalytically competent state only after substrate binding. - Highlights: • 3D structure of the novel aminoglycoside phosphotransferase AphVIII was obtained. • AphVIII activation loop is clearly identified in the electron density. • AphVIII has some unique structural features in its substrate C-ring binding pocket.« less

Thromboelastography during coronary artery bypass grafting surgery of severe hemophilia A patient - the effect of heparin and protamine on factor VIII activity.

PubMed

Misgav, Mudi; Mandelbaum, Tal; Kassif, Yigal; Berkenstadt, Haim; Tamarin, Ilia; Kenet, Gili

2017-06-01

: Coronary artery bypass grafting surgery (CABG) in hemophilia patients is challenging. Thromboelastography (TEG) is useful to assess hemostasis perioperatively. A patient with severe hemophilia A underwent CABG with TEG studies. After factor VIII (FVIII) bolus dose, TEG was normalized. Following 'on-pump' heparinization, protamine administration revealed prolonged TEG-R and TEG-R with heparinase confirming it, whereas the activated clotting time was normal, suggesting low FVIII activity rather than excess of heparin. Another FVIII bolus yielded complete normalization of all TEG parameters. Data are compatible with in-vitro assays performed in our laboratory, showing that both heparin and protamine may impair measurable FVIII activity. The rational use of TEG measurements enabled more accurate hemostatic therapy application with regard to FVIII, heparin and protamine administration. Adopting this approach may lead to a better therapy tailoring for hemophilia patients undergoing CABG surgery.

Ehlers–Danlos syndrome type VIII is clinically heterogeneous disorder associated primarily with periodontal disease, and variable connective tissue features

PubMed Central

Reinstein, Eyal; DeLozier, Celia Dawn; Simon, Ziv; Bannykh, Serguei; Rimoin, David L; Curry, Cynthia J

2013-01-01

Ehlers–Danlos syndrome (EDS) type VIII (periodontitis type) is a distinct form of EDS characterized by periodontal disease leading to precocious dental loss and a spectrum of joint and skin manifestations. EDS type VIII is transmitted in an autosomal dominant pattern; however, the mutated gene has not been identified. There are insufficient data on the spectrum of clinical manifestations and natural history of the disorder, and only a limited number of patients and pedigrees with this condition have been reported. We present a four-generation EDS type VIII kindred and show that EDS VIII is clinically variable and although some cases lack the associated skin and joint manifestations, microscopic evidence of collagen disorganization is detectable. We further propose that the diagnosis of EDS type VIII should be considered in familial forms of periodontitis, even when the associated skin and joint manifestations are unconvincing for the diagnosis of a connective tissue disorder. This novel observation highlights the uncertainty of using connective tissue signs in clinical practice to diagnose EDS type VIII. PMID:22739343

Metabolic aspects and viability of heparin/CPDA-1-stored red cell concentrate as a by-product of a high-yield factor VIII production method.

PubMed

de Jonge, J; Smit Sibinga, C T; Das, P C

1983-01-01

As a by-product of a new high-yield method of production of freeze-dried factor VIII, red cell concentrate (RCC) containing a small amount of heparin besides CPDA-1 was studied. Compared to CPDA-1 stored RCC no difference was found in hematology parameters and 2,3-DPG levels during 28 days storage. Although still in the normal range for transfusion, ATP levels were significantly lower compared to CPDA-1-stored RCC after 30 days shelf life. A survival study with 51Cr-labelled red cells showed good recovery and normal red cell half-life. Rapid transfusion of heparin/CPDA-1 RCC in 6 volunteers did not have any effect on aPTT. Heparin could not be detected in posttransfusion plasma samples.

Coagulation Factor Tests

MedlinePlus

... your coagulation factors. Coagulation factors are known by Roman numerals (I, II VIII, etc.) or by name ( ... need this test if you have a family history of bleeding disorders. Most bleeding disorders are inherited . ...

Novel repair activities of AlkA (3-methyladenine DNA glycosylase II) and endonuclease VIII for xanthine and oxanine, guanine lesions induced by nitric oxide and nitrous acid

PubMed Central

Terato, Hiroaki; Masaoka, Aya; Asagoshi, Kenjiro; Honsho, Akiko; Ohyama, Yoshihiko; Suzuki, Toshinori; Yamada, Masaki; Makino, Keisuke; Yamamoto, Kazuo; Ide, Hiroshi

2002-01-01

Nitrosation of guanine in DNA by nitrogen oxides such as nitric oxide (NO) and nitrous acid leads to formation of xanthine (Xan) and oxanine (Oxa), potentially cytotoxic and mutagenic lesions. In the present study, we have examined the repair capacity of DNA N-glycosylases from Escherichia coli for Xan and Oxa. The nicking assay with the defined substrates containing Xan and Oxa revealed that AlkA [in combination with endonuclease (Endo) IV] and Endo VIII recognized Xan in the tested enzymes. The activity (Vmax/Km) of AlkA for Xan was 5-fold lower than that for 7-methylguanine, and that of Endo VIII was 50-fold lower than that for thymine glycol. The activity of AlkA and Endo VIII for Xan was further substantiated by the release of [3H]Xan from the substrate. The treatment of E.coli with N-methyl-N′-nitro-N-nitrosoguanidine increased the Xan-excising activity in the cell extract from alkA+ but not alkA– strains. The alkA and nei (the Endo VIII gene) double mutant, but not the single mutants, exhibited increased sensitivity to nitrous acid relative to the wild type strain. AlkA and Endo VIII also exhibited excision activity for Oxa, but the activity was much lower than that for Xan. PMID:12434002

D-dimer, factor VIII and von Willebrand factor predict a non-dipping pattern of blood pressure in hypertensive patients.

PubMed

Agorasti, Athanasia; Trivellas, Theodoros; Mourvati, Efthimia; Papadopoulos, Vasilios; Tsatalas, Konstantinos; Vargemezis, Vasilios; Passadakis, Ploumis

2013-06-01

The aim of this study is to assess whether the haemostatic markers D-dimer, factor VIII (FVIII) and von Willebrand factor (VWF) are predictive of non-dipping status in treated hypertensive patients; so, as easy available laboratory data can predict non-dipping pattern and help with the selection of the patients whom circadian blood pressure should be re-examined. Forty treated hypertensive patients with essential hypertension were included in the study. Twenty-four-hour ambulatory blood pressure monitoring was performed in all patients. Daytime and nocturnal average systolic, diastolic and mean blood pressures were calculated. Patients were characterised as "non-dippers" on the basis of a less than 10 % decline in nocturnal blood pressure (BP); either systolic or diastolic or mean (MAP). D-dimer as marker of fibrinolytic function, FVIII activity and VWF antigen as marker of endothelial dysfunction were measured on plasma. The predictive efficiency was analysed by receiver operating characteristic (ROC) curves. Youden index was used for the estimation of the cut-off points and the associated values for sensitivity and 1-specificity. Plasma levels of D-dimer, FVIII and VWF were significantly higher in non-dippers as compared with dippers, irrespective of the classification used (BP index); all P < 0.05. The ROC curves indicated a good diagnostic efficiency for D-dimer (AUC(ROC) = 0.697, 0.715 and 0.774), FVIII (AUC(ROC) = 0.714, 0.692 and 0.755) and VWF (AUC(ROC) = 0.706, 0.740 and 0.708) in distinguishing non-dipping pattern (systolic, diastolic or mean) in the study population; all P < 0.05. Among the three haemostatic markers, D-dimer presents the most satisfactory sensitivity/1-specificity for the differentiation of non-dippers, with a cut-off point >168 ng/ml (sensitivity/1-specificity for systolic BP non-dippers of 0.789/0.381, for diastolic BP non-dippers 0.923/0.444 and for MAP non-dippers 0.875/0.375). In conclusion, D-dimer has a good predictive value for

Recombinant factor VIIa (eptacog alfa): a pharmacoeconomic review of its use in haemophilia in patients with inhibitors to clotting factors VIII or IX.

PubMed

Lyseng-Williamson, Katherine A; Plosker, Greg L

2007-01-01

Recombinant factor VIIa (NovoSeven; also known as recombinant activated factor VII or eptacog alfa) is indicated as an intravenous haemostatic agent in haemophilia patients with inhibitors to clotting factors VIII or IX. In noncomparative trials in haemophilia patients with inhibitors, on-demand home treatment with recombinant factor VIIa was effective in controlling episodes of mild to moderate bleeding and well tolerated, with early treatment being associated with a greater rate of success and the need for fewer doses than delayed treatment. Prophylactic treatment with recombinant factor VIIa was also effective in maintaining haemostasis in patients with this indication undergoing surgery. Relative to prior treatment with plasma-derived agents, treatment with recombinant factor VIIa was associated with improvements in health-related quality of life in a cost-utility study in haemophilia patients with inhibitors in Australia. In well designed decision-model cost analyses conducted from a healthcare payer perspective in several countries, on-demand treatment with recombinant factor VIIa to control mild to moderate bleeding episodes in this patient population was predicted to be cost saving or cost neutral relative to on-demand treatment with intravenous activated prothrombin complex concentrate (aPCC). Although the acquisition cost of recombinant factor VIIa was greater than that of aPCC in some studies, the greater initial efficacy of recombinant factor VIIa than aPCC resulted in lower predicted total medical costs. Results were generally robust to plausible changes in key parameters. Orthopaedic surgery with recombinant factor VIIa to maintain haemostasis in haemophilia patients with inhibitors was generally predicted to be cost saving, relative to not having surgery, over the medium to long term in modelled cost analyses from a healthcare payer perspective in the UK and US. The initial cost of surgery was high, but the difference in costs between patients

75 FR 1333 - Notice of New Fee Site; Federal Lands Recreation Enhancement Act (Title VIII, Pub. L. 108-447)

Federal Register 2010, 2011, 2012, 2013, 2014

2010-01-11

... New Fee Site; Federal Lands Recreation Enhancement Act (Title VIII, Pub. L. 108-447) AGENCY: Forest... Recreation Enhancement Act (Title VIII, Pub. L. 108-447) directed the Secretary of Agriculture to publish a...

77 FR 10740 - Lock+ Hydro Friends Fund VIII, FFP Project 92, LLC, Riverbank Hydro No. 24, LLC; Notice...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-23

... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission [Project Nos. 14262-000, 14276-000, 14280-000] Lock+ Hydro Friends Fund VIII, FFP Project 92, LLC, Riverbank Hydro No. 24, LLC; Notice... Counties, Kentucky. The applications were filed by Lock+ Hydro Friends Fund VIII for Project No. 14262-000...

Combined variants in factor VIII and prostaglandin synthase-1 amplify hemorrhage severity across three generations of descendants.

PubMed

Nance, D; Campbell, R A; Rowley, J W; Downie, J M; Jorde, L B; Kahr, W H; Mereby, S A; Tolley, N D; Zimmerman, G A; Weyrich, A S; Rondina, M T

2016-11-01

Essentials Co-existent damaging variants are likely to cause more severe bleeding and may go undiagnosed. We determined pathogenic variants in a three-generational pedigree with excessive bleeding. Bleeding occurred with concurrent variants in prostaglandin synthase-1 (PTGS-1) and factor VIII. The PTGS-1 variant was associated with functional defects in the arachidonic acid pathway. Background Inherited human variants that concurrently cause disorders of primary hemostasis and coagulation are uncommon. Nevertheless, rare cases of co-existent damaging variants are likely to cause more severe bleeding and may go undiagnosed. Objective We prospectively sought to determine pathogenic variants in a three-generational pedigree with excessive bleeding. Patients/methods Platelet number, size and light transmission aggregometry to multiple agonists were evaluated in pedigree members. Transmission electron microscopy determined platelet morphology and granule content. Thromboxane release studies and light transmission aggregometry in the presence or absence of prostaglandin G 2 assessed specific functional defects in the arachidonic acid pathway. Whole exome sequencing (WES) and targeted nucleotide sequence analysis identified potentially deleterious variants. Results Pedigree members with excessive bleeding had impaired platelet aggregation with arachidonic acid, epinephrine and low-dose ADP, as well as reduced platelet thromboxane B 2 release. Impaired platelet aggregation in response to 2MesADP was rescued with prostaglandin G 2 , a prostaglandin intermediate downstream of prostaglandin synthase-1 (PTGS-1) that aids in the production of thromboxane. WES identified a non-synonymous variant in the signal peptide of PTGS-1 (rs3842787; c.50C>T; p.Pro17Leu) that completely co-segregated with disease phenotype. A variant in the F8 gene causing hemophilia A (rs28935203; c.5096A>T; p.Y1699F) was also identified. Individuals with both variants had more severe bleeding

Effects of moderate-intensity physical exercise on pharmacokinetics of factor VIII and von Willebrand factor in young adults with severe haemophilia A: a pilot study.

PubMed

Zourikian, N; Merlen, C; Bonnefoy, A; St-Louis, J; Rivard, G E

2016-05-01

In persons with severe haemophilia A (pwshA), infused factor VIII (FVIII) half-life can vary according to such determinants as blood group, von Willebrand factor (VWF) level or age; however, FVIII pharmacokinetics (PK) has not been well studied in pwshA during exercise. To investigate FVIII PK in pwshA performing moderate-intensity aerobic exercise. Twelve young-adult pwshA with the intron-22 inversion mutation, on relatively low-dose FVIII prophylaxis regimens, and relatively good musculoskeletal status were recruited. Abbreviated PK of FVIII activity and von Willebrand factor antigen (VWF:Ag) level were compared - during rest, and with 60-min exercise (2 × 15 min each of moderate-intensity stationary cycling and treadmill walking). During rest and exercise visits, a baseline blood specimen was drawn, routine prophylaxis FVIII infused; then six blood specimens were taken over the following 24 h. For all subjects, mean half-life of infused FVIII did not change significantly with exercise vs. at rest (577 ± 190 vs. 614 ± 163 min; P = 0.4131). VWF:Ag rose transiently by 40-50% for 6-8 h with exercise (P < 0.01), particularly in non-O blood group subjects. No musculoskeletal bleeds occurred during the study. Four × 15 min of moderate-intensity aerobic exercise increased VWF:Ag levels for 6-8 h, and showed no evidence of accelerated FVIII clearance or of musculoskeletal bleeding in these young-adult pwshA with relatively good musculoskeletal status, on relatively low-dose FVIII prophylaxis regimens. However, O blood group impact would merit larger studies, with longer durations of similar or more vigorous exercise intensities. © 2016 John Wiley & Sons Ltd.

Tumbling and spaceflight: the Gemini VIII experience.

PubMed

Mohler, S R; Nicogossian, A E; McCormack, P D; Mohler, S R

1990-01-01

A malfunctioning orbital flight attitude thruster during the flight of Gemini VIII led to acceleration forces on astronauts Neil Armstrong (commander) and David Scott (pilot) that created the potential for derogation of oculo-vestibular and eye-hand coordination effects. The spacecraft attained an axial tumbling rotation of 50 rpm and would have exceeded this had not the commander accurately diagnosed the problem and taken immediate corrective action. By the time counter-measure controls were applied, both astronauts were experiencing vertigo and the physiological effects of the tumbling acceleration. Data from the recorders reveal that one astronaut experienced -Gy of 0.92 G-units, and the other +Gy of 0.92 for approximately 46 s. Both received a -Gz of 0.89 G-units from the waist up with a +Gz of 0.05 from the waist down. A substantial increase of time and/or an increase in rpm would ultimately have produced incapacitation of both astronauts. NASA corrected the Gemini thruster problem by changing the ignition system wiring. Future space-craft undertaking long-term missions could be equipped with unambiguous thruster fault displays and could have computer-controlled automatic cutoffs to control excessive thruster burns.

Efficacy and safety of BAY 81-8973, a full-length recombinant factor VIII: results from the LEOPOLD I trial.

PubMed

Saxena, K; Lalezari, S; Oldenburg, J; Tseneklidou-Stoeter, D; Beckmann, H; Yoon, M; Maas Enriquez, M

2016-09-01

BAY 81-8973 (Kovaltry(®) ) is a full-length, unmodified recombinant human factor VIII (FVIII) with the same amino acid sequence as sucrose-formulated recombinant FVIII and is produced using additional advanced manufacturing technologies. To demonstrate efficacy and safety of BAY 81-8973 for treatment of bleeds and as prophylaxis based on two different potency assignments. In LEOPOLD I (ClinicalTrials.gov identifier, NCT01029340), males aged 12-65 years with severe haemophilia A and ≥150 exposure days received BAY 81-8973 20-50 IU kg(-1) two or three times per week for 12 months. Potency was based on chromogenic substrate assay per European Pharmacopoeia and label adjusted to mimic one-stage assay potency. Patients were randomized for potency sequence and crossed over potency groups after 6 months, followed by an optional 12-month extension. Primary efficacy endpoint was annualized bleeding rate (ABR). Patients also received BAY 81-8973 during major surgeries. Sixty-two patients received BAY 81-8973 prophylaxis and were included in the analysis. Median ABR was 1.0 (quartile 1, 0; quartile 3, 5.1) without clinically relevant differences between potency periods. Median ABR was similar for twice-weekly vs. three times-weekly dosing (1.0 vs. 2.0). Haemostasis was maintained during 12 major surgeries. Treatment-related adverse event (AE) incidence was ≤7% overall; no patient developed inhibitors. One patient with risk factors for cardiovascular disease developed a myocardial infarction. BAY 81-8973 was efficacious in preventing and treating bleeding episodes, irrespective of the potency assignment method, with few treatment-related AEs. Caution should be used when treating older patients with cardiovascular risk factors. © 2016 Bayer. Haemophilia Published by John Wiley & Sons Ltd.

10. Historic American Buildings Survey Photocopy of Plate VIII (dated ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

10. Historic American Buildings Survey Photocopy of Plate VIII (dated 1889) in John Calvin Stevens and Albert Winslow Cobb, Examples of American Domestic Architecture, New York, William T. Comstock, 1889 PLANS AND INTERIOR DETAILS, 1889 - John Calvin Stevens House, 52 Bowdoin Street, Portland, Cumberland County, ME

Identification of a Chemical Probe for Family VIII Bromodomains through Optimization of a Fragment Hit.

PubMed

Gerstenberger, Brian S; Trzupek, John D; Tallant, Cynthia; Fedorov, Oleg; Filippakopoulos, Panagis; Brennan, Paul E; Fedele, Vita; Martin, Sarah; Picaud, Sarah; Rogers, Catherine; Parikh, Mihir; Taylor, Alexandria; Samas, Brian; O'Mahony, Alison; Berg, Ellen; Pallares, Gabriel; Torrey, Adam D; Treiber, Daniel K; Samardjiev, Ivan J; Nasipak, Brian T; Padilla-Benavides, Teresita; Wu, Qiong; Imbalzano, Anthony N; Nickerson, Jeffrey A; Bunnage, Mark E; Müller, Susanne; Knapp, Stefan; Owen, Dafydd R

2016-05-26

The acetyl post-translational modification of chromatin at selected histone lysine residues is interpreted by an acetyl-lysine specific interaction with bromodomain reader modules. Here we report the discovery of the potent, acetyl-lysine-competitive, and cell active inhibitor PFI-3 that binds to certain family VIII bromodomains while displaying significant, broader bromodomain family selectivity. The high specificity of PFI-3 for family VIII was achieved through a novel bromodomain binding mode of a phenolic headgroup that led to the unusual displacement of water molecules that are generally retained by most other bromodomain inhibitors reported to date. The medicinal chemistry program that led to PFI-3 from an initial fragment screening hit is described in detail, and additional analogues with differing family VIII bromodomain selectivity profiles are also reported. We also describe the full pharmacological characterization of PFI-3 as a chemical probe, along with phenotypic data on adipocyte and myoblast cell differentiation assays.

HST/COS detection of a Ne VIII absorber towards PG 1407+265: an unambiguous tracer of collisionally ionized hot gas?

NASA Astrophysics Data System (ADS)

Hussain, T.; Muzahid, S.; Narayanan, A.; Srianand, R.; Wakker, B. P.; Charlton, J. C.; Pathak, A.

2015-01-01

We report the detection of Ne VIII in a zabs = 0.599 61 absorber towards the QSO PG1407+265 (zem= 0.94). Besides Ne VIII, absorption from H I Lyman series lines (H I λ1025-λ915), several other low (C II, N II, O II and S II), intermediate (C III, N III, N IV, O III, S IV and S V) and high (S VI, O VI and Ne VIII) ionization metal lines are detected. Disparity in the absorption line kinematics between different ions implies that the absorbing gas comprises of multiple ionization phases. The low and the intermediate ions (except S V) trace a compact (˜410 pc), metal-rich (Z ˜ Z⊙) and overdense (log nH ˜ -2.6) photoionized region that sustained star formation for a prolonged period. The high ions, Ne VIII and O VI, can be explained as arising in a low density (-5.3 ≤ log nH ≤ -5.0), metal-rich (Z ≳ Z⊙) and diffuse (˜180 kpc) photoionized gas. The S V, S VI and C IV [detected in the Faint Object Spectrograph (FOS) spectrum] require an intermediate photoionization phase with -4.2 < log nH < -3.5. Alternatively, a pure collisional ionization model, as used to explain the previous known Ne VIII absorbers, with 5.65 < log T < 5.72, can reproduce the S VI, O VI and Ne VIII column densities simultaneously in a single phase. However, even such models require an intermediate phase to reproduce any observable S V and/or C IV. Therefore, we conclude that when multiple phases are present, the presence of Ne VIII is not necessarily an unambiguous indication of collisionally ionized hot gas.

American Indian Tribal Programs in Child Welfare in Region VIII.

ERIC Educational Resources Information Center

Goodluck, Charlotte; Elpers, Jenny

Designed to develop and to share information and resources on child abuse and neglect, child welfare, and youth services in Region VIII (Colorado, Utah, Wyoming, North Dakota, South Dakota, and Montana), the Family Resource Center, a federally funded two year program, has developed a directory containing names, addresses, phone numbers and…

Glioneuronal Heterotopia Presenting As a Cerebellopontine angle Tumor of the cranial Nerve VIII, Case Report.

PubMed

Peris-Celda, M; Giannini, C; Diehn, F E; Eckel, L J; Neff, B A; Van Gompel, J J

2018-04-03

Vestibular schwannomas and meningiomas account for the great majority of lesions arising in the cerebellopontine angle (CPA). In this report, we present a case of glioneuronal heterotopia, also known as glioneuronal hamartoma, arising from the VIII cranial nerve, which is an extremely uncommon lesion. Important radiologic and surgical aspects are reviewed, which may help in early recognition and intraoperative decision making when these lesions are encountered. A healthy 29-year-old female presented with intermittent right facial numbness. Magnetic resonance imaging (MRI) showed an incidental minimally enhancing cerebellopontine angle lesion on the right VII-VIII cranial nerve complex. The patient declined serial observation and opted for operative intervention for resection. Intraoperatively, the lesion resembled neural tissue and was continuous with the VIII cranial nerve. Pathological analysis demonstrated mature glioneuronal tissue consistent with hamartomatous brain tissue. The patient maintained normal hearing and facial nerve function after surgery. Radiologic, surgical and pathological characteristics are described. Ectopic glioneuronal tissue of the VIII cranial nerve is a rare non-neoplastic lesion, and should be considered in the differential diagnosis of unusual appearing intracanalicular and cerebellopontine angle lesions. The congenital and benign nature of this entity makes observation a valid option for these cases, although they are so infrequent that they are often presumptively managed as vestibular schwannomas. Attempts to radically resect these lesions may result in higher rates of hearing loss or facial palsy due to their continuity with the cranial nerves. Copyright © 2018 Elsevier Inc. All rights reserved.

Virus elimination during the recycling of chromatographic columns used during the manufacture of coagulation factors.

PubMed

Roberts, Peter L

2014-07-01

Various chromatographic procedures are used during the purification and manufacture of plasma products such as coagulation factors. These steps contribute to the overall safety of such products by removing potential virus contamination. Virus removal by two affinity chromatography procedures, i.e. monoclonal antibody chromatography and metal chelate chromatography (immobilised metal ion affinity chromatography), used during the manufacture of the high purity factor VIII (Replenate®) and factor IX (Replenine®-VF), respectively, has been investigated. In addition, as these columns are recycled after use, the effectiveness of the sanitisation procedures for preventing possible cross-contamination, has also been investigated. Both chromatographic steps proved effective for eliminating a range of model enveloped and non-enveloped viruses by 4 to >6 and 5 to >8 log for the monoclonal and metal chelate columns, respectively. The effectiveness of the relatively mild column sanitisation conditions used, i.e. ethanol for factor IX and acetic acid for factor VIII, was confirmed using non-spiked column runs. The chemicals used contributed to virus elimination by inactivation and/or by physical removal of the virus. In summary, these studies demonstrate that potential virus contamination between chromatographic runs can be prevented when an effective column recycling and sanitisation procedure is included. Copyright © 2014 The International Alliance for Biological Standardization. Published by Elsevier Ltd. All rights reserved.

Information Technology: Making It All Fit. Track VIII: Academic Computing Strategy.

ERIC Educational Resources Information Center

CAUSE, Boulder, CO.

Six papers from the 1988 CAUSE conference's Track VIII, Academic Computing Strategy, are presented. They include: "Achieving Institution-Wide Computer Fluency: A Five-Year Retrospective" (Paul J. Plourde); "A Methodology and a Policy for Building and Implementing a Strategic Computer Plan" (Frank B. Thomas); "Aligning…

Effect of V/III ratio on the surface morphology and electrical properties of m-plane (10 1 bar 0) GaN homoepitaxial layers

NASA Astrophysics Data System (ADS)

Barry, Ousmane I.; Tanaka, Atsushi; Nagamatsu, Kentaro; Bae, Si-Young; Lekhal, Kaddour; Matsushita, Junya; Deki, Manato; Nitta, Shugo; Honda, Yoshio; Amano, Hiroshi

2017-06-01

We have investigated the effect of V/III ratio on the surface morphology, impurity concentration and electrical properties of m-plane (10 1 bar 0) Gallium Nitride (GaN) homoepitaxial layers. Four-sided pyramidal hillocks are observed on the nominally on-axis m-plane GaN films. Hillocks sizes relatively increase by increasing the V/III ratio. All facets of pyramidal hillocks exhibit well-defined step-terrace features. Secondary ion mass spectrometry depth profiles reveal that carbon impurities decrease by increasing the V/III ratio while the lowest oxygen content is found at an optimized V/III ratio of 900. Vertical Schottky barrier diodes fabricated on the m-GaN samples were characterized. Low leakage current densities of the order of 10-10 A/cm2 at -5 V are obtained at the optimum V/III ratio. Oxygen impurities and screw-component dislocations around hillocks are found to have more detrimental impact on the leakage current mechanism.

76 FR 73616 - Lock Hydro Friends Fund VIII, FFP Project 92 LLC, Riverbank Hydro No. 24 LLC; Notice of Competing...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-11-29

... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission [Project Nos. 14262-000; 14276-000; 14280-000] Lock Hydro Friends Fund VIII, FFP Project 92 LLC, Riverbank Hydro No. 24 LLC; Notice of..., and Competing Applications On September 1, 2011, Lock Hydro Friends Fund VIII (Lock Hydro), FFP...

Effects of Mg/Ga and V/III source ratios on hole concentration of N-polar (000\\bar{1}) p-type GaN grown by metalorganic vapor phase epitaxy

NASA Astrophysics Data System (ADS)

Nonoda, Ryohei; Shojiki, Kanako; Tanikawa, Tomoyuki; Kuboya, Shigeyuki; Katayama, Ryuji; Matsuoka, Takashi

2016-05-01

The effects of growth conditions such as Mg/Ga and V/III ratios on the properties of N-polar (000\\bar{1}) p-type GaN grown by metalorganic vapor phase epitaxy were studied. Photoluminescence spectra from Mg-doped GaN depended on Mg/Ga and V/III ratios. For the lightly doped samples, the band-to-acceptor emission was observed at 3.3 eV and its relative intensity decreased with increasing V/III ratio. For the heavily doped samples, the donor-acceptor pair emission was observed at 2.8 eV and its peak intensity monotonically decreased with V/III ratio. The hole concentration was maximum for the Mg/Ga ratio. This is the same tendency as in group-III polar (0001) growth. The V/III ratio also reduced the hole concentration. The higher V/III ratio reduced the concentration of residual donors such as oxygen by substituting nitrogen atoms. The surface became rougher with increasing V/III ratio and the hillock density increased.

BAY 81-8973, a full-length recombinant factor VIII: Human heat shock protein 70 improves the manufacturing process without affecting clinical safety.

PubMed

Maas Enriquez, Monika; Thrift, John; Garger, Stephen; Katterle, Yvonne

2016-11-01

BAY 81-8973 is a full-length, unmodified recombinant human factor VIII (FVIII) approved for the treatment of hemophilia A. BAY 81-8973 has the same amino acid sequence as the currently marketed sucrose-formulated recombinant FVIII (rFVIII-FS) product and is produced using additional advanced manufacturing technologies. One of the key manufacturing advances for BAY 81-8973 is introduction of the gene for human heat shock protein 70 (HSP70) into the rFVIII-FS cell line. HSP70 facilitates proper folding of proteins, enhances cell survival by inhibiting apoptosis, and potentially impacts rFVIII glycosylation. HSP70 expression in the BAY 81-8973 cell line along with other manufacturing advances resulted in a higher-producing cell line and improvements in the pharmacokinetics of the final product as determined in clinical studies. HSP70 protein is not detected in the harvest or in the final BAY 81-8973 product. However, because this is a new process, clinical trial safety assessments included monitoring for anti-HSP70 antibodies. Most patients, across all age groups, had low levels of anti-HSP70 antibodies before exposure to the investigational product. During BAY 81-8973 treatment, 5% of patients had sporadic increases in anti-HSP70 antibody levels above a predefined threshold (cutoff value, 239 ng/mL). No clinical symptoms related to anti-HSP70 antibody development occurred. In conclusion, addition of HSP70 to the BAY 81-8973 cell line is an innovative technology for manufacturing rFVIII aimed at improving protein folding and expression. Improved pharmacokinetics and no effect on safety of BAY 81-8973 were observed in clinical trials in patients with hemophilia A. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Solid State Surfaces and Interfaces VIII

NASA Astrophysics Data System (ADS)

Pincik, Emil

2014-09-01

The conference SSSI VIII (November 25-28, 2013) was the 8th continuation of the series of the Solid State Surfaces and Interfaces conferences taking place usually in the Smolenice castle in the western part of the Slovak Republic. The event was organized by the following institutions of Slovak Republic: Institute of Physics of SAS Bratislava, Institute of Aurel Stodola of University of Žilina, and Faculty of Mathematics, Physics and Informatics of Comenius University Bratislava. More than 150 scientists of the three continents (Europe, Asia and Africa) participated on the event with almost 100 poster presentations. The representatives of all organizing institutions consider this event as very important for Middle Europe region.

The effect of different methods of leucoreduction on plasma coagulation factors.

PubMed

Aboul Enein, Azza A; Abdel Rahman, Hala A; Abdel Maged, Mohamed M M; El Sissy, Maha H

2017-03-01

Removal of leucocytes from blood products, namely leucoreduction, improves the safety of blood transfusion by reducing adverse events associated with the incidental transfusion of leucocytes. Coagulation factors might be compromised during leucoreduction because of exposure of plasma to a variety of filter materials. The aim of the current study was to assess the effect of different methods of prestorage leucofiltration (apheresis and whole blood filters) on prothrombin time, international normalized ratio, partial thromboplastin time and factors V and VIII. There was a significant prolongation of prothrombin time as well as elevation of international normalized ratio in plasma after leucoreduction (14.5 ± 0.7 s vs. 13.9 ± 0.7 s, P = 0.008 and 1.14 ± 0.07 vs. 1.09 ± 0.07, P = 0.005, respectively). Also, there was a statistically significant prolongation of activated partial thromboplastin time in nonleucoreduced plasma (55.6 ± 9.9 s vs. 43.2 ± 12.8 s, P = 0.001). There was no significant filtration effect on factors V and VIII levels. Furthermore, there was no significant difference in factors V and VIII levels between plasma filtered by inline whole blood filters and apheresis machine. Leucodepleted plasma originating from both inline whole blood filter and apheresis machine maintained satisfactory levels of factors V and VIII.

Inhibitor development in patients receiving recombinant factor VIII (Recombinate rAHF/Bioclate): a prospective pharmacovigilance study.

PubMed

Ewenstein, B M; Gomperts, E D; Pearson, S; O'Banion, M E

2004-09-01

Clinical trials to date have not been adequately powered to assess comparatively infrequent events such as inhibitor development in previously treated patients (PTPs). Comprehensive large-scale pharmacovigilance studies can be useful for this purpose. We prospectively collected inhibitor development reports worldwide among recipients of Recombinate rAHF recombinant factor VIII (rFVIII), also formerly distributed under the product name Bioclate, for the entire postlicensure period from 1993 through 2002. To determine level of exposure to rFVIII we also compiled the Recombinate rAHF/Bioclate International Units (IU) distributed annually. To estimate inhibitor incidence separately for previously untreated or minimally treated patients (PUPs) with 1-50 exposure days and PTPs with >50 exposure days, we used haemophilia A incidence and prevalence data and pooled mean annual rFVIII consumption per PUP and PTP from international multicentre prospective clinical trials. Documented inhibitor cases totalled 89, and the total quantity of Recombinate rAHF/Bioclate rFVIII distributed was 6.48 x10(9) IU. No lot association or other clustering of inhibitor events was evident in PTPs. The incidence of all reported inhibitors, expressed as a percentage of patients treated, was 11.9% (CI: 5.05-28.0%) for PUPs when compared with 0.123% (CI: 0.030-0.512%) for PTPs. The rates for high-titre inhibitors (>5 BU) only were 5.96% (CI: 3.00-11.8%) for PUPs and 0.0554% (CI: 0.0113-0.271%) for PTPs. Thus, incidence rates for both all inhibitors and high-titre inhibitors in PTPs were 1% of the corresponding rates in PUPs. Data from prospective PUP clinical trials involving intensive active monitoring suggest that true inhibitor incidence may be approximately twice that estimated in this pharmacovigilance study. Nevertheless, inhibitor development in PTPs receiving Recombinate rAHF/Bioclate is infrequent.

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

PubMed

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

2015-06-01

Prophylactic factor replacement, which prevents hemarthroses and thereby reduces the musculoskeletal disease burden in children with hemophilia A, requires frequent intravenous infusions (three to four times weekly). Kids A-LONG was a phase 3 open-label study evaluating the safety, efficacy and pharmacokinetics of a longer-acting factor, recombinant factor VIII Fc fusion protein (rFVIIIFc), in previously treated children with severe hemophilia A (endogenous FVIII level of < 1 IU dL(-1) [< 1%]). The study enrolled 71 subjects. The starting rFVIIIFc regimen was twice-weekly prophylaxis (Day 1, 25 IU kg(-1) ; Day 4, 50 IU kg(-1) ); dose (≤ 80 IU kg(-1) ) and dosing interval (≥ 2 days) were adjusted as needed. A subset of subjects had sequential pharmacokinetic evaluations of FVIII and rFVIIIFc. The primary endpoint was development of inhibitors (neutralizing antibodies). Secondary endpoints included pharmacokinetics, annualized bleeding rate (ABR), and number of infusions required to control a bleed. No subject developed an inhibitor to rFVIIIFc. Adverse events were typical of a pediatric hemophilic population. The rFVIIIFc half-life was prolonged relative to that of FVIII, consistent with observations in adults and adolescents. The median ABR was 1.96 overall, and 0.00 for spontaneous bleeds; 46.4% of subjects reported no bleeding episodes on study. Ninety-three per cent of bleeding episodes were controlled with one to two infusions. The median average weekly rFVIIIFc prophylactic dose was 88.11 IU kg(-1) . At study end, 62 of 69 subjects (90%) were infusing twice weekly. Among subjects who had been previously receiving FVIII prophylaxis, 74% reduced their dosing frequency with rFVIIIFc. Twice-weekly infusions with rFVIIIFc were well tolerated and yielded low bleeding rates in children with severe hemophilia A. © 2015 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and

Development, upscaling and validation of the purification process for human-cl rhFVIII (Nuwiq®), a new generation recombinant factor VIII produced in a human cell-line.

PubMed

Winge, Stefan; Yderland, Louise; Kannicht, Christoph; Hermans, Pim; Adema, Simon; Schmidt, Torben; Gilljam, Gustav; Linhult, Martin; Tiemeyer, Maya; Belyanskaya, Larisa; Walter, Olaf

2015-11-01

Human-cl rhFVIII (Nuwiq®), a new generation recombinant factor VIII (rFVIII), is the first rFVIII produced in a human cell-line approved by the European Medicines Agency. To describe the development, upscaling and process validation for industrial-scale human-cl rhFVIII purification. The purification process involves one centrifugation, two filtration, five chromatography columns and two dedicated pathogen clearance steps (solvent/detergent treatment and 20 nm nanofiltration). The key purification step uses an affinity resin (VIIISelect) with high specificity for FVIII, removing essentially all host-cell proteins with >80% product recovery. The production-scale multi-step purification process efficiently removes process- and product-related impurities and results in a high-purity rhFVIII product, with an overall yield of ∼50%. Specific activity of the final product was >9000 IU/mg, and the ratio between active FVIII and total FVIII protein present was >0.9. The entire production process is free of animal-derived products. Leaching of potential harmful compounds from chromatography resins and all pathogens tested were below the limit of quantification in the final product. Human-cl rhFVIII can be produced at 500 L bioreactor scale, maintaining high purity and recoveries. The innovative purification process ensures a high-purity and high-quality human-cl rhFVIII product with a high pathogen safety margin. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Effect of Biophysical Properties of Phosphatidylserine Particle on Immune Tolerance Induction Toward Factor VIII in a Hemophilia A Mouse Model.

PubMed

Ramakrishnan, Radha; Balu-Iyer, Sathy V

2016-10-01

A major complication in the replacement therapy of Factor VIII (FVIII) for Hemophilia A is the development of unwanted immune responses. Previous studies from our laboratory have shown that pretreatment of FVIII in the presence of phosphatidylserine (PS) resulted in hyporesponsiveness to subsequent administration of FVIII alone, due to the ability of PS to convert an immunogen to a tolerogen. We investigated the importance of biophysical properties of PS liposomes on its ability to convert an immunogen to a tolerogen. PS particles were prepared differing in size, protein-lipid topology, lamellarity, and % association to FVIII keeping the composition of the particle same. PS particles were prepared in 2 different sizes with differing biophysical properties: smaller particles in the nanometer range (200 nm) and larger size particles in the micron range (2 μm). Hemophilia A animals treated with both the nanometer and micron size PS particles showed a significant reduction in anti-FVIII antibody titers when compared to animals receiving free FVIII alone. Upon rechallenge with free FVIII animals that received FVIII along with the nanometer size particle continued to show reduced antibody responses. Animals receiving the micron size particle showed a slight increase in titers although they remained significantly lower than the free FVIII treated group. Upon culture with bone marrow derived dendritic cells, the nanometer size particle showed a reduction in CD40 expression and an increase in transforming growth factor-β cytokine production, which was not observed with the micron size particle. These results show that biophysical properties of PS play an important role in tolerance. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Transient blockade of the inducible costimulator pathway generates long-term tolerance to factor VIII after nonviral gene transfer into hemophilia A mice.

PubMed

Peng, Baowei; Ye, Peiqing; Blazar, Bruce R; Freeman, Gordon J; Rawlings, David J; Ochs, Hans D; Miao, Carol H

2008-09-01

Formation of inhibitory antibodies is a common problem encountered in clinical treatment for hemophilia. Human factor VIII (hFVIII) plasmid gene therapy in hemophilia A mice also leads to strong humoral responses. We demonstrate that short-term therapy with an anti-ICOS monoclonal antibody to transiently block the inducible costimulator/inducible costimulator ligand (ICOS/ICOSL) signaling pathway led to sustained tolerance to hFVIII in hFVIII plasmid-treated hemophilia A mice and allowed persistent, high-level FVIII functional activity (100%-300% of normal). Anti-ICOS treatment resulted in depletion of ICOS(+)CD4(+) T cells and activation of CD25(+)Foxp3(+) Tregs in the peripheral blood, spleen, and lymph nodes. CD4(+) T cells from anti-ICOS-treated mice did not proliferate in response to hFVIII stimulation and produced high levels of regulatory cytokines, including interleukin-10 and transforming growth factor-beta. Moreover, CD4(+)CD25(+) Tregs from tolerized mice adoptively transferred dominant tolerance in syngeneic hFVIII plasmid-treated hemophilia A mice and reduced the production of antibodies against FVIII. Anti-ICOS-treated mice tolerized to hFVIII generated normal primary and secondary antibody responses after immunization with the T-dependent antigen, bacteriophage Phix 174, indicating maintenance of immune competency. Our data indicate that transient anti-ICOS monoclonal antibody treatment represents a novel single-agent immunomodulatory strategy to overcome the immune responses against transgene product after gene therapy.

Synthesis of dispersive iron or iron-silver nanoparticles on engineered capsid pVIII of M13 virus with electronegative terminal peptides

NASA Astrophysics Data System (ADS)

Zhang, Shuai; Nakano, Kazuhiko; Zhang, Shu-liang; Yu, Hui-min

2015-10-01

M13 is a filamentous Escherichia coli virus covered with five types of capsid proteins, in which pVIII with 2700 copies was around the cylindered surface and pIII with five copies located at one end of the phage particle. The pIII-engineered M13 phages with enhanced binding specificity toward Fe were screened after five rounds of biopanning, and the one containing ATPTVAMSLSPL peptide at pIII-terminus was selected for mediated synthesis of zero valent (ZV) Fe nanoparticles (NPs) with the wild M13 as control. Under a reducing environment, uniformly dispersed ZVFeNPs with diameter of 5-10 nm were both synthesized and the morphologies after annealing were confirmed to be face-centered cubic type. The synthesized FeNPs mediated by the two phages showed no significant difference, revealing that the pVIII capsid did dominant contribution to metal binding in comparison with the pIII. A novel pVIII-engineered M13 containing AAEEEDPAK at terminus, named as 4ED-pVIII-M13, was constructed and it carried one more negatively charged residue than the wild one (AEGDDPAK). Metal adsorption quantification showed that the binding affinity of the 4ED-pVIII-M13 toward Ag and Ni ions improved to 62 and 18 % from original 21 and 6 %, respectively. The binding affinity toward Fe remained constant ( 85 %). ZVFe-Ag bi-NPs were successfully synthesized through mediation of 4ED-pVIII-M13. Particularly, the Fe:Ag ratio in the bi-NPs was conveniently controlled through changing the molar concentration of FeCl2 and AgNO3 solution before reduction.

Analysis of the recE locus of Escherichia coli K-12 by use of polyclonal antibodies to exonuclease VIII.

PubMed Central

Luisi-DeLuca, C; Clark, A J; Kolodner, R D

1988-01-01

Exonuclease VIII (exoVIII) of Escherichia coli has been purified from a strain carrying a plasmid-encoded recE gene by using a new procedure. This procedure yielded 30 times more protein per gram of cells, and the protein had a twofold higher specific activity than the enzyme purified by the previously published procedure (J. W. Joseph and R. Kolodner, J. Biol. Chem. 258:10411-10417, 1983). The sequence of the 12 N-terminal amino acids was also obtained and found to correspond to one of the open reading frames predicted from the nucleic acid sequence of the recE region of Rac (C. Chu, A. Templin, and A. J. Clark, manuscript in preparation). Polyclonal antibodies directed against purified exoVIII were also prepared. Cell-free extracts prepared from strains containing a wide range of chromosomal- or plasmid-encoded point, insertion, and deletion mutations which result in expression of exoVIII were examined by Western blot (immunoblot) analysis. This analysis showed that two point sbcA mutations (sbcA5 and sbcA23) and the sbc insertion mutations led to the synthesis of the 140-kilodalton (kDa) polypeptide of wild-type exoVIII. Plasmid-encoded partial deletion mutations of recE reduced the size of the cross-reacting protein(s) in direct proportion to the size of the deletion, even though exonuclease activity was still present. The analysis suggests that 39 kDa of the 140-kDa exoVIII subunit is all that is essential for exonuclease activity. One of the truncated but functional exonucleases (the pRAC3 exonuclease) has been purified and confirmed to be a 41-kDa polypeptide. The first 18 amino acids from the N terminus of the 41-kDa pRAC3 exonuclease were sequenced and fond to correspond to one of the translational start signals predicted from the nucleotide sequence of radC (Chu et al., in preparation). Images PMID:3056915

46 CFR 54.01-2 - Adoption of division 1 of section VIII of the ASME Boiler and Pressure Vessel Code.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 46 Shipping 2 2013-10-01 2013-10-01 false Adoption of division 1 of section VIII of the ASME Boiler and Pressure Vessel Code. 54.01-2 Section 54.01-2 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) MARINE ENGINEERING PRESSURE VESSELS General Requirements § 54.01-2 Adoption of division 1 of section VIII of the ASME Boiler and...

46 CFR 54.01-2 - Adoption of division 1 of section VIII of the ASME Boiler and Pressure Vessel Code.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 46 Shipping 2 2011-10-01 2011-10-01 false Adoption of division 1 of section VIII of the ASME Boiler and Pressure Vessel Code. 54.01-2 Section 54.01-2 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) MARINE ENGINEERING PRESSURE VESSELS General Requirements § 54.01-2 Adoption of division 1 of section VIII of the ASME Boiler and...

46 CFR 54.01-2 - Adoption of division 1 of section VIII of the ASME Boiler and Pressure Vessel Code.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 46 Shipping 2 2012-10-01 2012-10-01 false Adoption of division 1 of section VIII of the ASME Boiler and Pressure Vessel Code. 54.01-2 Section 54.01-2 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) MARINE ENGINEERING PRESSURE VESSELS General Requirements § 54.01-2 Adoption of division 1 of section VIII of the ASME Boiler and...

46 CFR 54.01-2 - Adoption of division 1 of section VIII of the ASME Boiler and Pressure Vessel Code.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 46 Shipping 2 2010-10-01 2010-10-01 false Adoption of division 1 of section VIII of the ASME Boiler and Pressure Vessel Code. 54.01-2 Section 54.01-2 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) MARINE ENGINEERING PRESSURE VESSELS General Requirements § 54.01-2 Adoption of division 1 of section VIII of the ASME Boiler and...

46 CFR 54.01-2 - Adoption of division 1 of section VIII of the ASME Boiler and Pressure Vessel Code.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 46 Shipping 2 2014-10-01 2014-10-01 false Adoption of division 1 of section VIII of the ASME Boiler and Pressure Vessel Code. 54.01-2 Section 54.01-2 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) MARINE ENGINEERING PRESSURE VESSELS General Requirements § 54.01-2 Adoption of division 1 of section VIII of the ASME Boiler and...

V/III ratio effects on high quality InAlAs for quantum cascade laser structures

NASA Astrophysics Data System (ADS)

Demir, Ilkay; Elagoz, Sezai

2017-04-01

In this study we report the V/III ratio effects on growth, structural, optical and doping characteristics of low growth rate (∼1 Å/s) heteroepitaxial Metal Organic Chemical Vapor Deposition (MOCVD) grown InxAl1-xAs layers, a part of Quantum Cascade Laser (QCL) structures, on InP substrate. Especially photoluminescence (PL) properties of InAlAs-InP interface show strong dependence on AsH3 overpressure. We have shown that the V/III ratio with fixed metalorganic precursor flow is a crucial parameter on InxAl1-xAs layers to have a good material quality in terms of crystallinity, optical and electrical characteristics with and without doping.

Zwitterionic Group VIII transition metal initiators supported by olefin ligands

DOEpatents

Bazan, Guillermo C [Goleta, CA; Chen, Yaofeng [Shanghai, CN

2011-10-25

A zwitterionic Group VIII transition metal complex containing the simple and relatively small 3-(arylimino)-but-1-en-2-olato ligand that catalyzes the formation of polypropylene and high molecular weight polyethylene. A novel feature of this catalyst is that the active species is stabilized by a chelated olefin adduct. The present invention also provides methods of polymerizing olefin monomers using zwitterionic catalysts, particularly polypropylene and high molecular weight polyethylene.

Vascular Permeability and Remodelling Coincide with Inflammatory and Reparative Processes after Joint Bleeding in Factor VIII-Deficient Mice.

PubMed

Cooke, Esther J; Zhou, Jenny Y; Wyseure, Tine; Joshi, Shweta; Bhat, Vikas; Durden, Donald L; Mosnier, Laurent O; Drygalski, Annette von

2018-06-01

Vascular remodelling is a prominent feature of haemophilic arthropathy (HA) that may underlie re-bleeding, yet the nature of vascular changes and underlying mechanisms remain largely unknown. Here, we aimed to characterize synovial vascular remodelling and vessel integrity after haemarthrosis, as well as temporal changes in inflammatory and tissue-reparative pathways. Thirty acutely painful joints in patients with haemophilia (PWH) were imaged by musculoskeletal ultrasound with Power Doppler (MSKUS/PD) to detect vascular abnormalities and bloody effusions. Nineteen out of 30 painful joint episodes in PWH were associated with haemarthrosis, and abnormal vascular perfusion was unique to bleeding joints. A model of induced haemarthrosis in factor VIII (FVIII)-deficient mice was used for histological assessment of vascular remodelling (α-smooth muscle actin [αSMA] expression), and monitoring of in vivo vascular perfusion and permeability by MSKUS/PD and albumin extravasation, respectively. Inflammatory (M1) and reparative (M2) macrophage markers were quantified in murine synovium over a 10-week time course by real-time polymerase chain reaction. The abnormal vascular perfusion observed in PWH was recapitulated in FVIII-deficient mice after induced haemarthrosis. Neovascularization and increased vessel permeability were apparent 2 weeks post-bleed in FVIII-deficient mice, after a transient elevation of inflammatory macrophage M1 markers. These vascular changes subsided by week 4, while vascular remodelling, evidenced by architectural changes and pronounced αSMA expression, persisted alongside a reparative macrophage M2 response. In conclusion, haemarthrosis leads to transient inflammation coupled with neovascularization and associated vascular permeability, while subsequent tissue repair mechanisms coincide with vascular remodelling. Together, these vascular changes may promote re-bleeding and HA progression. Schattauer GmbH Stuttgart.

Influence of Problem Based Learning on Critical Thinking Skills and Competence Class VIII SMPN 1 Gunuang Omeh, 2016/2017

NASA Astrophysics Data System (ADS)

Aswan, D. M.; Lufri, L.; Sumarmin, R.

2018-04-01

This research intends to determine the effect of Problem Based Learning models on students' critical thinking skills and competences. This study was a quasi-experimental research. The population of the study was the students of class VIII SMPN 1 Subdistrict Gunuang Omeh. Random sample selection is done by randomizing the class. Sample class that was chosen VIII3 as an experimental class given that treatment study based on problems and class VIII1 as control class that treatment usually given study. Instrument that used to consist of critical thinking test, cognitive tests, observation sheet of affective and psychomotor. Independent t-test and Mann Whitney U test was used for the analysis. Results showed that there was significant difference (sig <0.05) between control and experimental group. The conclusion of this study was Problem Based Learning models affected the students’ critical thinking skills and competences.

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.

Structure and stability of hexa-aqua V(III) cations in vanadium redox flow battery electrolytes.

PubMed

Vijayakumar, M; Li, Liyu; Nie, Zimin; Yang, Zhenguo; Hu, JianZhi

2012-08-07

The vanadium(III) cation structure in mixed acid based electrolyte solution from vanadium redox flow batteries is studied by (17)O and (35/37)Cl nuclear magnetic resonance (NMR) spectroscopy, electronic spectroscopy and density functional theory (DFT) based computational modelling. Both computational and experimental results reveal that the V(III) species can complex with counter anions (sulfate/chlorine) depending on the composition of its solvation sphere. By analyzing the powder precipitate it was found that the formation of sulfate complexed V(III) species is the crucial process in the precipitation reaction. The precipitation occurs through nucleation of neutral species formed through deprotonation and ion-pair formation process. However, the powder precipitate shows a multiphase nature which warrants multiple reaction pathways for precipitation reaction.

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.

VizieR Online Data Catalog: Atomic data for X-ray lines of FeVIII and FeIX (O'Dwyer+, 2012)

NASA Astrophysics Data System (ADS)

O'Dwyer, B.; Del Zanna, G.; Badnell, N. R.; Mason, H. E.; Storey, P. J.

2012-04-01

The distorted wave extension of the autostructure code has been used to calculate energy levels, radiative transition probabilities and collisional excitation rates of Fe VIII and Fe IX up to n=6 for Fe IX and n=7 for Fe VIII. We have compared some of the data with previous calculations, finding overall agreement for radiative transition rates, but interesting differences for some collisional data. ************************************************************************** * * * Sorry, but the author(s) never supplied the tabular material * * announced in the paper * * * **************************************************************************

Association of peak factor VIII levels and area under the curve with bleeding in patients with haemophilia A on every third day pharmacokinetic-guided prophylaxis.

PubMed

Valentino, L A; Pipe, S W; Collins, P W; Blanchette, V S; Berntorp, E; Fischer, K; Ewenstein, B M; Oh, M; Spotts, G

2016-07-01

We previously showed that pharmacokinetic-guided prophylaxis (PKP) allows the dosing interval to be extended while maintaining a specific trough level. However, the associations of peak factor VIII (FVIII) levels and area under the curve (AUC) with breakthrough bleeding have not been investigated. The aim of this study was to analyse data from the PKP arm to determine whether peak FVIII levels, AUC and time with FVIII levels in a haemostatically effective range are independent predictors of bleeding during prophylaxis. Post hoc analysis of the association of FVIII levels and AUC with annualized bleeding rate in 34 patients on PKP. During 1 year of PKP, 131 bleeding episodes occurred in 24/34 patients. Average peak FVIII levels ranged from 24 to 168 IU dL(-1) , with higher values associated with a decreased risk for all bleeding (joint and non-joint; P < 0.01) and joint bleeding (P < 0.01). Following rFVIII infusion, median percent of time spent with FVIII levels >20 IU dL(-1) was 22%; median AUC was 1363. Both values were significantly associated with a lower ABR when targeting a 1% trough at 72 h. When PKP was administered every third day, higher peak FVIII levels, higher AUC and more time spent per week with FVIII levels >20 IU dL(-1) provided increased protection from joint and non-joint bleeding. These data highlight the potential impact of variability in individual pharmacokinetic and bleeding risk and support the need for high peak levels and AUC in some patients treated every third day. The findings do not necessarily apply to alternate-day or other prophylactic dosing regimens. © 2016 The Authors. Haemophilia Published by John Wiley & Sons Ltd.

Significantly improved surface morphology of N-polar GaN film grown on SiC substrate by the optimization of V/III ratio

NASA Astrophysics Data System (ADS)

Deng, Gaoqiang; Zhang, Yuantao; Yu, Ye; Yan, Long; Li, Pengchong; Han, Xu; Chen, Liang; Zhao, Degang; Du, Guotong

2018-04-01

In this paper, N-polar GaN films with different V/III ratios were grown on vicinal C-face SiC substrates by metalorganic chemical vapor deposition. During the growth of N-polar GaN film, the V/III ratio was controlled by adjusting the molar flow rate of ammonia while keeping the trimethylgallium flow rate unchanged. The influence of the V/III ratio on the surface morphology of N-polar GaN film has been studied. We find that the surface root mean square roughness of N-polar GaN film over an area of 20 × 20 μm2 can be reduced from 8.13 to 2.78 nm by optimization of the V/III ratio. Then, using the same growth conditions, N-polar InGaN/GaN multiple quantum wells (MQWs) light-emitting diodes (LEDs) were grown on the rough and the smooth N-polar GaN templates, respectively. Compared with the LED grown on the rough N-polar GaN template, dramatically improved interface sharpness and luminescence uniformity of the InGaN/GaN MQWs are achieved for the LED grown on the smooth N-polar GaN template.

Effect of substrate temperature and V/III flux ratio on In incorporation for InGaN/GaN heterostructures grown by plasma-assisted molecular-beam epitaxy

NASA Astrophysics Data System (ADS)

O'Steen, M. L.; Fedler, F.; Hauenstein, R. J.

1999-10-01

Reflection high-energy electron diffraction (RHEED) and laterally spatially resolved high resolution x-ray diffraction (HRXRD) have been used to identify and characterize rf plasma-assisted molecular-beam epitaxial growth factors which strongly affect the efficiency of In incorporation into InxGa1-xN epitaxial materials. HRXRD results for InxGa1-xN/GaN superlattices reveal a particularly strong dependence of average alloy composition x¯ upon both substrate growth temperature and incident V/III flux ratio. For fixed flux ratio, results reveal a strong thermally activated behavior, with over an order-of-magnitude decrease in x¯ with increasing growth temperature within the narrow range 590-670 °C. Within this same range, a further strong dependence upon V/III flux ratio is observed. The decreased In incorporation at elevated substrate temperatures is tentatively attributed to In surface-segregation and desorption processes. RHEED observations support this segregation/desorption interpretation to account for In loss.

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.

Factor VIII assay

MedlinePlus

... sample from one person than another. Other slight risks from having blood drawn may include: Excessive bleeding Fainting or feeling lightheaded Hematoma (blood accumulating under the skin) Infection ( ...

Transforming growth factor (TGF. beta. ) decreases the proliferation of human bone marrow fibroblasts by inhibiting the platelet-derived growth factor (PDGF) binding

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

Bryckaert, M.C.; Tobelem, G.; Lindroth, M.

1988-12-01

Human bone marrow fibroblasts were cultivated and characterized by immunofluorescent staining and electron microscopy. Their interactions with PDGF and TGF{beta} were studied. While a positive intracellular antifibronectin staining was observed, the cultured cells were not labeled with specific antibodies toward factor VIII von Willebrand factor (F VIII/vWF), desmin, and macrophage antigen. The binding of pure human PDGF to the cultured bone marrow fibroblasts was investigated. Addition of an excess of unlabeled PDGF decreased the binding to 75 and 80%, which means that the nonspecific binding represented 20-25% of total binding, whereas epidermal growth factor (EGF) had no effect. Two classesmore » of sites were detected by Scatchard analysis. The stimulation of DNA synthesis of PDGF was quantified by ({sup 3}H)thymidine incorporation. The results suggested that PDGF and TGF{beta} could modulate the growth of bone marrow fibroblasts.« less

CONSTRAINING THE MILKY WAY'S HOT GAS HALO WITH O VII AND O VIII EMISSION LINES

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

Miller, Matthew J.; Bregman, Joel N., E-mail: mjmil@umich.edu, E-mail: jbregman@umich.edu

2015-02-10

The Milky Way hosts a hot (≈2 × 10{sup 6} K), diffuse, gaseous halo based on detections of z = 0 O VII and O VIII absorption lines in quasar spectra and emission lines in blank-sky spectra. Here we improve constraints on the structure of the hot gas halo by fitting a radial model to a much larger sample of O VII and O VIII emission line measurements from XMM-Newton/EPIC-MOS spectra compared to previous studies (≈650 sightlines). We assume a modified β-model for the halo density distribution and a constant-density Local Bubble from which we calculate emission to compare withmore » the observations. We find an acceptable fit to the O VIII emission line observations with χ{sub red}{sup 2} (dof) = 1.08 (644) for best-fit parameters of n{sub o}r{sub c}{sup 3β}=1.35±0.24 cm{sup –3} kpc{sup 3β} and β = 0.50 ± 0.03 for the hot gas halo and negligible Local Bubble contribution. The O VII observations yield an unacceptable χ{sub red}{sup 2} (dof) = 4.69 (645) for similar best-fit parameters, which is likely due to temperature or density variations in the Local Bubble. The O VIII fitting results imply hot gas masses of M(<50 kpc) = 3.8{sub −0.3}{sup +0.3}×10{sup 9} M{sub ⊙} and M(<250 kpc) = 4.3{sub −0.8}{sup +0.9}×10{sup 10} M{sub ⊙}, accounting for ≲50% of the Milky Way's missing baryons. We also explore our results in the context of optical depth effects in the halo gas, the halo gas cooling properties, temperature and entropy gradients in the halo gas, and the gas metallicity distribution. The combination of absorption and emission line analyses implies a sub-solar gas metallicity that decreases with radius, but that also must be ≥0.3 Z {sub ☉} to be consistent with the pulsar dispersion measure toward the Large Magellanic Cloud.« less

Development and validation of an affinity chromatography step using a peptide ligand for cGMP production of factor VIII.

PubMed

Kelley, Brian D; Tannatt, Molly; Magnusson, Robert; Hagelberg, Sigrid; Booth, James

2004-08-05

An affinity chromatography step was developed for purification of recombinant B-Domain Deleted Factor VIII (BDDrFVIII) using a peptide ligand selected from a phage display library. The peptide library had variegated residues, contained both within a disulfide bond-constrained ring and flanking the ring. The peptide ligand binds to BDDrFVIII with a dissociation constant of approximately 1 microM both in free solution and when immobilized on a chromatographic resin. The peptide is chemically synthesized and the affinity resin is produced by coupling the peptide to an agarose matrix preactivated with N-hydroxysuccinimide. Coupling conditions were optimized to give consistent and complete ligand incorporation and validated with a robustness study that tested various combinations of processing limits. The peptide affinity chromatographic operation employs conditions very similar to an immunoaffinity chromatography step currently in use for BDDrFVIII manufacture. The process step provides excellent recovery of BDDrFVIII from a complex feed stream and reduces host cell protein and DNA by 3-4 logs. Process validation studies established resin reuse over 26 cycles without changes in product recovery or purity. A robustness study using a factorial design was performed and showed that the step was insensitive to small changes in process conditions that represent normal variation in commercial manufacturing. A scaled-down model of the process step was qualified and used for virus removal studies. A validation package addressing the safety of the leached peptide included leaching rate measurements under process conditions, testing of peptide levels in product pools, demonstration of robust removal downstream by spiking studies, end product testing, and toxicological profiling of the ligand. The peptide ligand affinity step was scaled up for cGMP production of BDDrFVIII for clinical trials.

Long-term safety and efficacy of recombinant factor VIII Fc fusion protein (rFVIIIFc) in subjects with haemophilia A.

PubMed

Nolan, B; Mahlangu, J; Perry, D; Young, G; Liesner, R; Konkle, B; Rangarajan, S; Brown, S; Hanabusa, H; Pasi, K J; Pabinger, I; Jackson, S; Cristiano, L M; Li, X; Pierce, G F; Allen, G

2016-01-01

The safety, efficacy and prolonged half-life of recombinant factor VIII Fc fusion protein (rFVIIIFc) in previously treated patients with severe haemophilia A was demonstrated in the phase 3 A-LONG and Kids A-LONG studies. Here, we report interim safety and efficacy data from the rFVIIIFc extension study, ASPIRE (ClinicalTrials.gov #NCT01454739). Eligible subjects could enrol in ASPIRE upon completing A-LONG or Kids A-LONG. There were four treatment groups: individualized prophylaxis; weekly prophylaxis; modified prophylaxis (for subjects in whom optimal treatment could not be achieved with individualized or weekly prophylaxis); and episodic treatment. The primary endpoint was development of inhibitors. A total of 150 A-LONG subjects and 61 Kids A-LONG subjects enrolled in ASPIRE. As of the interim data cut (6 January 2014), the median time on study was 80.9 (A-LONG) and 23.9 (Kids A-LONG) weeks. The majority of subjects (A-LONG, 92.0%; Kids A-LONG, 57.4%) had ≥100 cumulative rFVIIIFc exposure days. No inhibitors were observed. Adverse events were generally consistent with those expected in the general haemophilia A population. Median annualized bleeding rates (ABRs) were low with individualized [A-LONG: 0.66; Kids A-LONG: 0.00 (<6 years old), 1.54 (6 to <12 years old)], weekly (A-LONG: 2.03) and modified (A-LONG: 1.97) prophylaxis. There was no change in prophylactic infusion frequency or total weekly prophylactic dose in the majority of subjects from A-LONG and Kids A-LONG. Interim data from ASPIRE confirm the long-term safety of rFVIIIFc and the maintenance of a low ABR with extended-interval prophylactic dosing in patients with severe haemophilia A. © 2015 The Authors. Haemophilia Published by John Wiley & Sons Ltd.

Ionospheric Results with Sounding Rockets and the Explorer VIII Satellite (1960 )

NASA Technical Reports Server (NTRS)

Bourdeau, R. E.

1961-01-01

A review is made of ionospheric data reported since the IGY from rocket and satellite-borne ionospheric experiments. These include rocket results on electron density (RF impedance probe), D-region conductivity (Gerdien condenser), and electron temperature (Langmuir probe). Also included are data in the 1000 kilometer region on ion concentration (ion current monitor) and electron temperature from the Explorer VIII Satellite (1960 xi). The review includes suggestions for second generation experiments and combinations thereof particularly suited for small sounding rockets.

Relationship between development of post-thrombotic syndrome and serial ultrasound, D-dimer, and factor VIII activity after a first deep venous thrombosis.

PubMed

Roberts, Lara N; Patel, Raj K; Goss, David E; Chitongo, Paradzai; Bonner, Lynda; Arya, Roopen

2016-01-01

The aim of this study was to evaluate the relationship of post-thrombotic syndrome (PTS) with residual vein thrombosis, deep venous reflux (DVT), D-dimer, and factor VIII (FVIII) after a first deep venous thrombosis (DVT). There were 133 participants with objectively confirmed DVT, of whom 114 were observed for 6 months after completion of anticoagulation. Ultrasound, D-dimer, and FVIII evaluations were undertaken at 6 weeks after completion of anticoagulation and at the end of follow-up. PTS was considered present in those with a score of ≥5 on the Villalta scale at either assessment. The cumulative incidence of PTS was 51.8%, with median duration of follow-up of 11 months. Median D-dimer and FVIII in those with PTS were significantly higher at both time points compared with those without. Similarly, residual vein thrombosis and deep venous reflux were more prevalent in those with PTS at both study assessments. On multivariable analysis, only FVIII at end of study remained significantly associated with PTS with an odds ratio of 2.83 (95% confidence interval, 1.09-7.42; P = .034). Ultrasound markers and D-dimer were not significantly associated with PTS after adjustment for age, body mass index, Charlson Index ≥1, and proximal extent of DVT. FVIII activity at end of follow-up was independently associated with PTS, suggesting underlying activation of coagulation. Copyright © 2016 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.

Physical activity in individuals with haemophilia and experience with recombinant factor VIII Fc fusion protein and recombinant factor IX Fc fusion protein for the treatment of active patients: a literature review and case reports.

PubMed

Wang, Michael; Álvarez-Román, María Teresa; Chowdary, Pratima; Quon, Doris V; Schafer, Kim

2016-10-01

The World Federation of Hemophilia and the National Hemophilia Foundation encourage people with haemophilia (PWH) to participate in routine physical activity. The benefits of physical activity for PWH include improvements in joint, bone, and muscle health. Accordingly, a number of studies suggest that levels of physical activity among PWH are similar to those of their healthy peers, especially among individuals who began prophylaxis at an early age (≤3 years). Importantly, several studies found either no increased risk or only a transient increase in risk of bleeding with more intensive physical activity compared with less intensive physical activity. Data on optimal prophylaxis regimens for PWH who participate in physical/sporting activities; however, remain sparse. Long-acting recombinant factor VIII Fc fusion protein (rFVIIIFc) and recombinant factor IX Fc fusion protein (rFIXFc) demonstrated efficacy for the prevention and treatment of bleeding episodes in Phase 3 clinical trials of participants with haemophilia A and B, respectively, with most individuals able to maintain or increase their physical activities. This manuscript reviews the current literature that describes physical activity in PWH. Additionally, case studies are presented to provide supplemental information to clinicians illustrating the use of rFVIIIFc and rFIXFc in physically active patients with haemophilia A and B, respectively. These case reports demonstrate that it is possible for patients to be physically active and maintain good control of their haemophilia with extended interval prophylactic dosing using rFVIIIFc or rFIXFc.

Physical activity in individuals with haemophilia and experience with recombinant factor VIII Fc fusion protein and recombinant factor IX Fc fusion protein for the treatment of active patients: a literature review and case reports

PubMed Central

Wang, Michael; Álvarez-Román, María Teresa; Chowdary, Pratima; Quon, Doris V.; Schafer, Kim

2016-01-01

The World Federation of Hemophilia and the National Hemophilia Foundation encourage people with haemophilia (PWH) to participate in routine physical activity. The benefits of physical activity for PWH include improvements in joint, bone, and muscle health. Accordingly, a number of studies suggest that levels of physical activity among PWH are similar to those of their healthy peers, especially among individuals who began prophylaxis at an early age (≤3 years). Importantly, several studies found either no increased risk or only a transient increase in risk of bleeding with more intensive physical activity compared with less intensive physical activity. Data on optimal prophylaxis regimens for PWH who participate in physical/sporting activities; however, remain sparse. Long-acting recombinant factor VIII Fc fusion protein (rFVIIIFc) and recombinant factor IX Fc fusion protein (rFIXFc) demonstrated efficacy for the prevention and treatment of bleeding episodes in Phase 3 clinical trials of participants with haemophilia A and B, respectively, with most individuals able to maintain or increase their physical activities. This manuscript reviews the current literature that describes physical activity in PWH. Additionally, case studies are presented to provide supplemental information to clinicians illustrating the use of rFVIIIFc and rFIXFc in physically active patients with haemophilia A and B, respectively. These case reports demonstrate that it is possible for patients to be physically active and maintain good control of their haemophilia with extended interval prophylactic dosing using rFVIIIFc or rFIXFc. PMID:27116081

Insight into resistance mechanism of anaplastic lymphoma kinase to alectinib and JH-VIII-157-02 caused by G1202R solvent front mutation.

PubMed

Wang, Han; Wang, Yao; Guo, Wentao; Du, Bin; Huang, Xiaobing; Wu, Riping; Yang, Baoyu; Lin, Xiaoyan; Wu, Yilan

2018-01-01

Mutated anaplastic lymphoma kinase (ALK) drives the development of advanced non-small cell lung cancer (NSCLC). Most reported small-molecule inhibitors targeting the ALK domain do not display good inhibition of the G1202R solvent front mutation. The solvent front mutation was assumed to hinder drug binding. However, a different fact could be uncovered by the simulations reported in this study through a structural analog of alectinib (JH-VIII-157-02), which demonstrated potent effects against the G1202R mutation. Molecular docking, conventional molecular dynamics (MD) simulations, free energy calculations, and umbrella sampling (US) simulations were carried out to make clear the principles of the binding preferences of alectinib and JH-VIII-157-02 toward ALK WT and the ALK G1202R (ALK G1202R ) mutation. JH-VIII-157-02 has similar binding affinities to both ALK WT and ALK G1202R whereas it has has a much lower binding affinity for alectinib to ALK G1202R . Analysis of individual energy terms indicate the major variation involves the van der Waals and entropy terms. Structural analysis reveals that the conformational change of the ATP-binding glycine-rich loop was primarily responsible for the alectinib resistance, not JH-VIII-157-02. In addition, US simulations prove JH-VIII-157-02 has similar dissociative processes from both ALK WT and ALK G1202R , while alectinib is more easily dissociated from ALK G1202R than from ALK WT , thus indicating lesser residence time. Both the binding affinity and the drug residence time should be emphasized in rational drug design to overcome the G1202R solvent front mutation in ALK resistance.

Insight into resistance mechanism of anaplastic lymphoma kinase to alectinib and JH-VIII-157-02 caused by G1202R solvent front mutation

PubMed Central

Wang, Han; Wang, Yao; Guo, Wentao; Du, Bin; Huang, Xiaobing; Wu, Riping; Yang, Baoyu; Lin, Xiaoyan; Wu, Yilan

2018-01-01

Background Mutated anaplastic lymphoma kinase (ALK) drives the development of advanced non-small cell lung cancer (NSCLC). Most reported small-molecule inhibitors targeting the ALK domain do not display good inhibition of the G1202R solvent front mutation. The solvent front mutation was assumed to hinder drug binding. However, a different fact could be uncovered by the simulations reported in this study through a structural analog of alectinib (JH-VIII-157-02), which demonstrated potent effects against the G1202R mutation. Methods Molecular docking, conventional molecular dynamics (MD) simulations, free energy calculations, and umbrella sampling (US) simulations were carried out to make clear the principles of the binding preferences of alectinib and JH-VIII-157-02 toward ALKWT and the ALK G1202R (ALKG1202R) mutation. Results JH-VIII-157-02 has similar binding affinities to both ALKWT and ALKG1202R whereas it has has a much lower binding affinity for alectinib to ALKG1202R. Analysis of individual energy terms indicate the major variation involves the van der Waals and entropy terms. Structural analysis reveals that the conformational change of the ATP-binding glycine-rich loop was primarily responsible for the alectinib resistance, not JH-VIII-157-02. In addition, US simulations prove JH-VIII-157-02 has similar dissociative processes from both ALKWT and ALKG1202R, while alectinib is more easily dissociated from ALKG1202R than from ALKWT, thus indicating lesser residence time. Conclusion Both the binding affinity and the drug residence time should be emphasized in rational drug design to overcome the G1202R solvent front mutation in ALK resistance. PMID:29785088

Anterior Inferior Cerebellar Arteries Juxtaposed with the Internal Acoustic Meatus and Their Relationship to the Cranial Nerve VII/VIII Complex

PubMed Central

Alonso, Fernando; Iwanaga, Joe; Oskouian, Rod J; Loukas, Marios; Demerdash, Amin; Tubbs, R. Shane

2017-01-01

Vascular loops in the cerebellopontine angle (CPA) and their relationship to cranial nerves have been used to explain neurological symptoms. The anterior inferior cerebellar artery (AICA) has variable branches producing vascular loops that can compress the facial cranial nerve (CN) VII and vestibulocochlear (CN VIII) nerves. AICA compression of the facial-vestibulocochlear nerve complex can lead to various clinical presentations, including hemifacial spasm (HFS), tinnitus, and hemiataxia. The formation of arterial loops inside or outside of the internal auditory meatus (IAM) can cause abutment or compression of CN VII and CN VIII. Twenty-five (50 sides) fresh adult cadavers underwent dissection of the cerebellopontine angle in the supine position. In regard to relationships between the AICA and the nerves of the facial/vestibulocochlear complex, 33 arteries (66%) traveled in a plane between the facial/nervus intermedius nerves and the cochlear and vestibular nerves. Five arteries (10%) traveled below the CN VII/VIII complex, six (12%) traveled posterior to the nerve complex, four (8%) formed a semi-circle around the upper half of the nerve complex, and two (4%) traveled between and partially separated the nervus intermedius and facial nerve proper. Our study found that the majority of AICA will travel in a plane between the facial/nervus intermedius nerves and the cochlear and vestibular nerves. Although the relationship between the AICA and porus acusticus and AICA and the nerves of the CN VII/VIII complex are variable, based on our findings, some themes exist. Surgeons should consider these with approaches to the cerebellopontine angle. PMID:29057182

Anterior Inferior Cerebellar Arteries Juxtaposed with the Internal Acoustic Meatus and Their Relationship to the Cranial Nerve VII/VIII Complex.

PubMed

Alonso, Fernando; Kassem, Mohammad W; Iwanaga, Joe; Oskouian, Rod J; Loukas, Marios; Demerdash, Amin; Tubbs, R Shane

2017-08-16

Vascular loops in the cerebellopontine angle (CPA) and their relationship to cranial nerves have been used to explain neurological symptoms. The anterior inferior cerebellar artery (AICA) has variable branches producing vascular loops that can compress the facial cranial nerve (CN) VII and vestibulocochlear (CN VIII) nerves. AICA compression of the facial-vestibulocochlear nerve complex can lead to various clinical presentations, including hemifacial spasm (HFS), tinnitus, and hemiataxia. The formation of arterial loops inside or outside of the internal auditory meatus (IAM) can cause abutment or compression of CN VII and CN VIII. Twenty-five (50 sides) fresh adult cadavers underwent dissection of the cerebellopontine angle in the supine position. In regard to relationships between the AICA and the nerves of the facial/vestibulocochlear complex, 33 arteries (66%) traveled in a plane between the facial/nervus intermedius nerves and the cochlear and vestibular nerves. Five arteries (10%) traveled below the CN VII/VIII complex, six (12%) traveled posterior to the nerve complex, four (8%) formed a semi-circle around the upper half of the nerve complex, and two (4%) traveled between and partially separated the nervus intermedius and facial nerve proper. Our study found that the majority of AICA will travel in a plane between the facial/nervus intermedius nerves and the cochlear and vestibular nerves. Although the relationship between the AICA and porus acusticus and AICA and the nerves of the CN VII/VIII complex are variable, based on our findings, some themes exist. Surgeons should consider these with approaches to the cerebellopontine angle.

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

Improving attitudes toward mathematics learning with problem posing in class VIII

NASA Astrophysics Data System (ADS)

Vionita, Alfha; Purboningsih, Dyah

2017-08-01

This research is classroom action research which is collaborated to improve student's behavior toward math and mathematics learning at class VIII by using problem posing approach. The subject of research is all of students grade VIIIA which consist of 32 students. This research has been held on two period, first period is about 3 times meeting, and second period is about 4 times meeting. The instrument of this research is implementation of learning observation's guidance by using problem posing approach. Cycle test has been used to measure cognitive competence, and questionnaire to measure the students' behavior in mathematics learning process. The result of research shows the students' behavior has been improving after using problem posing approach. It is showed by the behavior's criteria of students that has increasing result from the average in first period to high in second period. Furthermore, the percentage of test result is also improve from 68,75% in first period to 78,13% in second period. On the other hand, the implementation of learning observation by using problem posing approach has also improving and it is showed by the average percentage of teacher's achievement in first period is 89,2% and student's achievement 85,8%. These results get increase in second period for both teacher and students' achievement which are 94,4% and 91,11%. As a result, students' behavior toward math learning process in class VIII has been improving by using problem posing approach.

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

PubMed

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

2015-03-01

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

78 FR 42486 - Notice of New Recreation Fees; Federal Lands Recreation Enhancement Act, (Title VIII, Pub. L. 108...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-07-16

... New Recreation Fees; Federal Lands Recreation Enhancement Act, (Title VIII, Pub. L. 108-447) AGENCY... Enhancement Act (Title VII, Pub. L. 108-447) directed the Secretary of Agriculture to publish a six month...

20 CFR 408.930 - Are title II and title XVI benefits subject to adjustment to recover title VIII overpayments?

Code of Federal Regulations, 2012 CFR

2012-04-01

... SECURITY ADMINISTRATION SPECIAL BENEFITS FOR CERTAIN WORLD WAR II VETERANS Underpayments and Overpayments... recover title VIII overpayments? (a) Definitions—(1) Cross-program recovery. Cross-program recovery is the...

20 CFR 408.930 - Are title II and title XVI benefits subject to adjustment to recover title VIII overpayments?

Code of Federal Regulations, 2013 CFR

2013-04-01

... SECURITY ADMINISTRATION SPECIAL BENEFITS FOR CERTAIN WORLD WAR II VETERANS Underpayments and Overpayments... recover title VIII overpayments? (a) Definitions—(1) Cross-program recovery. Cross-program recovery is the...

20 CFR 408.930 - Are title II and title XVI benefits subject to adjustment to recover title VIII overpayments?

Code of Federal Regulations, 2010 CFR

2010-04-01

... SECURITY ADMINISTRATION SPECIAL BENEFITS FOR CERTAIN WORLD WAR II VETERANS Underpayments and Overpayments... recover title VIII overpayments? (a) Definitions—(1) Cross-program recovery. Cross-program recovery is the...

20 CFR 408.930 - Are title II and title XVI benefits subject to adjustment to recover title VIII overpayments?

Code of Federal Regulations, 2014 CFR

2014-04-01

... SECURITY ADMINISTRATION SPECIAL BENEFITS FOR CERTAIN WORLD WAR II VETERANS Underpayments and Overpayments... recover title VIII overpayments? (a) Definitions—(1) Cross-program recovery. Cross-program recovery is the...

20 CFR 408.930 - Are title II and title XVI benefits subject to adjustment to recover title VIII overpayments?

Code of Federal Regulations, 2011 CFR

2011-04-01

... SECURITY ADMINISTRATION SPECIAL BENEFITS FOR CERTAIN WORLD WAR II VETERANS Underpayments and Overpayments... recover title VIII overpayments? (a) Definitions—(1) Cross-program recovery. Cross-program recovery is the...

20 CFR 408.913 - When would overpayment recovery defeat the purpose of the title VIII program?

Code of Federal Regulations, 2011 CFR

2011-04-01

... 20 Employees' Benefits 2 2011-04-01 2011-04-01 false When would overpayment recovery defeat the purpose of the title VIII program? 408.913 Section 408.913 Employees' Benefits SOCIAL SECURITY ADMINISTRATION SPECIAL BENEFITS FOR CERTAIN WORLD WAR II VETERANS Underpayments and Overpayments Waiver of...

20 CFR 408.913 - When would overpayment recovery defeat the purpose of the title VIII program?

Code of Federal Regulations, 2014 CFR

2014-04-01

... 20 Employees' Benefits 2 2014-04-01 2014-04-01 false When would overpayment recovery defeat the purpose of the title VIII program? 408.913 Section 408.913 Employees' Benefits SOCIAL SECURITY ADMINISTRATION SPECIAL BENEFITS FOR CERTAIN WORLD WAR II VETERANS Underpayments and Overpayments Waiver of...

20 CFR 408.913 - When would overpayment recovery defeat the purpose of the title VIII program?

Code of Federal Regulations, 2010 CFR

2010-04-01

... 20 Employees' Benefits 2 2010-04-01 2010-04-01 false When would overpayment recovery defeat the purpose of the title VIII program? 408.913 Section 408.913 Employees' Benefits SOCIAL SECURITY ADMINISTRATION SPECIAL BENEFITS FOR CERTAIN WORLD WAR II VETERANS Underpayments and Overpayments Waiver of...

76 FR 36518 - Notice of Meeting; Federal Lands Recreation Enhancement Act (Title VIII, Pub. L. 108-447)

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-22

... DEPARTMENT OF AGRICULTURE Forest Service Notice of Meeting; Federal Lands Recreation Enhancement Act (Title VIII, Pub. L. 108-447) AGENCY: Rocky Mountain Region, USDA Forest Service. ACTION: Notice of Meeting. SUMMARY: The Colorado Recreation Resource Advisory Committee will tentatively meet in...

Potential misdiagnosis of von Willebrand disease and haemophilia caused by ineffective mixing of thawed plasma.

PubMed

Favaloro, E J; Oliver, S; Mohammed, S; Ahuja, M; Grzechnik, E; Azimulla, S; McDonald, J; Lima-Oliveira, G; Lippi, G

2017-09-01

von Willebrand disease (VWD) reflects a loss or dysfunction in von Willebrand factor (VWF), while haemophilia represents a loss or dysfunction of clotting factors such as factor VIII (FVIII) or FIX. Their diagnosis requires laboratory testing, with this potentially compromised by preanalytical events, including poor sample quality. This study assessed the effect of inadequate mixing as a potential cause of VWD and haemophilia misdiagnosis. After completion of requested testing, 48 consecutive patient samples comprising separate aliquots from single collections were individually pooled, appropriately mixed, then frozen in separate aliquots, either at -20°C or -80°C for 2-7 days. Each sample set was then thawed and the separate aliquots subjected to separate mixing protocols (several inversions, blood roller, vortex) vs a non-mix sample, and all aliquots then tested for various VWF and factor assays. Non-mixing led to substantial reduction in VWF and factors in about 25% of samples, that in some cases could lead to misdiagnosis of VWD or haemophilia. Interestingly, there were also some differences observed with respect to different mixing protocols. Our study identified ineffective or variable mixing of thawed plasma samples as potential causes of misdiagnosis of VWD or haemophilia. Further education regarding the importance of appropriate mixing appears warranted. © 2017 John Wiley & Sons Ltd.

Structural Mimics of the [Fe]-Hydrogenase: A Complete Set for Group VIII Metals.

PubMed

Barik, Chandan Kr; Ganguly, Rakesh; Li, Yongxin; Leong, Weng Kee

2018-06-18

A set of structural mimics of the [Fe]-hydrogenase active site comprising all the group VIII metals, viz., [M(2-NHC(O)C 5 H 4 N)(CO) 2 (2-S-C 5 H 4 N)], has been synthesized. They exist as a mixture of isomers in solution, and the relative stability of the isomers depends on the nature of the metal and the substituent at the 6-position of the pyridine ligand.

75 FR 30366 - Notice of Meeting; Federal Lands Recreation Enhancement Act (Title VIII, Pub. L. 108-447)

Federal Register 2010, 2011, 2012, 2013, 2014

2010-06-01

... DEPARTMENT OF AGRICULTURE Forest Service Notice of Meeting; Federal Lands Recreation Enhancement Act (Title VIII, Pub. L. 108-447) AGENCY: Pacific Southwest Region, Forest Service, U.S. Department of Agriculture. ACTION: Notice of meeting. SUMMARY: The Pacific Southwest Recreation Resource Advisory Committee...

75 FR 1749 - Notice of Meeting; Federal Lands Recreation Enhancement Act (Title VIII, Pub. L. 108-447)

Federal Register 2010, 2011, 2012, 2013, 2014

2010-01-13

... DEPARTMENT OF AGRICULTURE Forest Service Notice of Meeting; Federal Lands Recreation Enhancement Act (Title VIII, Pub. L. 108-447) AGENCY: Pacific Northwest Region, Forest Service, USDA. ACTION: Notice of Meeting. SUMMARY: The Pacific Northwest Recreation Resource Advisory Committee will meet via a...

7 CFR 42.112 - Defects of containers: Tables IV, V, VI, VII, VIII, IX, and X.

Code of Federal Regulations, 2014 CFR

2014-01-01

..., and X. 42.112 Section 42.112 Agriculture Regulations of the Department of Agriculture AGRICULTURAL... Stationary Lot Sampling and Inspection § 42.112 Defects of containers: Tables IV, V, VI, VII, VIII, IX, and X... Table X—Unitizing [Plastic or other type of casing/unitizing] Defects Categories Major Minor Not...

75 FR 27770 - Lock+ Hydro Friends Fund VIII; Notice of Preliminary Permit Application Accepted for Filing and...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-05-18

... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission [Project No. 13710-000] Lock+ Hydro Friends Fund VIII; Notice of Preliminary Permit Application Accepted for Filing and Soliciting Comments, Motions To Intervene, and Competing Applications May 11, 2010. On April 13, 2010 Lock+ Hydro Friends Fund...

Factoring nonviral gene therapy into a cure for hemophilia A.

PubMed

Gabrovsky, Vanessa; Calos, Michele P

2008-10-01

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

75 FR 26196 - Notice of Proposed New Recreation Fee Site; Federal Lands Recreation Enhancement Act, (Title VIII...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-05-11

... DEPARTMENT OF AGRICULTURE Forest Service Notice of Proposed New Recreation Fee Site; Federal Lands Recreation Enhancement Act, (Title VIII, Pub. L. 108-447) AGENCY: National Forests in Mississippi, Forest... Enhancement Act (Title VII, Pub. L. 108-447) directed the Secretary of Agriculture to publish advance notice...

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

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.

The Safety and Feasibility of Three-Dimensional Visualization Technology Assisted Right Posterior Lobe Allied with Part of V and VIII Sectionectomy for Right Hepatic Malignancy Therapy.

PubMed

Hu, Min; Hu, Haoyu; Cai, Wei; Mo, Zhikang; Xiang, Nan; Yang, Jian; Fang, Chihua

2018-05-01

Hepatectomy is the optimal method for liver cancer; the virtual liver resection based on three-dimensional visualization technology (3-DVT) could provide better preoperative strategy for surgeon. We aim to introduce right posterior lobe allied with part of V and VIII sectionectomy assisted by 3-DVT as a promising treatment for massive or multiple right hepatic malignancies to retain maximum residual liver volume on the basis of R0 resection. Among 126 consecutive patients who underwent hepatectomy, 9 (7%) underwent right posterior lobe allied with part of V and VIII sectionectomy. 21 (17%) underwent right hemihepatectomy (RH). The virtual RH was performed with 3-DVT, which provided better observation of spatial position relationship between tumor and vessels, and the more accurate estimation of the remnant liver volume. If remnant liver volume was <40%, right posterior lobe allied with part of V and VIII sectionectomy should be undergone. Then, the precut line ought to be planned on the basis of protecting the portal branch of subsegment 5 and 8. The postoperative outcome of patients was compared before and after propensity score matching. Nine patients meeting the eligibility criteria received right posterior lobe allied with part of V and VIII sectionectomy. The variables, including the overall mean operation time, blood transfusion, operation length, liver function, and postoperative complications, were similar between two groups before and after propensity matching. The postoperative first, third, fifth, and seventh days mean value of aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin (ALB), and total bilirubin had no significant difference compared with preoperative value. One patient in each group had recurrence six months after surgery. Right posterior lobe allied with part of V and VIII sectionectomy based on 3-DVT is safe and feasible surgery way, and can be a very promising method in massive or multiple right hepatic malignancy

75 FR 36426 - Legislative Changes to Nursing Student Loan Program Authorized Under Title VIII of the Public...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-06-25

... Changes to Nursing Student Loan Program Authorized Under Title VIII of the Public Health Service Act....) 111-148. Section 5202 of the ACA changes the Nursing Student Loan (NSL) program by: (1) Increasing the.... SUPPLEMENTARY INFORMATION: The Nursing Student Loan (NSL) program was authorized by the Nurse Training Act of...

Characteristics of Minimally Oversized Adeno-Associated Virus Vectors Encoding Human Factor VIII Generated Using Producer Cell Lines and Triple Transfection.

PubMed

Nambiar, Bindu; Cornell Sookdeo, Cathleen; Berthelette, Patricia; Jackson, Robert; Piraino, Susan; Burnham, Brenda; Nass, Shelley; Souza, David; O'Riordan, Catherine R; Vincent, Karen A; Cheng, Seng H; Armentano, Donna; Kyostio-Moore, Sirkka

2017-02-01

Several ongoing clinical studies are evaluating recombinant adeno-associated virus (rAAV) vectors as gene delivery vehicles for a variety of diseases. However, the production of vectors with genomes >4.7 kb is challenging, with vector preparations frequently containing truncated genomes. To determine whether the generation of oversized rAAVs can be improved using a producer cell-line (PCL) process, HeLaS3-cell lines harboring either a 5.1 or 5.4 kb rAAV vector genome encoding codon-optimized cDNA for human B-domain deleted Factor VIII (FVIII) were isolated. High-producing "masterwells" (MWs), defined as producing >50,000 vg/cell, were identified for each oversized vector. These MWs provided stable vector production for >20 passages. The quality and potency of the AAVrh8R/FVIII-5.1 and AAVrh8R/FVIII-5.4 vectors generated by the PCL method were then compared to those prepared via transient transfection (TXN). Southern and dot blot analyses demonstrated that both production methods resulted in packaging of heterogeneously sized genomes. However, the PCL-derived rAAV vector preparations contained some genomes >4.7 kb, whereas the majority of genomes generated by the TXN method were ≤4.7 kb. The PCL process reduced packaging of non-vector DNA for both the AAVrh8R/FVIII-5.1 and the AAVrh8R/FVIII-5.4 kb vector preparations. Furthermore, more DNA-containing viral particles were obtained for the AAVrh8R/FVIII-5.1 vector. In a mouse model of hemophilia A, animals administered a PCL-derived rAAV vector exhibited twofold higher plasma FVIII activity and increased levels of vector genomes in the liver than mice treated with vector produced via TXN did. Hence, the quality of oversized vectors prepared using the PCL method is greater than that of vectors generated using the TXN process, and importantly this improvement translates to enhanced performance in vivo.

Development of Integrated Natural Science Teaching Materials Webbed Type with Applying Discourse Analysis on Students Grade VIII in Physics Class

NASA Astrophysics Data System (ADS)

Sukariasih, Luh

2017-05-01

This study aims to produce teaching materials integrated natural science (IPA) webbed type of handout types are eligible for use in integrated science teaching. This type of research IS a kind of research and development / Research and Development (R & D) with reference to the 4D development model that is (define, design, develop, and disseminate). Data analysis techniques used to process data from the results of the assessment by the validator expert, and the results of the assessment by teachers and learners while testing is limited (12 students of class VIII SMPN 10 Kendari) using quantitative descriptive data analysis techniques disclosed in the distribution of scores on the scale of five categories grading scale that has been determined. The results of due diligence material gain votes validator material in the category of “very good” and “good”, of the data generated in the feasibility test presentation obtained the category of “good” and “excellent”, from the data generated in the feasibility of graphic test obtained the category of “very good “and” good “, as well as of the data generated in the test the feasibility of using words and language obtained the category of“very good “and” good “, so with qualifications gained the teaching materials IPA integrated type webbed by applying discourse analysis on the theme of energy and food for Junior High School (SMP) grade VIII suitable as teaching materials. In limited testing, data generated in response to a science teacher at SMPN 10 Kendari to product instructional materials as “excellent”, and from the data generated while testing is limited by the 12 students of class VIII SMPN 10 Kendari are more students who score indicates category “very good”, so that the qualification obtained by the natural science (IPA) teaching material integrated type webbed by applying discourse analysis on the theme of energy and food for SMP / class VIII fit for use as teaching material.

Revised and extended analysis of the eighth spectrum of platinum (Pt VIII)

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

Azarov, Vladimir I., E-mail: vlad_azarov@yahoo.com; Gayasov, Robert R.

2017-05-15

The spectrum of platinum was observed in the 300–2100 Å wavelength region. Grazing and normal incidence VUV spectrographs have been used to record the spectrum. The (5d{sup 3}+5d{sup 2}6s)−5d{sup 2}6p transition array of seven times ionized platinum, Pt VIII, has been investigated. The configurations 5d{sup 3} and 5d{sup 2}6p had been previously studied, and all levels of these configurations (19 and 45 levels, respectively) had been established. The previous analysis was based on 178 classified spectral lines. In the current analysis we have confirmed identification of all previously found levels and all but 10 previously assigned spectral lines, although we havemore » detected a large (up to 35 mÅ) systematic shift in wavelength measurements used in the previous analysis. Based on new wavelength measurements, we have corrected the 5d{sup 3} and 5d{sup 2}6p energy level values (by up to 55 cm{sup −1}) and established for the first time 14 out of 16 theoretically possible 5d{sup 2}6s levels in Pt VIII. The total list of identified lines (including 180 new lines) contains 349 entries. The orthogonal operators technique was used to calculate the level structure and transition probabilities. The energy parameters have been determined by the least squares fit to the observed levels. Calculated transition probability and energy values, as well as LS-compositions obtained from the fitted parameters are presented.« less

Increased thromboplastic potential in diabetes: a multifactorial phenomenon.

PubMed

Landgraf-Leurs, M M; Ladik, T; Smolka, B; Bock, T; Schramm, W; Spannagl, M; Landgraf, R

1987-07-01

Coagulation parameters, platelet aggregation, and thromboxane production as well as metabolic parameters were measured in 31 diabetic patients, 12 without and 19 with clinically manifest late complications, and in 14 healthy control subjects. Spontaneous in vitro aggregation as well as ADP, collagen, and arachidonic acid induced aggregation were higher in both groups of diabetic patients, without an increase in thromboxane B2 production. In diabetic patients with late complications an increase in fibrinogen, fibrinogen cyanogen bromide peptide, factor VIII related antigen, C1-esterase inhibitor, and antithrombin III was observed in comparison to healthy subjects. Fibrinogen, C1-esterase inhibitor, and factor VIII related antigen were already elevated in diabetic patients without clinically manifest late vascular complications. No strict correlations were found between serum glucose, glycosylated hemoglobin, and glycosylated albumin, on the one hand, and coagulation promoting or inhibiting factors, aggregation or thromboxane B2 production, on the other, in either control or diabetic subjects. Also no correlations existed between the coagulation parameters and the aggregation results. In vitro incubation of pooled normal plasma with different glucose concentrations had no influence on the methods by which the coagulation parameters were measured. These data indicate that rather early in the diabetic state many changes take place in different phases of the thrombostatic process, all resulting in an increased hemostatic diathesis.

Non-genetic risk factors and their influence on the management of patients in the clinic.

PubMed

Álvarez, Teresa; Soto, Immaculada; Astermark, Jan

2015-02-01

The development of inhibitors is the most serious iatrogenic complication affecting patients with haemophilia. This complication is associated with impaired vital or functional prognosis, reduced quality of life and increased cost of treatment. The reasons why some patients develop antibodies to factor replacement and others do not remain unclear. It is however clear that inhibitor development results from a complex multifactorial interaction between genetic and non-genetic risk factors. Environmental influences implicated in increasing the risk of inhibitor formation can be viewed as modifiable risk factors. Therefore, identification of the non-genetic risk factors may offer the possibility of personalising haemophilia therapy by modifying treatment strategies in high-risk patients in the critical early phase of factor VIII exposure. In this article, we review the non-genetic factors reported as well as the potential impact of danger signals and the different scores for inhibitor development risk stratification. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

77 FR 62215 - Notice of Proposed New Fee Site; Federal Lands Recreation Enhancement Act, (Title VIII, Pub. L...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-10-12

... DEPARTMENT OF AGRICULTURE Forest Service Notice of Proposed New Fee Site; Federal Lands Recreation Enhancement Act, (Title VIII, Pub. L. 108-447) AGENCY: Payette National Forest, Forest Service, USDA. ACTION... INFORMATION: The Federal Recreation Lands Enhancement Act (Title VII, Pub. L. 108-447) directed the Secretary...

Bloodcurdling movies and measures of coagulation: Fear Factor crossover trial.

PubMed

Nemeth, Banne; Scheres, Luuk J J; Lijfering, Willem M; Rosendaal, Frits R

2015-12-16

To assess whether, as has been hypothesised since medieval times, acute fear can curdle blood. Crossover trial. Main meeting room of Leiden University's Department of Clinical Epidemiology, the Netherlands, converted to a makeshift cinema. 24 healthy volunteers aged ≤30 years recruited among students, alumni, and employees of the Leiden University Medical Center: 14 were assigned to watch a frightening (horror) movie followed by a non-threatening (educational) movie and 10 to watch the movies in reverse order. The movies were viewed more than a week apart at the same time of day and both lasted approximately 90 minutes. The primary outcome measures were markers, or "fear factors" of coagulation activity: blood coagulant factor VIII, D-dimer, thrombin-antithrombin complexes, and prothrombin fragments 1+2. The secondary outcome was participant reported fear experienced during each movie using a visual analogue fear scale. All participants completed the study. The horror movie was perceived to be more frightening than the educational movie on a visual analogue fear scale (mean difference 5.4, 95% confidence interval 4.7 to 6.1). The difference in factor VIII levels before and after watching the movies was higher for the horror movie than for the educational movie (mean difference of differences 11.1 IU/dL (111 IU/L), 95% confidence interval 1.2 to 21.0 IU/dL). The effect of either movie on levels of thrombin-antithrombin complexes, D-dimer, and prothrombin fragments 1+2 did not differ. Frightening (in this case, horror) movies are associated with an increase of blood coagulant factor VIII without actual thrombin formation in young and healthy adults. Trial registration ClinicalTrials.gov NCT02601053. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

FcRn Rescues Recombinant Factor VIII Fc Fusion Protein from a VWF Independent FVIII Clearance Pathway in Mouse Hepatocytes

PubMed Central

van der Flier, Arjan; Liu, Zhan; Tan, Siyuan; Chen, Kai; Drager, Douglas; Liu, Tongyao; Patarroyo-White, Susannah; Jiang, Haiyan; Light, David R.

2015-01-01

We recently developed a longer lasting recombinant factor VIII-Fc fusion protein, rFVIIIFc, to extend the half-life of replacement FVIII for the treatment of people with hemophilia A. In order to elucidate the biological mechanism for the elongated half-life of rFVIIIFc at a cellular level we delineated the roles of VWF and the tissue-specific expression of the neonatal Fc receptor (FcRn) in the biodistribution, clearance and cycling of rFVIIIFc. We find the tissue biodistribution is similar for rFVIIIFc and rFVIII and that liver is the major clearance organ for both molecules. VWF reduces the clearance and the initial liver uptake of rFVIIIFc. Pharmacokinetic studies in FcRn chimeric mice show that FcRn expressed in somatic cells (hepatocytes or liver sinusoidal endothelial cells) mediates the decreased clearance of rFVIIIFc, but FcRn in hematopoietic cells (Kupffer cells) does not affect clearance. Immunohistochemical studies show that when rFVIII or rFVIIIFc is in dynamic equilibrium binding with VWF, they mostly co localize with VWF in Kupffer cells and macrophages, confirming a major role for liver macrophages in the internalization and clearance of the VWF-FVIII complex. In the absence of VWF a clear difference in cellular localization of VWF-free rFVIII and rFVIIIFc is observed and neither molecule is detected in Kupffer cells. Instead, rFVIII is observed in hepatocytes, indicating that free rFVIII is cleared by hepatocytes, while rFVIIIFc is observed as a diffuse liver sinusoidal staining, suggesting recycling of free-rFVIIIFc out of hepatocytes. These studies reveal two parallel linked clearance pathways, with a dominant pathway in which both rFVIIIFc and rFVIII complexed with VWF are cleared mainly by Kupffer cells without FcRn cycling. In contrast, the free fraction of rFVIII or rFVIIIFc unbound by VWF enters hepatocytes, where FcRn reduces the degradation and clearance of rFVIIIFc relative to rFVIII by cycling rFVIIIFc back to the liver sinusoid and

Evaluation of Consequences of Dust Positioned in Southwest of Iran on Coagulant Factors

PubMed Central

Saeb, Keivan; Sarizade, Gholamreza; Khodadi, Mohammad; Biazar, Esmaeil

2013-01-01

Background: Various regions in Iran, especially the Khuzestan Province, have been covered by dust and dirt during the past two years due to environmental changes in the Middle East. We sought to evaluate the effect of these pollutants on the coagulant factors of people residing in Abadan and Khoramshahr, two major cities of Khuzestan Province. Methods: One hundred twenty-nine healthy individuals were enrolled into this study, and their prothrombin time as well as fibrinogen, platelet, and Factor VIII levels were measured before and after climate changes. Results: After climate changes, the mean prothrombin time decreased, while the fibrinogen, platelet, and Factor VIII levels rose. Conclusion: The results of this study suggest that the pollutants deployed in the Middle East can affect prothrombin time as well as fibrinogen, platelet, and Factor VII levels considerably and increase coagulant state. The pollutants can, consequently, increase the risk of cardiovascular diseases. It seems that cooperation at government levels between Iran and its neighboring countries is required to reverse desertification and avoid inaccurate usage of subterranean water resources so as to lessen air pollution. PMID:23825886

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

PubMed

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

2016-01-01

A rapidly growing evidence showed that regulatory T cells (Tregs) play a crucial role in tolerance to coagulation factors and may be involved in the pathogenesis of inhibitor formation in patients with hemophilia. We determined the percentage of Tregs (CD4CD25CD127) in 45 children with hemophilia A compared with 45 healthy controls, and assessed their relation to the clinical characteristics of patients and factor VIII (FVIII) inhibitors. Patients were studied stressing on frequency of bleeding attacks, joint pain, history of viral hepatitis, and the received therapy (FVIII precipitate/cryotherapy). FVIII activity and FVIII inhibitors were assessed with flow cytometric analysis of CD4CD25CD127 Tregs. According to residual FVIII activity levels, 30 patients (66.7%) had mild/moderate hemophilia A, whereas 15 (33.3%) patients had severe hemophilia A. The frequency of Tregs was significantly lower among all patients with hemophilia A compared with controls (2.59 ± 1.1 versus 3.73 ± 1.12%; P = 0.002). Tregs were significantly decreased among patients with FVIII inhibitors compared with the inhibitor-negative group (P < 0.001). Patients with hematuria or severe hemophilia A had lower Tregs levels than those without (P = 0.34 and P = 0.011, respectively). A significant positive correlation was found between the percentage of Tregs and FVIII among hemophilia A patients. ROC curve analysis revealed that the cut-off value of Tregs at 1.91% could differentiate patients with and without FVIII inhibitors, with a sensitivity of 100% and a specificity of 91.3%. We suggest that alteration in the frequency of Tregs in young patients with hemophilia A may contribute to inhibitor formation and disease severity.

Redox reactions of V(III) and Cr(III)picolinate complexes in aqueous solutions

NASA Astrophysics Data System (ADS)

Vinayakumar, C. K.; Dey, G. R.; Kishore, K.; Moorthy, P. N.

1996-12-01

Reactions of e aq-, H-atoms, OH, (CH 3) 2COH, and CO 2- radicals with V(III)picolinate and Cr(III)picolinate have been studied by the pulse radiolysis technique. The spectra of V(II)picolinate, V(IV)picolinate, Cr(II)picolinate, OH adduct of Cr(III)picolinate and Cr(IV)picolinate have been obtained and the rate constants of the reactions of various radicals with V(III) and Cr(III)picolinate have been determined. The implications of these results to the chemical decontamination of nuclear reactor systems are discussed.

Heckathorn's disease: variable functional dificiency of antihemophilic factor (factor VIII).

PubMed

Ratnoff, O D; Lewis, J H

1975-08-01

A family is described in which a syndrome resembling moderately severe classic hemophilia was apparently inherited as an X chromosome-linked trait. In two affected individuals, the titer of functional antihemophilic factor varied dramatically from time to time, while the conversion of prothrombin to thrombin was impaired in no apparent relationship to AHF functional activity. A transfusion of 200 ml of fresh-frozen plasma did not correct the serum prothrombin times in either patient. In vitro, the additions of 10% of normal plasma or serum or washed plain or frozen platelets also did not normalize the serum prothrombin times. No inhibitor could be demonstrated in the blood of either patient. In one patient, RH, dissipation of infused cryoprecipitated AHF was abnormally slow, and, after an intensive course of transfusion of cryoprecipitate and whole blood, the titer of functional AHF remained at normal levels for at least 1 wk. The plasma of RH inhibited a human antibody against AHF in proportion to its titer of functional AHF (i.e., the defect was CRM-) despite the presence of relatively greater amounts of antigenic material recognized by heterologous antiserum. No qualitative abnormality of the AHF-like material in RH's plasma was identified. Inheritance of the abnormality appears superficially to be X chromosome-linked; on this assumption, three of four obligate carriers of the disorder were recognized by the presence of excess amounts of AHF-like antigens relative to AHF functional activity. This coagulation disorder has been designated Heckathorn's disease and may presage the discovery of other examples of hemophilia-related syndromes.

75 FR 80789 - Notice of New Fee Site; Federal Lands Recreation Enhancement Act, (Title VIII, Pub. L. 108-447)

Federal Register 2010, 2011, 2012, 2013, 2014

2010-12-23

... DEPARTMENT OF AGRICULTURE Forest Service Notice of New Fee Site; Federal Lands Recreation Enhancement Act, (Title VIII, Pub. L. 108-447) AGENCY: Rio Grande National Forest, USDA Forest Service. ACTION.... SUPPLEMENTARY INFORMATION: The Federal Recreation Lands Enhancement Act (Title VII, Pub. L. 108-447) directed...

77 FR 42696 - Notice of New Fee Sites; Federal Lands Recreation Enhancement Act, (Title VIII, Pub. L. 108-447)

Federal Register 2010, 2011, 2012, 2013, 2014

2012-07-20

... DEPARTMENT OF AGRICULTURE Forest Service Notice of New Fee Sites; Federal Lands Recreation Enhancement Act, (Title VIII, Pub. L. 108-447) AGENCY: Kootenai National Forest, Forest Service, USDA. ACTION... SUPPLEMENTARY INFORMATION: The Federal Recreation Lands Enhancement Act (Title VII, Pub. L. 108-447) directed...

Design local exhaust ventilation on sieve machine at PT.Perkebunan Nusantara VIII Ciater using design for assembly (DFA) approach with Boothroyd and Dewhurst method

NASA Astrophysics Data System (ADS)

Khalqihi, K. I.; Rahayu, M.; Rendra, M.

2017-12-01

PT Perkebunan Nusantara VIII Ciater is a company produced black tea orthodox more or less 4 tons every day. At the production section, PT Perkebunan Nusantara VIII will use local exhaust ventilation specially at sortation area on sieve machine. To maintain the quality of the black tea orthodox, all machine must be scheduled for maintenance every once a month and takes time 2 hours in workhours, with additional local exhaust ventilation, it will increase time for maintenance process, if maintenance takes time more than 2 hours it will caused production process delayed. To support maintenance process in PT Perkebunan Nusantara VIII Ciater, designing local exhaust ventilation using design for assembly approach with Boothroyd and Dewhurst method, design for assembly approach is choosen to simplify maintenance process which required assembly process. There are 2 LEV designs for this research. Design 1 with 94 components, assembly time 647.88 seconds and assembly efficiency level 23.62%. Design 2 with 82 components, assembly time 567.84 seconds and assembly efficiency level 24.83%. Design 2 is choosen for this research based on DFA goals, minimum total part that use, optimization assembly time, and assembly efficiency level.

78 FR 52499 - Notice of New Fee Site; Federal Lands Recreation Enhancement Act, (Title VIII, Pub. L. 108-447)

Federal Register 2010, 2011, 2012, 2013, 2014

2013-08-23

... DEPARTMENT OF AGRICULTURE Forest Service Notice of New Fee Site; Federal Lands Recreation Enhancement Act, (Title VIII, Pub. L. 108-447) AGENCY: Monongahela National Forest, Forest Service, USDA... Act (Title VII, Pub. L. 108-447) directed the Secretary of Agriculture to publish a six month advance...

[Effects of various adsorbants on coagulation factors (author's transl)].

PubMed

Soulier, J P; Prou-Wartelle, O

1975-01-01

Adsorption of clotting factors by various adsorbants is studied (tricalcium phosphate, baryum sulfate or carbonate or citrate, calcium oxalate, aluminium hydroxyde and several silicate such as: kaolin, celite, bentonite, attapulgite, beidellite, asbestos). The main properties of each adsorbant are listed as well as several applications such as: selective adsorption of fibrinogen, separation between fibrinogen and factor VIII, separation of factor II from the other components of the prothrombin complex. Activation of factors XII and XI by the various silicates, as well as the activation of factor V by attapulgite are studied. Finally, the action of such adsorbants on the fibrinolytic system is summarized.

Quality control in the development of coagulation factor concentrates.

PubMed

Snape, T J

1987-01-01

Limitation of process change is a major factor contributing to assurance of quality in pharmaceutical manufacturing. This is particularly true in the manufacture of coagulation factor concentrates, for which presumptive testing for poorly defined product characteristics is an integral feature of finished product quality control. The development of new or modified preparations requires that this comfortable position be abandoned, and that the effect on finished product characteristics of changes to individual process steps (and components) be assessed. The degree of confidence in the safety and efficacy of the new product will be determined by, amongst other things, the complexity of the process alteration and the extent to which the results of finished product tests can be considered predictive. The introduction of a heat-treatment step for inactivation of potential viral contaminants in coagulation factor concentrates presents a significant challenge in both respects, quite independent of any consideration of assessment of the effectiveness of the viral inactivation step. These interactions are illustrated by some of the problems encountered with terminal dry heat-treatment (72 h. at 80 degrees C) of factor VIII and prothrombin complex concentrates manufactured by the Blood Products Laboratory.

Bloodcurdling movies and measures of coagulation: Fear Factor crossover trial

PubMed Central

Nemeth, Banne; Scheres, Luuk J J; Lijfering, Willem M

2015-01-01

Objective To assess whether, as has been hypothesised since medieval times, acute fear can curdle blood. Design Crossover trial. Setting Main meeting room of Leiden University’s Department of Clinical Epidemiology, the Netherlands, converted to a makeshift cinema. Participants 24 healthy volunteers aged ≤30 years recruited among students, alumni, and employees of the Leiden University Medical Center: 14 were assigned to watch a frightening (horror) movie followed by a non-threatening (educational) movie and 10 to watch the movies in reverse order. The movies were viewed more than a week apart at the same time of day and both lasted approximately 90 minutes. Main outcome measures The primary outcome measures were markers, or “fear factors” of coagulation activity: blood coagulant factor VIII, D-dimer, thrombin-antithrombin complexes, and prothrombin fragments 1+2. The secondary outcome was participant reported fear experienced during each movie using a visual analogue fear scale. Results All participants completed the study. The horror movie was perceived to be more frightening than the educational movie on a visual analogue fear scale (mean difference 5.4, 95% confidence interval 4.7 to 6.1). The difference in factor VIII levels before and after watching the movies was higher for the horror movie than for the educational movie (mean difference of differences 11.1 IU/dL (111 IU/L), 95% confidence interval 1.2 to 21.0 IU/dL). The effect of either movie on levels of thrombin-antithrombin complexes, D-dimer, and prothrombin fragments 1+2 did not differ. Conclusion Frightening (in this case, horror) movies are associated with an increase of blood coagulant factor VIII without actual thrombin formation in young and healthy adults. Trial registration ClinicalTrials.gov NCT02601053. PMID:26673787

A Drosophila haemocyte-specific protein, hemolectin, similar to human von Willebrand factor.

PubMed Central

Goto, A; Kumagai, T; Kumagai, C; Hirose, J; Narita, H; Mori, H; Kadowaki, T; Beck, K; Kitagawa, Y

2001-01-01

We identified a novel Drosophila protein of approximately 400 kDa, hemolectin (d-Hml), secreted from haemocyte-derived Kc167 cells. Its 11.7 kbp cDNA contains an open reading frame of 3843 amino acid residues, with conserved domains in von Willebrand factor (VWF), coagulation factor V/VIII and complement factors. The d-hml gene is located on the third chromosome (position 70C1-5) and consists of 26 exons. The major part of d-Hml consists of well-known motifs with the organization: CP1-EG1-CP2-EG2-CP3-VD1-VD2-VD'-VD3-VC1-VD"-VD"'-FC1-FC2-VC2-LA1-VD4-VD5-VC3-VB1-VB2-VC4-VC5-CK1 (CP, complement-control protein domain; EG, epidermal-growth-factor-like domain; VB, VC, VD, VWF type B-, C- and D-like domains; VD', VD", VD"', truncated C-terminal VDs; FC, coagulation factor V/VIII type C domain; LA, low-density-lipoprotein-receptor class A domain; CK, cysteine knot domain). The organization of VD1-VD2-VD'-VD3, essential for VWF to be processed by furin, to bind to coagulation factor VIII and to form interchain disulphide linkages, is conserved. The 400 kDa form of d-Hml was sensitive to acidic cleavage near the boundary between VD2 and VD', where the cleavage site of pro-VWF is located. Agarose-gel electrophoresis of metabolically radiolabelled d-Hml suggested that it is secreted from Kc167 cells mainly as dimers. Resembling VWF, 7.9% (305 residues) of cysteine residues on the d-Hml sequence had well-conserved positions in each motif. Coinciding with the development of phagocytic haemocytes, d-hml transcript was detected in late embryos and larvae. Its low-level expression in adult flies was induced by injury at any position on the body. PMID:11563973

Effectiveness of Peer Tutoring in Learning English among Tutors and Tutees of Class VIII Students in Kancheepuram DT

ERIC Educational Resources Information Center

Marieswari, M.; Prema, N.

2016-01-01

The peer who teaches to their mates is peer tutoring. It is a common instructional strategy used in classrooms. The aim of this study is to know whether there is any improvement in achievement marks of tutors and tutees after the process of peer tutoring. Class VIII students were selected as the sample for the present experimental study. The…

VizieR Online Data Catalog: Stark broadening of XeVIII spectral lines (Dimitrijevic+, 2015)

NASA Astrophysics Data System (ADS)

Dimitrijevic, M. S.; Simic, Z.; Kovacevic, A.; Valjarevic, A.; Sahal-Brechot, S.

2018-01-01

By means of the code based on semiclassical perturbation theory we have calculated widths and shifts for 60 transitions of Xe VIII. The needed energy levels have been taken from Saloman (2004JPCRD..33..765S). Oscillator strengths have been calculated by using the method of Bates & Damgaard (1949RSPTA.242..101B) and the tables of Oertel & Shomo (1968ApJS...16..175O). For higher levels, oscillator strengths have been calculated according to Van Regemorter, Hoang Binh & Prud'homme (1979, J. Phys. B, 12, 1073). (1 data file).

Purchasing factor concentrates in the 21st century through competitive tendering.

PubMed

Hay, C R M

2013-09-01

The increasing intensity of treatment, the widespread adoption of factor VIII and IX prophylaxis and increasing usage over the past decade have led to haemophilia becoming an almost uniquely expensive condition to treat. The average adult with severe haemophilia A in the UK used 250,000 IU of factor VIII in 2011/2012, at a cost in excess of £ 100,000 p.a. The cost to the end-user may be considerably higher than this for some US patients supplied by home care companies with high on-costs. This has led to a high level of administrative scrutiny of treatment and an imperative to procure clotting factor concentrates more efficiently and collectively. National procurement schemes have run successfully in various countries and will become commoner. The UK system of procurement is described. This system, following EU procurement rules, evaluated products technically and by price. The price of bioequivalent products was determined by reverse e-auction. Considerable cost reductions were achieved whilst retaining all suppliers and maintaining a degree of prescribing freedom. Elements of this system could be more widely applied. © 2013 John Wiley & Sons Ltd.

Categorization of potential project cost overrun factors in construction industry

NASA Astrophysics Data System (ADS)

Karunakaran, P.; Abdullah, A. H.; Nagapan, S.; Sohu, S.; Kasvar, K. K.

2018-04-01

Cost overrun has been severely hit down the economy and reputations for many construction industry around the world. Many project management tools developed to control the budget of a project. However, the cost management is still considered poor as there are many cost overrun issues occurred in the construction industry. Thus, this paper aims to identify and cluster the potential construction project cost overrun factors according to their originating groups using the thematic approach. Basically, through literature review, all the potential factors that may cause cost overrun were screened thoroughly before they were clustered into seven (7) groups of the originating factors, namely project, contract, client, contractor, consultant, labour and external. Each potential factor was explained clearly with some examples based on the Malaysian case studies to illustrate the cost overrun scenario. These findings may aid in the future to highlight on how to mitigate the critical potential factors of cost overrun to reduce or overcome its impact on all the stakeholders involved.

Hepatitis C treatment with triple therapy in a patient with hemophilia A

PubMed Central

Singh, Gurshawn; Sass, Reuben; Alamiry, Rayan; Zein, Nizar; Alkhouri, Naim

2013-01-01

We report a case of successful treatment of chronic hepatitis C infection with telaprevir-based triple therapy in a patient with hemophilia A complicated by factor VIII inhibitor. A twenty-two years old male with hereditary hemophilia A and high-titer factor VIII inhibitor was taking maintenance doses of recombinant factor VIII. He visited our clinic for treatment of his chronic hepatitis C with the newly instituted protease inhibitor based therapy. He was diagnosed with hepatitis C genotype 1a at one year of age. He was initiated on telaprevir, ribavirin and peg-interferon for treatment of hepatitis C and qualified for response-guided therapy. He completed treatment at 24 wk with minimal adverse effects. Notably, after 4 wk of hepatitis C treatment, his factor VIII inhibitor screen was negative and the dose for recombinant factor VIII decreased by half of the initial dosing before he was treated for hepatitis C. We suspect that suppressing hepatitis C may help decrease factor VIII inhibitor level and the need for recombinant factor VIII. PMID:24303477

Report on corrections and future considerations for Appendices II–VIII of the International Code of Nomenclature for Algae, Fungi, and Plants

USDA-ARS?s Scientific Manuscript database

For the first time, the main text and Appendices II–VIII of the International Code of Nomenclature were separately published following decisions of the Melbourne Nomenclature Section, which contributed to subsequent development of an online resource capable of producing the Appendices in real time. ...

Increased coagulation and fibrinolytic potential of solvent-detergent plasma: a comparative study between Omniplasma and fresh frozen plasma.

PubMed

van Beers, J J B C; van Egmond, L T; Wetzels, R J H; Verhezen, P W M; Beckers, E A M; van Oerle, R; Spronk, H M H; Straat, R J M H E; Henskens, Y M C

2016-07-01

In this study, differences in levels of proteins involved in coagulation and fibrinolysis were compared between fresh frozen (quarantine plasma) and Omniplasma. Furthermore, thawing conditions and plasma stability after thawing were studied. 10 Omniplasma and 10 quarantine plasma units were used to study different procoagulation, anticoagulation and fibrinolytic parameters. Analysis took place at different time-points during plasma storage at 2-6°C. At baseline, significant reduced levels of factor V, free protein S, α2-antiplasmin and tPA-induced ROTEM lysis time were observed in Omniplasma as compared to quarantine plasma. Moreover, thrombin generation, IXa-AT complex levels and factor XIa were significantly increased in Omniplasma. The majority of the parameters studied remained stable in Omniplasma 48 h after thawing, with the exception of factor VIII (decrease) and IXa-AT (increase). Our results suggest an increased coagulation potential, presumingly as a result of contact activation during the production process and also, an increased fibrinolytic potential in Omniplasma. The stability of Omniplasma, based upon the different parameters studied, is comparable to Q-plasma. A maximum post-thawing time of 48 hfor Omniplasma can be suggested. © 2016 International Society of Blood Transfusion.

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

PubMed

Staber, Janice M; Pollpeter, Molly J

2016-01-01

Hemophilia A animal models have helped advance our understanding of factor VIII deficiency. Previously, factor VIII deficient mouse models were reported to have a normal life span without spontaneous bleeds. However, the bleeding frequency and survival in these animals has not been thoroughly evaluated. To investigate the survival and lethal bleeding frequency in two strains of E-16 hemophilia A mice. We prospectively studied factor VIII deficient hemizygous affected males (n = 83) and homozygous affected females (n = 55) for survival and bleeding frequency. Animals were evaluated for presence and location of bleeds as potential cause of death. Hemophilia A mice had a median survival of 254 days, which is significantly shortened compared to wild type controls (p < 0.0001). In addition, the hemophilia A mice experienced hemorrhage in several tissues. This previously-underappreciated shortened survival in the hemophilia A murine model provides new outcomes for investigation of therapeutics and also reflects the shortened lifespan of patients if left untreated.

Reductive transformation of V(iii) precursors into vanadium(ii) oxide nanowires.

PubMed

Ojelere, Olusola; Graf, David; Ludwig, Tim; Vogt, Nicholas; Klein, Axel; Mathur, Sanjay

2018-05-15

Vanadium(ii) oxide nanostructures are promising materials for supercapacitors and electrocatalysis because of their excellent electrochemical properties and high surface area. In this study, new homoleptic vanadium(iii) complexes with bi-dentate O,N-chelating heteroarylalkenol ligands (DmoxCH[double bond, length as m-dash]COCF3, PyCH[double bond, length as m-dash]COCF3 and PyN[double bond, length as m-dash]COCF3) were synthesized and successfully transformed by reductive conversion into VO nanowires. The chemical identity of V(iii) complexes and their redox behaviour were unambiguously established by single crystal X-ray diffraction studies, cyclic voltammetry, spectrometric studies and DFT calculations. Transformation into the metastable VO phase was verified by powder X-ray diffraction and thermo-gravimetry. Transmission electron microscopy and X-ray photoelectron spectroscopy data confirmed the morphology and chemical composition of VO nanostructures, respectively.

Tolerance in Maturity Groups V-VIII Soybean Cultivars to Heterodera glycines

PubMed Central

Hussey, R. S.; Boerma, H. R.

1989-01-01

Twenty-six susceptible and resistant soybean, Glycine max, cultivars in Maturity Groups V, VI, VII, and VIII were compared with Coker 156, Wright, and PI97100 for tolerance to Heterodera glycines races 3 and 14. Seed yields were compared in nematicide-treated (EDB, fenamiphos) and untreated plots at two H. glycines-infested locations over 3 years. Coker 488, DP 417, and NK S72-60 had the highest average tolerance indices ([yield in untreated plot + yield in nematicide-treated plot] x 100) of the race 3-susceptible cultivars to races 3 and 14. Plant height and seed weight of untreated soybean plants were suppressed in race 3-infested soil, but only plant height was suppressed at the race 14-infested location. Several race 3-resistant and race 14-susceptible cultivars were moderately tolerant to race 14. PMID:19287673

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

PubMed

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

2017-07-01

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

Thromboelastography to Direct the Administration of Recombinant Activated Factor VII in a Child with Traumatic Injury Requiring Massive Transfusion

DTIC Science & Technology

2009-01-01

in a child with hemophilia and high titer inhibitors to factor VIII: A case report and brief review. J Extra Cor- por Technol 2006; 38:254–259 16...J Trauma 1969; 9:939–965 20. Sorensen B, Ingerslev J: Thromboelastogra- phy and recombinant factor VIIa- hemophilia and beyond. Semin Hematol 2004; 41

Efficacy, safety and tolerability of recombinant factor VIII (REFACTO) in patients with haemophilia A: interim data from a postmarketing surveillance study in Germany and Austria.

PubMed

Pollmann, H; Externest, D; Ganser, A; Eifrig, B; Kreuz, W; Lenk, H; Pabinger, I; Schramm, W; Schwarz, T F; Zimmermann, R; Zavazava, N; Oldenburg, J; Klamroth, R

2007-03-01

An open-label, multicentre, postmarketing surveillance study conducted in Germany and Austria with recombinant factor VIII (REFACTO) has enrolled 217 patients (mean age 26.3 years) from 38 haemophilia centres during the first 4.8 years. Most patients (188/217; 86.6%) had severe to moderately severe haemophilia A, of whom 153 completed sufficient diary information for the main efficacy analysis. These 153 patients experienced a median of 6.6 (interquartile range 1.4-18.6) bleeding episodes per year. Patients treated with prophylaxis experienced a median of 4.4 (1.1-9.3) bleeds per year, while patients treated on-demand experienced a median of 22.8 (11.3-29.0) bleeds per year. Overall, most physicians (41/43 [95.3%]) were 'very satisfied' or 'satisfied' with the efficacy of REFACTO in the treatment of bleeding episodes. A total of 137 non-serious adverse events have been reported in 52/217 patients (24.0%) to date. In addition, 129 serious adverse events in 87 patients (40%) were reported, including 41 cases of 'less than expected therapeutic effect' (LETE). Of these, 39 LETE cases were reported in one centre; however, patients in this centre experienced considerably fewer bleeding episodes per year than patients outside this centre. Overall, six patients (2.8%) have developed de novo inhibitors, three of which were considered high titre. Four of these patients were at high risk (0-50 exposure days [ED]) of inhibitor formation, one was at intermediate risk (51-100 ED) and one was at low risk (>100 ED). These results emphasize the benefit of postmarketing surveillance and, overall, this study confirms the efficacy, safety and tolerability of REFACTO in the treatment of patients with haemophilia A.

Phase I study of BAY 94-9027, a PEGylated B-domain-deleted recombinant factor VIII with an extended half-life, in subjects with hemophilia A.

PubMed

Coyle, T E; Reding, M T; Lin, J C; Michaels, L A; Shah, A; Powell, J

2014-04-01

BAY 94-9027 is a B-domain-deleted recombinant factor VIII (rFVIII) with site-specific attachment of poly(ethylene glycol) that has shown an extended half-life in animal models of hemophilia. To assess the pharmacokinetics and safety of BAY 94-9027 after single and repeated administration in subjects with severe hemophilia A. This 8-week, prospective, multicenter, open-label, phase I trial was conducted in 14 subjects aged 21–58 years with FVIII of < 1%, ≥ 150 days of exposure to FVIII, and no history of FVIII inhibitors. After a ≥ 3-day washout, subjects received a single dose of sucrose-formulated rFVIII (rFVIII-FS) (cohort 1 [n = 7], 25 IU kg−1; cohort 2 [n = 7], 50 IU kg−1) for a 48-h pharmacokinetic (PK) study. After another ≥ 3-day washout, cohort 1 received twice-weekly BAY 94-9027 at 25 IU kg−1 (16 doses), and cohort 2 received once-weekly BAY 94-9027 at 60 IU kg−1 (nine doses). A 168-h PK study was performed after the first and last BAY 94-9027 doses. BAY 94-9027 showed equivalent recovery and an improved PK profile vs. rFVIII-FS, with a half-life of ~ 19 h (vs. ~ 13.0 h for rFVIII-FS). BAY 94-9027 was well tolerated, and no immunogenicity was observed. This phase I study demonstrates that BAY 94-9027 has an extended half-life in subjects with hemophilia A and, after multiple dosing, was well tolerated with no immunogenicity during the 8-week trial. A phase III study in a larger number of subjects is underway to fully characterize how this prolonged half-life will permit less frequent prophylaxis dosing for patients with hemophilia.

Enzymatically oxidized phospholipids restore thrombin generation in coagulation factor deficiencies.

PubMed

Slatter, David A; Percy, Charles L; Allen-Redpath, Keith; Gajsiewicz, Joshua M; Brooks, Nick J; Clayton, Aled; Tyrrell, Victoria J; Rosas, Marcela; Lauder, Sarah N; Watson, Andrew; Dul, Maria; Garcia-Diaz, Yoel; Aldrovandi, Maceler; Heurich, Meike; Hall, Judith; Morrissey, James H; Lacroix-Desmazes, Sebastien; Delignat, Sandrine; Jenkins, P Vincent; Collins, Peter W; O'Donnell, Valerie B

2018-03-22

Hemostatic defects are treated using coagulation factors; however, clot formation also requires a procoagulant phospholipid (PL) surface. Here, we show that innate immune cell-derived enzymatically oxidized phospholipids (eoxPL) termed hydroxyeicosatetraenoic acid-phospholipids (HETE-PLs) restore hemostasis in human and murine conditions of pathological bleeding. HETE-PLs abolished blood loss in murine hemophilia A and enhanced coagulation in factor VIII- (FVIII-), FIX-, and FX-deficient human plasma . HETE-PLs were decreased in platelets from patients after cardiopulmonary bypass (CPB). To explore molecular mechanisms, the ability of eoxPL to stimulate individual isolated coagulation factor/cofactor complexes was tested in vitro. Extrinsic tenase (FVIIa/tissue factor [TF]), intrinsic tenase (FVIIIa/FIXa), and prothrombinase (FVa/FXa) all were enhanced by both HETE-PEs and HETE-PCs, suggesting a common mechanism involving the fatty acid moiety. In plasma, 9-, 15-, and 12-HETE-PLs were more effective than 5-, 11-, or 8-HETE-PLs, indicating positional isomer specificity. Coagulation was enhanced at lower lipid/factor ratios, consistent with a more concentrated area for protein binding. Surface plasmon resonance confirmed binding of FII and FX to HETE-PEs. HETE-PEs increased membrane curvature and thickness, but not surface charge or homogeneity, possibly suggesting increased accessibility to cations/factors. In summary, innate immune-derived eoxPL enhance calcium-dependent coagulation factor function, and their potential utility in bleeding disorders is proposed.

Enzymatically oxidized phospholipids restore thrombin generation in coagulation factor deficiencies

PubMed Central

Slatter, David A.; Percy, Charles L.; Allen-Redpath, Keith; Gajsiewicz, Joshua M.; Brooks, Nick J.; Tyrrell, Victoria J.; Lauder, Sarah N.; Watson, Andrew; Dul, Maria; Garcia-Diaz, Yoel; Aldrovandi, Maceler; Heurich, Meike; Hall, Judith; Lacroix-Desmazes, Sebastien; Delignat, Sandrine; Jenkins, P. Vincent; Collins, Peter W.; O’Donnell, Valerie B.

2018-01-01

Hemostatic defects are treated using coagulation factors; however, clot formation also requires a procoagulant phospholipid (PL) surface. Here, we show that innate immune cell–derived enzymatically oxidized phospholipids (eoxPL) termed hydroxyeicosatetraenoic acid–phospholipids (HETE-PLs) restore hemostasis in human and murine conditions of pathological bleeding. HETE-PLs abolished blood loss in murine hemophilia A and enhanced coagulation in factor VIII- (FVIII-), FIX-, and FX-deficient human plasma . HETE-PLs were decreased in platelets from patients after cardiopulmonary bypass (CPB). To explore molecular mechanisms, the ability of eoxPL to stimulate individual isolated coagulation factor/cofactor complexes was tested in vitro. Extrinsic tenase (FVIIa/tissue factor [TF]), intrinsic tenase (FVIIIa/FIXa), and prothrombinase (FVa/FXa) all were enhanced by both HETE-PEs and HETE-PCs, suggesting a common mechanism involving the fatty acid moiety. In plasma, 9-, 15-, and 12-HETE-PLs were more effective than 5-, 11-, or 8-HETE-PLs, indicating positional isomer specificity. Coagulation was enhanced at lower lipid/factor ratios, consistent with a more concentrated area for protein binding. Surface plasmon resonance confirmed binding of FII and FX to HETE-PEs. HETE-PEs increased membrane curvature and thickness, but not surface charge or homogeneity, possibly suggesting increased accessibility to cations/factors. In summary, innate immune-derived eoxPL enhance calcium-dependent coagulation factor function, and their potential utility in bleeding disorders is proposed. PMID:29563336

Characterization of potential fire regimes: applying landscape ecology to fire management in Mexico

NASA Astrophysics Data System (ADS)

Jardel, E.; Alvarado, E.; Perez-Salicrup, D.; Morfín-Rios, J.

2013-05-01

Knowledge and understanding of fire regimes is fundamental to design sound fire management practices. The high ecosystem diversity of Mexico offers a great challenge to characterize the fire regime variation at the landscape level. A conceptual model was developed considering the main factors controlling fire regimes: climate and vegetation cover. We classified landscape units combining bioclimatic zones from the Holdridge life-zone system and actual vegetation cover. Since bioclimatic conditions control primary productivity and biomass accumulation (potential fuel), each landscape unit was considered as a fuel bed with a particular fire intensity and behavior potential. Climate is also a determinant factor of post-fire recovery rates of fuel beds, and climate seasonality (length of the dry and wet seasons) influences fire probability (available fuel and ignition efficiency). These two factors influence potential fire frequency. Potential fire severity can be inferred from fire frequency, fire intensity and behavior, and vegetation composition and structure. Based in the conceptual model, an exhaustive literature review and expert opinion, we developed rules to assign a potential fire regime (PFR) defined by frequency, intensity and severity (i.e. fire regime) to each bioclimatic-vegetation landscape unit. Three groups and eight types of potential fire regimes were identified. In Group A are fire-prone ecosystems with frequent low severity surface fires in grasslands (PFR type I) or forests with long dry season (II) and infrequent high-severity fires in chaparral (III), wet temperate forests (IV, fire restricted by humidity), and dry temperate forests (V, fire restricted by fuel recovery rate). Group B includes fire-reluctant ecosystems with very infrequent or occasional mixed severity surface fires limited by moisture in tropical rain forests (VI) or fuel availability in seasonally dry tropical forests (VII). Group C and PFR VIII include fire-free environments

Oral manifestations, dental management, and a rare homozygous mutation of the PRDM12 gene in a boy with hereditary sensory and autonomic neuropathy type VIII: a case report and review of the literature.

PubMed

Elhennawy, Karim; Reda, Seif; Finke, Christian; Graul-Neumann, Luitgard; Jost-Brinkmann, Paul-Georg; Bartzela, Theodosia

2017-08-15

Hereditary sensory and autonomic neuropathy type VIII is a rare autosomal recessive inherited disorder. Chen et al. recently identified the causative gene and characterized biallelic mutations in the PR domain-containing protein 12 gene, which plays a role in the development of pain-sensing nerve cells. Our patient's family was included in Chen and colleagues' study. We performed a literature review of the PubMed library (January 1985 to December 2016) on hereditary sensory and autonomic neuropathy type I to VIII genetic disorders and their orofacial manifestations. This case report is the first to describe the oral manifestations, and their treatment, of the recently discovered hereditary sensory and autonomic neuropathy type VIII in the medical and dental literature. We report on the oral manifestations and dental management of an 8-month-old white boy with hereditary sensory and autonomic neuropathy-VIII over a period of 16 years. Our patient was homozygous for a mutation of PR domain-containing protein 12 gene and was characterized by insensitivity to pain and thermal stimuli, self-mutilation behavior, reduced sweat and tear production, absence of corneal reflexes, and multiple skin and bone infections. Oral manifestations included premature loss of teeth, associated with dental traumata and self-mutilation, severe soft tissue injuries, dental caries and submucosal abscesses, hypomineralization of primary teeth, and mandibular osteomyelitis. The lack of scientific knowledge on hereditary sensory and autonomic neuropathy due to the rarity of the disease often results in a delay in diagnosis, which is of substantial importance for the prevention of many complications and symptoms. Interdisciplinary work of specialized medical and dental teams and development of a standardized treatment protocols are essential for the management of the disease. There are many knowledge gaps concerning the management of patients with hereditary sensory and autonomic neuropathy-VIII

Underground Test Area Subproject Phase I Data Analysis Task. Volume VIII - Risk Assessment Documentation Package

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

None

Volume VIII of the documentation for the Phase I Data Analysis Task performed in support of the current Regional Flow Model, Transport Model, and Risk Assessment for the Nevada Test Site Underground Test Area Subproject contains the risk assessment documentation. Because of the size and complexity of the model area, a considerable quantity of data was collected and analyzed in support of the modeling efforts. The data analysis task was consequently broken into eight subtasks, and descriptions of each subtask's activities are contained in one of the eight volumes that comprise the Phase I Data Analysis Documentation.

Montana SIP: Table c, (viii) Administrative Rules of Montana, Subchapter 10, Preconstruction Permit Requirements for Major Stationary Sources or Major Modifications Locating Within Attainment or Unclassified Areas

EPA Pesticide Factsheets

Montana SIP: Table c, (viii) Administrative Rules of Montana, Subchapter 10, Preconstruction Permit Requirements for Major Stationary Sources or Major Modifications Locating Within Attainment or Unclassified Areas

Factor Activity Assays for Monitoring Extended Half-Life FVIII and Factor IX Replacement Therapies.

PubMed

Kitchen, Steve; Tiefenbacher, Stefan; Gosselin, Robert

2017-04-01

The advent of modified factor VIII (FVIII) and factor IX (FIX) molecules with extended half-lives (EHLs) compared with native FVIII and FIX represents a major advance in the field of hemophilia care, with the potential to reduce the frequency of prophylactic injections and/or to increase the trough level prior to subsequent injections. Monitoring treatment through laboratory assays will be an important part of ensuring patient safety, including any tailoring of prophylaxis. Several approaches have been used to extend half-lives, including PEGylation, and fusion to albumin or immunoglobulin. Some of these modifications affect factor assays as routinely performed in hemophilia centers; so, laboratories will need to use FVIII and FIX assays which have been shown to be suitable on a product-by-product basis. For some products, there are marked differences between results obtained using one-stage or chromogenic assays and results obtained using different reagents in the one-stage assay. The laboratory should use an assay in which the recovery of the product closely aligns with the assay used by the pharmaceutical company to assign potency to the product, so that the units reported by the laboratory agree with those used to demonstrate efficacy of the product during clinical trials. Reported assay differences in relation to several of the EHL FVIII and FIX molecules will be reviewed in this article. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Post-weaning increases in the milk-fat globule EGF-factor VIII on fat globules in mouse milk and in the uptake of the fat globules by HC11 mammary epithelial cells

PubMed Central

Nakatani, Hajime; Yasueda, Takehiko; Oshima, Kenzi; Okajima, Tetsuya; Nadano, Daita; Flint, David J.; Matsuda, Tsukasa

2013-01-01

Milk fat globules (MFGs) secreted by lactating mammary gland are unique lipid surrounded by a phospholipid bi-layer. We report here post-weaning changes in MFG EGF factor VIII (MFG-E8) and annexin V-accessible phosphatidyl-l-serine on the surface of MFGs. The MFG content in milk markedly decreased to about one-half within 2 days after forced weaning, despite a slight increase in milk protein content. Immunofluorescence-staining of MFGs using anti-MFG-E8 and annexin V indicated that MFG-E8 was present on some, but not all, MFGs before weaning, whereas most of MFGs were MFG-E8-positive and annexin V-negative after weaning. Free MFG-E8 with binding activity to phosphatidyl-l-serine was present abundantly in the post-weaning milk, and indeed exhibited binding to MFGs in pre-weaning milk. MFGs were taken up by HC11 mouse mammary epithelial cells in vitro, and those from post-weaning milk were remarkable for such cellular uptake. Moreover, the uptake of MFGs by the cells was inhibited by an anti-MFG-E8 antibody. Taken together, these findings suggest that MFG-E8 plays a critical role in regulation of MFG dynamics after weaning or during the suckling interval through the control of MFG-epithelial cell interaction in lactating mammary glands. PMID:23038672

Measurement of Blood Coagulation Factor Synthesis in Cultures of Human Hepatocytes.

PubMed

Heinz, Stefan; Braspenning, Joris

2015-01-01

An important function of the liver is the synthesis and secretion of blood coagulation factors. Within the liver, hepatocytes are involved in the synthesis of most blood coagulation factors, such as fibrinogen, prothrombin, factor V, VII, IX, X, XI, XII, as well as protein C and S, and antithrombin, whereas liver sinusoidal endothelial cells produce factor VIII and von Willebrand factor. Here, we describe methods for the detection and quantification of most blood coagulation factors in hepatocytes in vitro. Hepatocyte cultures indeed provide a valuable tool to study blood coagulation factors. In addition, the generation and expansion of hepatocytes or hepatocyte-like cells may be used in future for cell-based therapies of liver diseases, including blood coagulation factor deficiencies.

Human factors in waste management - potential and reality

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

Thompson, J.S.

There is enormous potential for human factors contributions in the realm of waste management. The reality, however, is very different from the potential. This is particularly true for low-level and low-level mixed-waste management. The hazards are less severe; therefore, health and safety requirements (including human factors) are not as rigorous as for high-level waste. High-level waste management presents its own unique challenges and opportunities. Waste management is strongly driven by regulatory compliance. When regulations are flexible and open to interpretation and the environment is driven so strongly by regulatory compliance, standard practice is to drop {open_quotes}nice to have{close_quotes} features, likemore » a human factors program, to save money for complying with other requirements. The challenge is to convince decision makers that human factors can help make operations efficient and cost-effective, as well as improving safety and complying with regulations. A human factors program should not be viewed as competing with compliance efforts; in fact, it should complement them and provide additional cost-effective means of achieving compliance with other regulations. Achieving this synergy of human factors with ongoing waste management operations requires educating program and facility managers and other technical specialists about human factors and demonstrating its value {open_quotes}through the back door{close_quotes} on existing efforts. This paper describes ongoing projects at Los Alamos National Laboratory (LANL) in support of their waste management groups. It includes lessons learned from hazard and risk analyses, safety analysis reports, job and task analyses, operating procedure development, personnel qualification/certification program development, and facility- and job-specific training program and course development.« less

Bioequivalence between two serum-free recombinant factor VIII preparations (N8 and ADVATE®)--an open-label, sequential dosing pharmacokinetic study in patients with severe haemophilia A.

PubMed

Martinowitz, U; Bjerre, J; Brand, B; Klamroth, R; Misgav, M; Morfini, M; Santagostino, E; Tiede, A; Viuff, D

2011-11-01

Recombinant coagulation factor VIII (rFVIII) concentrates provide a safe and efficacious replacement therapy for treatment and prevention of bleeding in patients with severe haemophilia A. The aim of this study was to compare the pharmacokinetic (PK) and safety profiles of two serum-free rFVIII products: N8, a new rFVIII manufactured by Novo Nordisk and Advate(®), a marketed product. Patients with severe haemophilia A with >150 exposure days to FVIII, without current or past inhibitors, were enrolled in an open-label, first human dose (FHD), multicentre trial. Twenty-three patients first received a single dose of 50 IU kg(-1) body weight Advate(®) followed by 50 IU kg(-1) body weight N8 at the next visit. A 4-day washout period was required prior to each dosing. Blood samples for PK and safety analyses were drawn prior to dosing and at intervals up until 48 h postdosing. The PK parameters were based on FVIII clotting activity (FVIII:C) measurements. Occurrence of adverse events was closely monitored. The mean profiles of FVIII:C and all primary and secondary parameters for Advate(®) and N8 were comparable. The 90% CI for the treatment ratio (Advate(®)/N8) for all primary endpoints (incremental recovery, t(1/2), AUC and Cl), and the secondary endpoints (AUC(last) and C(max)) were within the bioequivalence interval of 0.8-1.25. There were no safety concerns in the study and no reports of inhibitor formation in the 72-h period following exposure to a single N8 dose. In conclusion, N8 is bioequivalent to Advate(®). Furthermore, N8 is well tolerated in the FHD trial. © 2011 Blackwell Publishing Ltd.

Joint health scores in a haemophilia A cohort from Pakistan with minimal or no access to factor VIII concentrate: correlation with thrombin generation and underlying mutation.

PubMed

Khanum, F; Bowen, D J; Kerr, B C; Collins, P W

2014-05-01

Haemophilia A is associated with recurrent joint bleeding which leads to synovitis and debilitating arthropathy. Coagulation factor VIII level is an important determinant of bleed number and development of arthropathy . The aim of this study was to compare the haemophilia joint health score (HJHS) and Gilbert score with severity, age, thrombin generation (TG) and underlying mutation in a haemophilia A cohort which had minimal access to haemostatic replacement therapy. Ninety-two haemophilia A individuals were recruited from Pakistan. Age, age at first bleed, target joints, haemophilic arthropathy joints, HJHS and Gilbert score were recorded. A strong correlation was found between HJHS and Gilbert score (r = 0.98), both were significantly higher in severe (n = 59) compared with non-severe (n = 29) individuals before the age of 12 years (P ≤ 0.01) but not thereafter. When individuals were divided according to developmental age (<12 years, 12-16 years and >16 years), both HJHS and Gilbert score were significantly lower in the youngest group (P ≤ 0.001), there was no difference between 12-16 years and >16 years. In severe individuals there was no correlation between in vitro TG and joint score, whereas in non-severe individuals there was a weak negative correlation. In the severe group, no significant difference was observed for either joint score according to the underlying mutation type (inversion, missense, nonsense, frameshift). In this cohort of haemophilia A individuals with minimal access to haemostatic treatment, haemophilic arthropathy correlated with severity and age; among severe individuals, joint health scores did not relate to either the underlying mutation or in vitro TG. © 2013 John Wiley & Sons Ltd.

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.

Love and/in psychoanalysis: a commentary on Lacan's reading of Plato's Symposium in Seminar VIII: Transference.

PubMed

Fink, Bruce

2015-02-01

What is love and what part does it play in psychoanalysis? Where are the analyst and the analysand situated in relation to the roles defined as those of the "lover" and the "beloved"? Jacques Lacan explores these and other questions in his soon-to-be-published Seminar VIII: Transference by providing an extensive commentary on Plato's most famous dialogue on love, the Symposium. This paper outlines some of the major points about love that grow out of Lacan's reading of the dialogue and examines their relevance to the analytic setting. Can the analyst be characterized as a sort of modern-day Socrates?

20 CFR 404.535 - How much will we withhold from your title VIII and title XVI benefits to recover a title II...

Code of Federal Regulations, 2010 CFR

2010-04-01

... 20 Employees' Benefits 2 2010-04-01 2010-04-01 false How much will we withhold from your title... Officer § 404.535 How much will we withhold from your title VIII and title XVI benefits to recover a title II overpayment? (a) If past-due benefits are payable to you, we will withhold the lesser of the...

The Funnel Geometry of Open Flux Tubes in the Low Solar Corona Constrained by O VI and Ne VIII Outflow

NASA Technical Reports Server (NTRS)

Byhring, Hanne S.; Esser, Ruth; Lie-Svendsen, Oystein

2008-01-01

Model calculations show that observed outflow velocities of order 7-10 km/s of C IV and O VI ions, and 15-20 km/s of Ne VIII ions, are not only consistent with models of the solar wind from coronas holes, but also place unique constraints on the degree of flow tube expansion as well as the location of the expansion in the transition region/lower corona.

Bioprocess development for the production of mouse-human chimeric anti-epidermal growth factor receptor vIII antibody C12 by suspension culture of recombinant Chinese hamster ovary cells.

PubMed

Hu, Suwen; Deng, Lei; Wang, Huamao; Zhuang, Yingping; Chu, Ju; Zhang, Siliang; Li, Zhonghai; Guo, Meijin

2011-05-01

The mouse-human chimeric anti-epidermal growth factor receptor vIII (EGFRvIII) antibody C12 is a promising candidate for the diagnosis of hepatocellular carcinoma (HCC). In this study, 3 processes were successfully developed to produce C12 by cultivation of recombinant Chinese hamster ovary (CHO-DG44) cells in serum-free medium. The effect of inoculum density was evaluated in batch cultures of shaker flasks to obtain the optimal inoculum density of 5 × 10(5) cells/mL. Then, the basic metabolic characteristics of CHO-C12 cells were studied in stirred bioreactor batch cultures. The results showed that the limiting concentrations of glucose and glutamine were 6 and 1 mM, respectively. The culture process consumed significant amounts of aspartate, glutamate, asparagine, serine, isoleucine, leucine, and lysine. Aspartate, glutamate, asparagine, and serine were particularly exhausted in the early growth stage, thus limiting cell growth and antibody synthesis. Based on these findings, fed-batch and perfusion processes in the bioreactor were successfully developed with a balanced amino acid feed strategy. Fed-batch and especially perfusion culture effectively maintained high cell viability to prolong the culture process. Furthermore, perfusion cultures maximized the efficiency of nutrient utilization; the mean yield coefficient of antibody to consumed glucose was 44.72 mg/g and the mean yield coefficient of glutamine to antibody was 721.40 mg/g. Finally, in small-scale bioreactor culture, the highest total amount of C12 antibody (1,854 mg) was realized in perfusion cultures. Therefore, perfusion culture appears to be the optimal process for small-scale production of C12 antibody by rCHO-C12 cells.

Resin Glycosides from Ipomoea alba Seeds as Potential Chemosensitizers in Breast Carcinoma Cells.

PubMed

Cruz-Morales, Sara; Castañeda-Gómez, Jhon; Rosas-Ramírez, Daniel; Fragoso-Serrano, Mabel; Figueroa-González, Gabriela; Lorence, Argelia; Pereda-Miranda, Rogelio

2016-12-23

Multidrug resistance is the expression of one or more efflux pumps, such as P-glycoprotein, and is a major obstacle in cancer therapy. The use of new potent and noncytotoxic efflux pump modulators, coadministered with antineoplastic agents, is an alternative approach for increasing the success rate of therapy regimes with different drug combinations. This report describes the isolation and structure elucidation of six new resin glycosides from moon vine seeds (Ipomoea alba) as potential mammalian multidrug-resistance-modifying agents. Albinosides IV-IX (1-6), along with the known albinosides I-III (7-9), were purified from the CHCl 3 -soluble extract. Degradative chemical reactions in combination with NMR spectroscopy and mass spectrometry were used for their structural elucidation. Four new glycosidic acids, albinosinic acids D-G (10-13), were released by saponification of natural products 3-6. They were characterized as tetrasaccharides of either convolvulinolic (11S-hydroxytetradecanoic) or jalapinolic (11S-hydroxyhexadecanoic) acids. The potentiation of vinblastine susceptibility in multidrug-resistant human breast carcinoma cells of albinosides 1-6 was evaluated by modulation assays. The noncytotoxic albinosides VII (4) and VIII (5), at a concentration of 25 μg/mL, exerted the strongest potentiation of vinblastine susceptibility, with a reversal factor (RF MCF-7/Vin + ) of 201- and >2517-fold, respectively.

Effectiveness of Adaptive Contextual Learning Model of Integrated Science by Integrating Digital Age Literacy on Grade VIII Students

NASA Astrophysics Data System (ADS)

Asrizal, A.; Amran, A.; Ananda, A.; Festiyed, F.

2018-04-01

Educational graduates should have good competencies to compete in the 21st century. Integrated learning is a good way to develop competence of students in this century. Besides that, literacy skills are very important for students to get success in their learning and daily life. For this reason, integrated science learning and literacy skills are important in 2013 curriculum. However, integrated science learning and integration of literacy in learning can’t be implemented well. Solution of this problem is to develop adaptive contextual learning model by integrating digital age literacy. The purpose of the research is to determine the effectiveness of adaptive contextual learning model to improve competence of grade VIII students in junior high school. This research is a part of the research and development or R&D. Research design which used in limited field testing was before and after treatment. The research instruments consist of three parts namely test sheet of learning outcome for assessing knowledge competence, observation sheet for assessing attitudes, and performance sheet for assessing skills of students. Data of student’s competence were analyzed by three kinds of analysis, namely descriptive statistics, normality test and homogeneity test, and paired comparison test. From the data analysis result, it can be stated that the implementation of adaptive contextual learning model of integrated science by integrating digital age literacy is effective to improve the knowledge, attitude, and literacy skills competences of grade VIII students in junior high school at 95% confidence level.

Prospective surveillance study of haemophilia A patients switching from moroctocog alfa or other factor VIII products to moroctocog alfa albumin-free cell culture (AF-CC) in usual care settings.

PubMed

Parra Lopez, Rafael; Nemes, Laszlo; Jimenez-Yuste, Victor; Rusen, Luminita; Cid, Ana R; Charnigo, Robert J; Baumann, James A; Smith, Lynne; Korth-Bradley, Joan M; Rendo, Pablo

2015-10-01

This prospective, open-label, postauthorisation safety surveillance study assessed clinically significant inhibitor development in patients with severe haemophilia A transitioning from moroctocog alfa or other factor VIII (FVIII) replacement products to reformulated moroctocog alfa (AF-CC). Males aged ≥ 12 years with severe haemophilia A (FVIII:C) < 1 IU/dl), > 150 exposure days (EDs) to recombinant or plasma-derived FVIII products, and no detectable inhibitor at screening were enrolled. Primary end point was the incidence of clinically significant FVIII inhibitor development. Secondary end points included annualised bleeding rate (ABR), less-than-expected therapeutic effect (LETE), and FVIII recovery. Patients were assigned to one of two cohorts based on whether they were transitioning to moroctocog alfa (AF-CC) from moroctocog alfa (cohort 1; n=146) or from another recombinant or plasma-derived FVIII product (cohort 2; n=62). Mean number of EDs on study was 94 (range, 1-139). Six positive FVIII inhibitor results, as determined by local laboratories, were reported in four patients; none were confirmed by a central laboratory, no inhibitor-related clinical manifestations were reported, and all anti-FVIII antibody assays were negative. Median ABRs were 23.4 and 3.4 in patients categorised at baseline as following on-demand and prophylactic regimens, respectively; 86.5% of bleeding episodes resolved after one infusion. LETE incidence was 0.06% and 0.19% in the on-demand and prophylaxis settings, respectively. FVIII recovery remained constant throughout the study. No new safety concerns were identified. This study found no increased risk of clinically significant FVIII inhibitor development in patients transitioning from moroctocog alfa or other FVIII replacement products to moroctocog alfa (AF-CC).

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.

Normal Hemostatic Profiles and Coagulation Factors in Healthy Free-Living Florida Manatees ( Trichechus manatus latirostris).

PubMed

Barratclough, Ashley; Floyd, Ruth Francis; Conner, Bobbi; Reep, Roger; Ball, Ray; Stacy, Nicole

2016-10-01

Hemostatic disorders presumptively play an important role in the pathophysiology of several important disease conditions in the Florida manatee ( Trichechus manatus latirostris). Prior to pursuing such clinical implications, it is essential to establish normal hemostatic profiles in clinically healthy animals. During annual health assessments of free-living manatees organized by the US Geological Survey, blood samples were collected from 12 healthy animals from the Atlantic coast and 28 from the Gulf of Mexico coast of Florida, with body lengths of 210-324 cm. The following analyses were performed on citrated plasma: prothrombin (PT), partial thromboplastin time (PTT), and concentrations of fibrinogen, D-dimers, and coagulation factors VII, VIII, IX, X, XI, and XII. Compared to other mammalian species, manatees had short PT (9.2±1.5 s) and PTT (10.7±0.5 s), fibrinogen was 369±78.7 mg/dL, antithrombin III was 132±11%, and D-dimer was 142±122 ng/mL. Baseline concentrations for the listed coagulation factors were established. When comparing coagulation factors between locations, Atlantic coast manatees had significantly higher factors VIII, IX, and X than did Gulf Coast manatees. This finding may reflect differences in water salinity, diet, or genetics. There were no differences in coagulation factors when among sexes and sizes. These baselines for hemostatic profiles and coagulation factors in healthy free-living manatees lay the foundation for diagnosis and future research of hemostatic disorders and contribute to understanding their role in the pathophysiology of manatees affected by various diseases.

Prophylaxis vs. on-demand treatment with BAY 81-8973, a full-length plasma protein-free recombinant factor VIII product: results from a randomized trial (LEOPOLD II).

PubMed

Kavakli, K; Yang, R; Rusen, L; Beckmann, H; Tseneklidou-Stoeter, D; Maas Enriquez, M

2015-03-01

BAY 81-8973 is a new full-length human recombinant factor VIII product manufactured with technologies to improve consistency in glycosylation and expression to optimize clinical performance. To demonstrate superiority of prophylaxis vs. on demand therapy with BAY 81-8973 in patients with severe hemophilia A. In this multinational,randomized, open-label crossover study (LEOPOLD II;ClinicalTrials.gov identifier: NCT01233258), males aged 12–65 years with severe hemophilia A were randomized to twice-weekly prophylaxis (20-30 IU kg(-1)), 3-times-weekly prophylaxis (30-40 IU kg(-1)), or on-demand treatment with BAY 81-8973. Potency labeling for BAY 81-8973 was based on the chromogenic substrate assay or adjusted to the one-stage assay. Primary efficacy endpoint was annualized number of all bleeds (ABR). Adverse events (AEs)and immunogenicity were also assessed. Eighty patients (on demand, n = 21; twice-weekly prophylaxis, n = 28; 3-times-weekly prophylaxis, n = 31) were treated and analyzed. Mean ± SD ABR was significantly lower with prophylaxis (twice-weekly, 5.7 ± 7.2; 3-times-weekly, 4.3 ± 6.5; combined, 4.9 ± 6.8) vs. on-demand treatment (57.7 ± 24.6; P < 0.0001, ANOVA). Median ABR was reduced by 97% with prophylaxis (twice-weekly, 4.0;3-times-weekly, 2.0; combined, 2.0) vs. on-demand treatment (60.0). Median ABR was higher with twice-weekly vs. 3-times-weekly prophylaxis during the first 6-month treatment period (4.1 vs. 2.0) but was comparable in the second 6-month period (1.1 vs. 2.0). Few patients reported treatment-related AEs (4%); no treatment-related serious AEs or inhibitors were reported. Twice weekly or 3-times-weekly prophylaxis with BAY 81-8973 reduced median ABR by 97% compared with on-demand therapy, confirming the superiority of prophylaxis. Treatment with BAY 81-8973 was well tolerated.

ENDF/B-VIII.0: The 8 th Major Release of the Nuclear Reaction Data Library with CIELO-project Cross Sections, New Standards and Thermal Scattering Data

DOE PAGES

Brown, D. A.; Chadwick, M. B.; Capote, R.; ...

2018-02-01

We describe the new ENDF/B-VIII.0 evaluated nuclear reaction data library. ENDF/B-VIII.0 fully incorporates the new IAEA standards, includes improved thermal neutron scattering data and uses new evaluated data from the CIELO project for neutron reactions on 1H, 16O, 56Fe, 235U, 238U and 239Pu described in companion papers in the present issue of Nuclear Data Sheets. The evaluations benefit from recent experimental data obtained in the U.S. and Europe, and improvements in theory and simulation. Notable advances include updated evaluated data for light nuclei, structural materials, actinides, fission energy release, prompt fission neutron and γ-ray spectra, thermal neutron scattering data, andmore » charged-particle reactions. Integral validation testing is shown for a wide range of criticality, reaction rate, and neutron transmission benchmarks. In general, integral validation performance of the library is improved relative to the previous ENDF/B-VII.1 library.« less

ENDF/B-VIII.0: The 8th Major Release of the Nuclear Reaction Data Library with CIELO-project Cross Sections, New Standards and Thermal Scattering Data

NASA Astrophysics Data System (ADS)

Brown, D. A.; Chadwick, M. B.; Capote, R.; Kahler, A. C.; Trkov, A.; Herman, M. W.; Sonzogni, A. A.; Danon, Y.; Carlson, A. D.; Dunn, M.; Smith, D. L.; Hale, G. M.; Arbanas, G.; Arcilla, R.; Bates, C. R.; Beck, B.; Becker, B.; Brown, F.; Casperson, R. J.; Conlin, J.; Cullen, D. E.; Descalle, M.-A.; Firestone, R.; Gaines, T.; Guber, K. H.; Hawari, A. I.; Holmes, J.; Johnson, T. D.; Kawano, T.; Kiedrowski, B. C.; Koning, A. J.; Kopecky, S.; Leal, L.; Lestone, J. P.; Lubitz, C.; Márquez Damián, J. I.; Mattoon, C. M.; McCutchan, E. A.; Mughabghab, S.; Navratil, P.; Neudecker, D.; Nobre, G. P. A.; Noguere, G.; Paris, M.; Pigni, M. T.; Plompen, A. J.; Pritychenko, B.; Pronyaev, V. G.; Roubtsov, D.; Rochman, D.; Romano, P.; Schillebeeckx, P.; Simakov, S.; Sin, M.; Sirakov, I.; Sleaford, B.; Sobes, V.; Soukhovitskii, E. S.; Stetcu, I.; Talou, P.; Thompson, I.; van der Marck, S.; Welser-Sherrill, L.; Wiarda, D.; White, M.; Wormald, J. L.; Wright, R. Q.; Zerkle, M.; Žerovnik, G.; Zhu, Y.

2018-02-01

We describe the new ENDF/B-VIII.0 evaluated nuclear reaction data library. ENDF/B-VIII.0 fully incorporates the new IAEA standards, includes improved thermal neutron scattering data and uses new evaluated data from the CIELO project for neutron reactions on 1H, 16O, 56Fe, 235U, 238U and 239Pu described in companion papers in the present issue of Nuclear Data Sheets. The evaluations benefit from recent experimental data obtained in the U.S. and Europe, and improvements in theory and simulation. Notable advances include updated evaluated data for light nuclei, structural materials, actinides, fission energy release, prompt fission neutron and γ-ray spectra, thermal neutron scattering data, and charged-particle reactions. Integral validation testing is shown for a wide range of criticality, reaction rate, and neutron transmission benchmarks. In general, integral validation performance of the library is improved relative to the previous ENDF/B-VII.1 library.

ENDF/B-VIII.0: The 8 th Major Release of the Nuclear Reaction Data Library with CIELO-project Cross Sections, New Standards and Thermal Scattering Data

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

Brown, D. A.; Chadwick, M. B.; Capote, R.

We describe the new ENDF/B-VIII.0 evaluated nuclear reaction data library. ENDF/B-VIII.0 fully incorporates the new IAEA standards, includes improved thermal neutron scattering data and uses new evaluated data from the CIELO project for neutron reactions on 1H, 16O, 56Fe, 235U, 238U and 239Pu described in companion papers in the present issue of Nuclear Data Sheets. The evaluations benefit from recent experimental data obtained in the U.S. and Europe, and improvements in theory and simulation. Notable advances include updated evaluated data for light nuclei, structural materials, actinides, fission energy release, prompt fission neutron and γ-ray spectra, thermal neutron scattering data, andmore » charged-particle reactions. Integral validation testing is shown for a wide range of criticality, reaction rate, and neutron transmission benchmarks. In general, integral validation performance of the library is improved relative to the previous ENDF/B-VII.1 library.« less

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.

N-acetylcysteine potentiates platelet inhibition by endothelium-derived relaxing factor.

PubMed

Stamler, J; Mendelsohn, M E; Amarante, P; Smick, D; Andon, N; Davies, P F; Cooke, J P; Loscalzo, J

1989-09-01

Recent evidence suggests that endothelium-derived relaxing factor exhibits properties of nitric oxide. Like nitric oxide, it inhibits platelet function and mediates its effects by elevating intracellular cyclic GMP. In this study we have investigated the role of reduced thiol in the mechanism of action of endothelium-derived relaxing factor on platelets. Bovine aortic endothelial cells were grown on microcarrier beads and pretreated with aspirin before use. Endothelial cells stimulated with bradykinin or exposed to stirred medium expressed a dose-dependent inhibition of platelet aggregation that was potentiated by the reduced thiol, N-acetylcysteine. Endothelial cell-mediated platelet inhibition was attenuated by methylene blue. Inhibition of platelet aggregation by endothelial cells was associated with a rise in platelet intracellular cyclic GMP, an effect that was enhanced by N-acetylcysteine. These data show that 1) the reduced thiol N-acetylcysteine potentiates platelet inhibition by endothelium-derived relaxing factor and 2) this effect is associated with increasing intracellular platelet cyclic GMP levels.

High-resolution X-ray spectroscopy of M87 with the Einstein observatory - The detection of an O VIII emission line

NASA Technical Reports Server (NTRS)

Canizares, C. R.; Clark, G. W.; Markert, T. H.; Berg, C.; Smedira, M.; Bardas, D.; Schnopper, H.; Kalata, K.

1979-01-01

The paper deals with high-resolution X-ray spectroscopy performed to study the extended source surrounding the giant elliptical galaxy, M87, in the Virgo cluster. From observations carried out with a focal plane crystal spectrometer, L-alpha emission was detected from hydrogenic oxygen (O VIII). Upper limits could be set on lines from intermediate ionization states of iron. The presence of a quantity of cooler matter surrounding M87 was revealed, which has important implications for cluster models and favors a radiatively controlled accretion mechanism.

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

PubMed

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

2017-07-01

Hemophilia A represents up to 80% of all hemophilia cases in China. In patients with this condition, bleeding can be prevented and controlled by administering clotting factor VIII (FVIII). Since their initial availability, recombinant FVIII products have undergone several iterations to enhance their safety. Moroctocog alfa albumin-free cell culture (AF-CC) is among the third generation of recombinant FVIII products and received regulatory approval in China in August 2012. The present study characterizes the single-dose pharmacokinetic parameters of FVIII activity (FVIII:C) after administration of moroctocog alfa (AF-CC) in male Chinese patients with hemophilia A. This multicenter, open-label, single-dose study enrolled 13 male Chinese patients diagnosed with severe hemophilia A (FVIII:C <1%) and a history of at least 150 exposure-days to any FVIII-containing product. Eligible patients received a single dose of moroctocog alfa (AF-CC) 50 IU/kg IV within 10 minutes. Blood samples were collected within 2 hours before administration and through 72 hours after dosing. Pharmacokinetic parameters were assessed based on FVIII:C and were analyzed by age groups: ages 6 to <12 years (n = 3) and ≥12 years (n = 10). The mean plasma concentration-time profile for FVIII:C activity was consistently lower in patients aged 6 to <12 years compared with those aged ≥12 years. Geometric AUC 0-∞ and C max were approximately 57% and 28% lower in the younger patients relative to the older patients, respectively. A total of 4 adverse events occurred in 4 patients. Low-titer, transient FVIII inhibitors were observed in 2 patients and were considered serious adverse events. Neither case resulted in clinical manifestations nor required treatment. This is the first report of the pharmacokinetic parameters of FVIII:C after moroctocog alfa (AF-CC) in an all-Chinese population of males with hemophilia A. The pharmacokinetic profile in older patients was similar to that previously reported

DOD Residential Proton Exchange Membrane (PEM) Fuel Cell Demonstration Program. Volume 1. Summary of the Fiscal Year 2001 Program

DTIC Science & Technology

2004-02-01

Potential new stan- dard ASME Boiler and Pressure Vessel Code, Section VIII ( BPVC -VIII), Division 1 Rules for Construction of Pressure Vessels...Published and avail- able for sale. ASME BPVC -VIII Division 2 Rules for Construction of Pressure Vessels, Division 2, Gerry Eisenberg, ASME ...Vessels, Division 3, Alternate ASME BPVC -VIII Division 3 Gerry Eisenberg, ASME Published and avail- able for sale. Rules High

Proceedings of the EMU Conference on Foreign Languages for Business and the Professions (Dearborn, Michigan, April 5-7, 1984). Part VIII: Spanish for Business and the Professions.

ERIC Educational Resources Information Center

Voght, Geoffrey M., Ed.

Part VIII of the proceedings includes 16 presentations. They are: "Strengthening Internationalism through the Establishment of a Center for Spanish Language Training for Engineering Students" (David C. Kraft, Pamela J. Madl, Robert C. Spires, and Rusty McClanahan); "Training Court Interpreters: A Practitioner's Perspective" (Linda E. Haughton);…

Recombinant von Willebrand factor: preclinical development.

PubMed

Plaimauer, B; Schlokat, U; Turecek, P L; Mitterer, A; Mundt, W; Auer, W; Pichler, L; Gritsch, H; Schwarz, H P

2001-08-01

Von Willebrand factor (vWF) is a multimeric glycoprotein (GP) that attracts platelets to the site of vascular injury, mediates platelet-platelet interaction, and stabilizes factor VIII (FVIII) in the circulation. Quantitative and qualitative defects of vWF result in von Willebrand disease (vWD), manifested by modest to severe bleeding episodes. Substitution therapy, with plasma-derived FVIII/vWF complex concentrates, is used for patients suffering the more severe forms of vWD. Efficacy of these preparations is often unsatisfactory because inadvertent proteolytic degradation during the manufacturing process causes them to lack the hemostatically most active high-molecular-weight multimers. In contrast, recombinant vWF (r-vWF), which is constitutively expressed at high yields in Chinese hamster ovary (CHO) cells and secreted into the conditioned medium under perfusion fermentation in "protein-free" medium, has high-molecular-weight multimers of extraordinary structural integrity. Functional analysis has shown that r-vWF promotes ristocetin cofactor-mediated platelet aggregation, collagen interaction and FVIII binding, and platelet-collagen adhesion under shear stress. Infusing vWF-deficient animals with r-vWF corrected vWF concentration and reduced blood loss, subsequently stabilizing endogenous FVIII associated with the reduction of bleeding time. Compared with plasma-derived vWF preparations, r-vWF was found to have a prolonged half-life, further enhancing the potential value of r-vWF as a therapeutic agent for treating patients suffering from vWD.

Buzz Factor or Innovation Potential: What Explains Cryptocurrencies’ Returns?

PubMed Central

Wang, Sha

2017-01-01

Cryptocurrencies have become increasingly popular since the introduction of bitcoin in 2009. In this paper, we identify factors associated with variations in cryptocurrencies’ market values. In the past, researchers argued that the “buzz” surrounding cryptocurrencies in online media explained their price variations. But this observation obfuscates the notion that cryptocurrencies, unlike fiat currencies, are technologies entailing a true innovation potential. By using, for the first time, a unique measure of innovation potential, we find that the latter is in fact the most important factor associated with increases in cryptocurrency returns. By contrast, we find that the buzz surrounding cryptocurrencies is negatively associated with returns after controlling for a variety of factors, such as supply growth and liquidity. Also interesting is our finding that a cryptocurrency’s association with fraudulent activity is not negatively associated with weekly returns—a result that further qualifies the media’s influence on cryptocurrencies. Finally, we find that an increase in supply is positively associated with weekly returns. Taken together, our findings show that cryptocurrencies do not behave like traditional currencies or commodities—unlike what most prior research has assumed—and depict an industry that is much more mature, and much less speculative, than has been implied by previous accounts. PMID:28085906

Buzz Factor or Innovation Potential: What Explains Cryptocurrencies' Returns?

PubMed

Wang, Sha; Vergne, Jean-Philippe

2017-01-01

Cryptocurrencies have become increasingly popular since the introduction of bitcoin in 2009. In this paper, we identify factors associated with variations in cryptocurrencies' market values. In the past, researchers argued that the "buzz" surrounding cryptocurrencies in online media explained their price variations. But this observation obfuscates the notion that cryptocurrencies, unlike fiat currencies, are technologies entailing a true innovation potential. By using, for the first time, a unique measure of innovation potential, we find that the latter is in fact the most important factor associated with increases in cryptocurrency returns. By contrast, we find that the buzz surrounding cryptocurrencies is negatively associated with returns after controlling for a variety of factors, such as supply growth and liquidity. Also interesting is our finding that a cryptocurrency's association with fraudulent activity is not negatively associated with weekly returns-a result that further qualifies the media's influence on cryptocurrencies. Finally, we find that an increase in supply is positively associated with weekly returns. Taken together, our findings show that cryptocurrencies do not behave like traditional currencies or commodities-unlike what most prior research has assumed-and depict an industry that is much more mature, and much less speculative, than has been implied by previous accounts.

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

PubMed

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

2016-10-20

Inhibitor formation in hemophilia A is the most feared treatment-related complication of factor VIII (fVIII) therapy. Most inhibitor patients with hemophilia A develop antibodies against the fVIII A2 and C2 domains. Recent evidence demonstrates that the C1 domain contributes to the inhibitor response. Inhibitory anti-C1 monoclonal antibodies (mAbs) have been identified that bind to putative phospholipid and von Willebrand factor (VWF) binding epitopes and block endocytosis of fVIII by antigen presenting cells. We now demonstrate by competitive enzyme-linked immunosorbent assay and hydrogen-deuterium exchange mass spectrometry that 7 of 9 anti-human C1 mAbs tested recognize an epitope distinct from the C1 phospholipid binding site. These mAbs, designated group A, display high binding affinities for fVIII, weakly inhibit fVIII procoagulant activity, poorly inhibit fVIII binding to phospholipid, and exhibit heterogeneity with respect to blocking fVIII binding to VWF. Another mAb, designated group B, inhibits fVIII procoagulant activity, fVIII binding to VWF and phospholipid, fVIIIa incorporation into the intrinsic Xase complex, thrombin generation in plasma, and fVIII uptake by dendritic cells. Group A and B epitopes are distinct from the epitope recognized by the canonical, human-derived inhibitory anti-C1 mAb, KM33, whose epitope overlaps both groups A and B. Antibodies recognizing group A and B epitopes are present in inhibitor plasmas from patients with hemophilia A. Additionally, group A and B mAbs increase fVIII clearance and are pathogenic in a hemophilia A mouse tail snip bleeding model. Group A anti-C1 mAbs represent the first identification of pathogenic, weakly inhibitory antibodies that increase fVIII clearance. © 2016 by The American Society of Hematology.

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

PubMed Central

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

2016-01-01

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

Towards improved migraine management: Determining potential trigger factors in individual patients.

PubMed

Peris, Francesc; Donoghue, Stephen; Torres, Ferran; Mian, Alec; Wöber, Christian

2017-04-01

Background Certain chronic diseases such as migraine result in episodic, debilitating attacks for which neither cause nor timing is well understood. Historically, possible triggers were identified through analysis of aggregated data from populations of patients. However, triggers common in populations may not be wholly responsible for an individual's attacks. To explore this hypothesis we developed a method to identify individual 'potential trigger' profiles and analysed the degree of inter-individual variation. Methods We applied N = 1 statistical analysis to a 326-migraine-patient database from a study in which patients used paper-based diaries for 90 days to track 33 factors (potential triggers or premonitory symptoms) associated with their migraine attacks. For each patient, univariate associations between factors and migraine events were analysed using Cox proportional hazards models. Results We generated individual factor-attack association profiles for 87% of the patients. The average number of factors associated with attacks was four per patient: Factor profiles were highly individual and were unique in 85% of patients with at least one identified association. Conclusion Accurate identification of individual factor-attack profiles is a prerequisite for testing which are true triggers and for development of trigger avoidance or desensitisation strategies. Our methodology represents a necessary development toward this goal.

Thyroid carcinoma at King Edward VIII Hospital, Durban, South Africa.

PubMed

Mulaudzi, T V; Ramdial, P K; Madiba, T E; Callaghan, R A

2001-05-01

Western literature depicts papillary carcinoma as the most common thyroid malignancy followed by follicular carcinoma. To assess the clinical pattern of thyroid carcinoma among African and Indian patients. King Edward VIII Hospital, Durban, South Africa. A retrospective study. One hundred patients with thyroid carcinoma treated at a tertiary teaching hospital between 1990 and 1997. Seventy seven patients were Africans and 23 were Indians. The male to female ratio was 1:6. Ninety eight patients presented with goitre with or without regional lymph node involvement or distant disease. The duration of symptoms ranged from one to 360 months. The mean age at presentation was 48.6 +/- 16.0 years. Follicular carcinoma was the most common malignancy among African patients (68%), followed by papillary carcinoma (16%), anaplastic carcinoma (13%) and medullary carcinoma (2.6%). Papillary carcinoma was the most common malignancy among Indian patients (57%) followed by follicular carcinoma and medullary carcinoma. There was no anaplastic carcinoma among Indian patients. Fifty five patients underwent lobectomy with 32 undergoing subsequent completion thyroidectomy. Nine patients had near total thyroidectomy, 27 were offered total thyroidectomy as primary surgery and eight had biopsy only. The in-hospital mortality was 8%. Recurrence rate was 8%. Most patients present long after the development of symptoms. Follicular carcinoma is the most common thyroid malignancy among Africans. Further studies are required to explain this phenomenon.

Non-genetic risk factors in haemophilia A inhibitor management - the danger theory and the use of animal models.

PubMed

Lövgren, K M; Søndergaard, H; Skov, S; Wiinberg, B

2016-09-01

In haemophilia A (HA) management, antidrug antibodies, or inhibitors, are a serious complication that renders factor VIII (FVIII) replacement therapy ineffective, increases morbidity and reduces quality of life for affected patients. Inhibitor development aetiology is multifactorial and covers both genetic and therapy related risk factors. Many therapy-related risk factors have proven difficult to confirm due to several confounding factors and the small study populations available. However, clinical studies indicate that e.g. on-demand treatment and surgery affect inhibitor development, and explanations for this association are being investigated. A potential explanation is the danger signal effect, where the immune response is activated by endogenous or exogenous danger or damage signals present at the time and site of FVIII administration. The danger theory explains how alarm signals from stressed, injured or dying cells can activate an immune reaction, without the involvement of foreign antigens. Bleeds, trauma, surgery or concomitant infection could be events initiating danger signalling in HA patients, resulting in an immune reaction towards administered FVIII that otherwise would pass unnoticed. This role of danger in HA inhibitor formation has previously been suggested, but a thorough discussion of this subject is lacking. The present review will discuss the potential role of danger signals in haemophilia and inhibitor development, with focus on treatment related risk factors with a suspected danger signal aetiology; on-demand treatment, treatment during major bleeds or surgery, and treatment during infection or vaccination. Clinical studies as well as animal experiments addressing these factors will be reviewed. © 2016 John Wiley & Sons Ltd.

Factors potentially influencing aminoglycoside use and expenditure

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

DiPiro, J.T.; Kilsdonk, G.F.; Amerson, A.B.

1982-07-01

Factors that may have influenced aminoglycoside use and expenditure in one hospital were examined. Factors that were evaluated as to their influence on aminoglycoside-use patterns were: (1) formulary status; (2) bacterial susceptibility patterns; (3) identified or perceived differences in toxicity; (4) changes in patient population; (5) price paid by the hospital for aminoglycosides; (6) distribution of newsletters or memoranda; (7) advertising and detailing; and (8) pharmacy policies. For FY 1976-77 to 1979-80, the largest proportion of aminoglycoside expense was for gentamicin. During FY 1980-81, the expenditure for gentamicin decreased and tobramycin accounted for the largest proportion of total expenditure. Monthlymore » gentamicin use decreased 20% during FY 1980-81 from the previous year. Tobramycin use increased from January 1979 to November 1980 and decreased from December 1980 to June 1981. Kanamycin use and amikacin use were fairly constant during the study period. Based on temporal relationships, the following factors appeared to influence aminoglycoside use and expenditure: (1) a study conducted at the institution from June 1977 to June 1979 comparing gentamicin and tobramycin nephrotoxicity; (2) a comparative nephrotoxicity study published in a widely circulated medical journal in May 1980; and (3) an intramural newsletter and memorandum distributed in March 1981 encouraging selective aminoglycoside use. The identification of factors that potentially influenced aminoglycoside use can be used to anticipate the future impact of similar events and to devise strategies to influence antimicrobial use.« less

[The beneficial effect of mineral waters of Fiuggi on Pope Bonifacio VIII and Michelangelo: two prominent calculous patients].

PubMed

Androutsos, Georges

2005-09-01

Going back to the dawn of time, we deal with two historical figures, that of Pope Bonifacio VIII, and that of the hierophant of art, Michelangelo Buonarroti. The texts and the codes of the British Museum (Department of Manuscripts), of the Biblioteca Medica Laurenziana (Archivio Buonarroti) of Florence, and the Biblioteca Apostolica of Vatican, convincing detalled evidence that both figures were urological patients. It concerns two clinical cases with especially pertain to the history of lithiasis of urinary tract. Even though, both of them--the first with nephrolithiasis or gravel, and the second with a bladder stone--were historically bound with the well-known cures of Fiuggi in Italy.

Unveiling interfaces between In-rich and Ga-rich GaInP vertical slabs of laterally composition modulated structures

DOE PAGES

Park, Kwangwook; Kang, Seokjin; Ravindran, Sooraj; ...

2017-01-16

Here, we report changes at the interface between Ga-rich/In-rich GaInP vertical slabs in laterally composition modulated (LCM) GaInP as a function of the V/III ratio. The photoluminescence exhibits satellite peaks, indicating that the parasitic potential between the GaInP vertical slabs disappears as the V/III ratio decreases. However, a high V/III ratio leads to an abrupt interface, increasing the parasitic potential because of the phosphorus-amount-dependent diffusion of group-III atoms during growth. These results suggest that the V/III ratio is an important parameter that must be wisely chosen in designing optoelectronic devices incorporating LCM structure.

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

Park, Kwangwook; Kang, Seokjin; Ravindran, Sooraj

Here, we report changes at the interface between Ga-rich/In-rich GaInP vertical slabs in laterally composition modulated (LCM) GaInP as a function of the V/III ratio. The photoluminescence exhibits satellite peaks, indicating that the parasitic potential between the GaInP vertical slabs disappears as the V/III ratio decreases. However, a high V/III ratio leads to an abrupt interface, increasing the parasitic potential because of the phosphorus-amount-dependent diffusion of group-III atoms during growth. These results suggest that the V/III ratio is an important parameter that must be wisely chosen in designing optoelectronic devices incorporating LCM structure.

Hemophilia and von Willebrand's disease: 2. Management. Association of Hemophilia Clinic Directors of Canada.

PubMed Central

1995-01-01

of life. Economic gains are realized through the reduction of mortality and morbidity and their associated costs. The patient has a better opportunity to contribute to society through gainful employment and the fulfillment of social roles. Potential harms include HIV infection, hepatitis B, hepatitis C and the development of inhibitor antibodies to clotting-factor concentrates. The risk of viral transmission has been minimized through the development of procedures for the viral inactivation of plasma-derived clotting-factor concentrates and through the use of recombinant coagulation-factor concentrates and other non-plasma-derived hemostatic agents. RECOMMENDATIONS: DDAVP is the drug of choice for patients with mild hemophilia or type 1 or 2 (except 2B) von Willebrand's disease whose response to DDAVP in previous testing has been found to be adequate. Therapeutic blood components of choice include recombinant products and virally inactivated plasma-derived products. In Canada the recommended products are recombinant Factor VIII for hemophilia A, high-purity plasma-derived Factor IX for hemophilia B and plasma-derived Factor VIII concentrates containing adequate von Willebrand factor (e.g., Haemate P) for von Willebrand's disease. Dosages vary according to specific indications. Adjunctive antifibrinolytic agents, topical thrombin and fibrin sealant are useful for the treatment of oral or dental bleeds and localized bleeds in accessible sites. In patients with inhibitor antibodies, high-dose human or porcine Factor VIII is usually effective when the inhibitor titre is less than 5 Bethesda units/mL. In nonresponsive patients, or in those whose inhibitor titre is higher, "bypassing" agents (e.g., activated prothrombin-complex concentrate and recombinant Factor VIIa) are useful. Long-term management may include immune-tolerance induction.VALIDATION: These recommendations were reviewed and approved by the Association of Hemophilia Clinic Directors of Canada (AHCDC) and the

Hyperdynamics boost factor achievable with an ideal bias potential

DOE PAGES

Huang, Chen; Perez, Danny; Voter, Arthur F.

2015-08-20

Hyperdynamics is a powerful method to significantly extend the time scales amenable to molecular dynamics simulation of infrequent events. One outstanding challenge, however, is the development of the so-called bias potential required by the method. In this work, we design a bias potential using information about all minimum energy pathways (MEPs) out of the current state. While this approach is not suitable for use in an actual hyperdynamics simulation, because the pathways are generally not known in advance, it allows us to show that it is possible to come very close to the theoretical boost limit of hyperdynamics while maintainingmore » high accuracy. We demonstrate this by applying this MEP-based hyperdynamics (MEP-HD) to metallic surface diffusion systems. In most cases, MEP-HD gives boost factors that are orders of magnitude larger than the best existing bias potential, indicating that further development of hyperdynamics bias potentials could have a significant payoff. Lastly, we discuss potential practical uses of MEP-HD, including the possibility of developing MEP-HD into a true hyperdynamics.« less

Motivating Factors and Potential Deterrents to Blood Donation in High School Aged Blood Donors

PubMed Central

Phan-Tang, Michelle

2016-01-01

Background. To ensure an adequate supply of blood, collection centers must design campaigns that successfully recruit and maintain an active donor pool. Understanding factors that motivate and deter individuals from donating may help centers develop targeted recruitment campaigns. These factors among high school aged blood donors have not yet been fully investigated. Study Design and Methods. A voluntary, anonymous survey was administered to student donors at high school mobile blood drives. The survey instrument asked the students to rate several potential motivating factors in their importance in the decision to donate blood and several potential deterring factors in their future decision whether or not to donate blood again. The survey also asked the students to rate the desirability of several potential incentives. Results. Motivating factors that reflected prosocial, empathetic, and altruistic thoughts and beliefs were rated highly by students. Pain from phlebotomy was most commonly chosen as potential deterrent. Movie tickets and cookies/snacks at the drive were rated as the most attractive incentives. Conclusion. High school aged blood donors are similar to other donor groups in their expressed motives for donating blood. This group may be unique in the factors that deter them from donating and in their preferences for different incentives. PMID:27293985

Potentially modifiable factors contributing to sepsis-associated encephalopathy.

PubMed

Sonneville, Romain; de Montmollin, Etienne; Poujade, Julien; Garrouste-Orgeas, Maïté; Souweine, Bertrand; Darmon, Michael; Mariotte, Eric; Argaud, Laurent; Barbier, François; Goldgran-Toledano, Dany; Marcotte, Guillaume; Dumenil, Anne-Sylvie; Jamali, Samir; Lacave, Guillaume; Ruckly, Stéphane; Mourvillier, Bruno; Timsit, Jean-François

2017-08-01

Identifying modifiable factors for sepsis-associated encephalopathy may help improve patient care and outcomes. We conducted a retrospective analysis of a prospective multicenter database. Sepsis-associated encephalopathy (SAE) was defined by a score on the Glasgow coma scale (GCS) <15 or when features of delirium were noted. Potentially modifiable risk factors for SAE at ICU admission and its impact on mortality were investigated using multivariate logistic regression analysis and Cox proportional hazard modeling, respectively. We included 2513 patients with sepsis at ICU admission, of whom 1341 (53%) had sepsis-associated encephalopathy. After adjusting for baseline characteristics, site of infection, and type of admission, the following factors remained independently associated with sepsis-associated encephalopathy: acute renal failure [adjusted odds ratio (aOR) = 1.41, 95% confidence interval (CI) 1.19-1.67], hypoglycemia <3 mmol/l (aOR = 2.66, 95% CI 1.27-5.59), hyperglycemia >10 mmol/l (aOR = 1.37, 95% CI 1.09-1.72), hypercapnia >45 mmHg (aOR = 1.91, 95% CI 1.53-2.38), hypernatremia >145 mmol/l (aOR = 2.30, 95% CI 1.48-3.57), and S. aureus (aOR = 1.54, 95% CI 1.05-2.25). Sepsis-associated encephalopathy was associated with higher mortality, higher use of ICU resources, and longer hospital stay. After adjusting for age, comorbidities, year of admission, and non-neurological SOFA score, even mild alteration of mental status (i.e., a score on the GCS of 13-14) remained independently associated with mortality (adjusted hazard ratio = 1.38, 95% CI 1.09-1.76). Acute renal failure and common metabolic disturbances represent potentially modifiable factors contributing to sepsis-associated encephalopathy. However, a true causal relationship has yet to be demonstrated. Our study confirms the prognostic significance of mild alteration of mental status in patients with sepsis.

Prophylaxis vs. on-demand treatment with BAY 81-8973, a full-length plasma protein-free recombinant factor VIII product: results from a randomized trial (LEOPOLD II)

PubMed Central

Kavakli, K; Yang, R; Rusen, L; Beckmann, H; Tseneklidou-Stoeter, D; Maas Enriquez, M

2015-01-01

Background BAY 81-8973 is a new full-length human recombinant factor VIII product manufactured with technologies to improve consistency in glycosylation and expression to optimize clinical performance. Objectives To demonstrate superiority of prophylaxis vs. on-demand therapy with BAY 81-8973 in patients with severe hemophilia A. Patients/Methods In this multinational, randomized, open-label crossover study (LEOPOLD II; ClinicalTrials.gov identifier: NCT01233258), males aged 12–65 years with severe hemophilia A were randomized to twice-weekly prophylaxis (20–30 IU kg−1), 3-times-weekly prophylaxis (30–40 IU kg−1), or on-demand treatment with BAY 81-8973. Potency labeling for BAY 81-8973 was based on the chromogenic substrate assay or adjusted to the one-stage assay. Primary efficacy endpoint was annualized number of all bleeds (ABR). Adverse events (AEs) and immunogenicity were also assessed. Results Eighty patients (on demand, n = 21; twice-weekly prophylaxis, n = 28; 3-times-weekly prophylaxis, n = 31) were treated and analyzed. Mean ± SD ABR was significantly lower with prophylaxis (twice-weekly, 5.7 ± 7.2; 3-times-weekly, 4.3 ± 6.5; combined, 4.9 ± 6.8) vs. on-demand treatment (57.7 ± 24.6; P < 0.0001, anova). Median ABR was reduced by 97% with prophylaxis (twice-weekly, 4.0; 3-times-weekly, 2.0; combined, 2.0) vs. on-demand treatment (60.0). Median ABR was higher with twice-weekly vs. 3-times-weekly prophylaxis during the first 6-month treatment period (4.1 vs. 2.0) but was comparable in the second 6-month period (1.1 vs. 2.0). Few patients reported treatment-related AEs (4%); no treatment-related serious AEs or inhibitors were reported. Conclusions Twice-weekly or 3-times-weekly prophylaxis with BAY 81-8973 reduced median ABR by 97% compared with on-demand therapy, confirming the superiority of prophylaxis. Treatment with BAY 81-8973 was well tolerated. PMID:25546368

Evaluation of Neutron Reactions on Iron Isotopes for CIELO and ENDF/B-VIII.0

DOE PAGES

Herman, M.; Trkov, A.; Capote, R.; ...

2018-02-01

A new suite of evaluations for 54,56,57,58Fe has been developed in the framework of the CIELO international collaboration. New resolved resonance ranges were evaluated for 54Fe and 57Fe, while modifications were applied to resonances in 56Fe. The low energy part of the 56Fe file is almost totally based on measurements. At higher energies in 56Fe and in the whole fast neutron range for minor isotopes the evaluation consists of model predictions carefully adjusted to available experimental data. We also make use of the high quality and well experimentally-constrained dosimetry evaluations from the IRDFF library. Special attention was dedicated to themore » elastic angular distributions, which were found to affect results of the integral benchmarking. The new set of iron evaluations was developed in concert with other CIELO evaluations and they were tested together in the integral experiments before being adopted for the ENDF/B-VIII.0 library.« less

Evaluation of Neutron Reactions on Iron Isotopes for CIELO and ENDF/B-VIII.0

NASA Astrophysics Data System (ADS)

Herman, M.; Trkov, A.; Capote, R.; Nobre, G. P. A.; Brown, D. A.; Arcilla, R.; Danon, Y.; Plompen, A.; Mughabghab, S. F.; Jing, Q.; Zhigang, G.; Tingjin, L.; Hanlin, L.; Xichao, R.; Leal, L.; Carlson, B. V.; Kawano, T.; Sin, M.; Simakov, S. P.; Guber, K.

2018-02-01

A new suite of evaluations for 54,56,57,58Fe has been developed in the framework of the CIELO international collaboration. New resolved resonance ranges were evaluated for 54Fe and 57Fe, while modifications were applied to resonances in 56Fe. The low energy part of the 56Fe file is almost totally based on measurements. At higher energies in 56Fe and in the whole fast neutron range for minor isotopes the evaluation consists of model predictions carefully adjusted to available experimental data. We also make use of the high quality and well experimentally-constrained dosimetry evaluations from the IRDFF library. Special attention was dedicated to the elastic angular distributions, which were found to affect results of the integral benchmarking. The new set of iron evaluations was developed in concert with other CIELO evaluations and they were tested together in the integral experiments before being adopted for the ENDF/B-VIII.0 library.

Evaluation of Neutron Reactions on Iron Isotopes for CIELO and ENDF/B-VIII.0

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

Herman, M.; Trkov, A.; Capote, R.

A new suite of evaluations for 54,56,57,58Fe has been developed in the framework of the CIELO international collaboration. New resolved resonance ranges were evaluated for 54Fe and 57Fe, while modifications were applied to resonances in 56Fe. The low energy part of the 56Fe file is almost totally based on measurements. At higher energies in 56Fe and in the whole fast neutron range for minor isotopes the evaluation consists of model predictions carefully adjusted to available experimental data. We also make use of the high quality and well experimentally-constrained dosimetry evaluations from the IRDFF library. Special attention was dedicated to themore » elastic angular distributions, which were found to affect results of the integral benchmarking. The new set of iron evaluations was developed in concert with other CIELO evaluations and they were tested together in the integral experiments before being adopted for the ENDF/B-VIII.0 library.« less

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

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

Targeted exome sequencing identifies novel compound heterozygous mutations in P3H1 in a fetus with osteogenesis imperfecta type VIII.

PubMed

Huang, Yanru; Mei, Libin; Lv, Weigang; Li, Haoxian; Zhang, Rui; Pan, Qian; Tan, Hu; Guo, Jing; Luo, Xiaomei; Chen, Chen; Liang, Desheng; Wu, Lingqian

2017-01-01

Osteogenesis imperfecta (OI) is a highly clinically and genetically heterogeneous group of disorders. It is difficult to identify severe OI in the perinatal period. Here, a Chinese woman with a suspected history of fetal OI was referred to our institution at 19weeks of gestation, due to ultrasound inspection during antenatal screening, which revealed bulbous metaphyses, short humeri, and short thick bent femora in the fetus. Using targeted exome sequencing of 248 genes known to be involved in skeletal system diseases, we identified novel compound heterozygous mutation in the P3H1 gene in the fetus with OI type VIII: c.105_120del (p.D36Rfs*16) and c.2164C>T (p.Q722*). These two mutations were inherited from the father and mother, respectively. The mRNA level of P3H1 wasn't changed suggested that mRNA with this mutation escaped from nonsense-mediated RNA decay. Besides, the level of P3H1 was absence while the CRTAP was mildly decreased. In conclusion, our findings imply this novel compound heterozygous mutation as the molecular pathogenetic in a Chinese fetus with OI type VIII, and demonstrate that targeted next-generation sequencing (NGS) is an accurate, rapid, and cost-effective method in the genetic diagnosis of fetal skeletal dysplasia with genetic and clinical heterogeneity, especially for autosomal recessive skeletal disorders. Copyright © 2016 Elsevier B.V. All rights reserved.

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.

The Development of Geometri Teaching Materials Based on Constructivism to Improve the Students' Mathematic Reasoning Ability through Cooperative Learing Jigsaw at the Class VIII of SMP Negeri 3 Padangsidimpuan

ERIC Educational Resources Information Center

Dewi, Izwita; Harahap, Muhammad Syahri

2016-01-01

The purposes of this research were to know the validity, practicality, and effectivity of geometrical learning material based on the constructivism to Increase students' mathematic reasoning ability and increasing students' mathematic reasoning ability by using learning material at the grade VIII of SMP Negeri 3 Padangsidimpuan. Type of the…

Vascular endothelial growth factor and platelet-derived growth factor are potential angiogenic and metastatic factors in human breast cancer.

PubMed

Anan, K; Morisaki, T; Katano, M; Ikubo, A; Kitsuki, H; Uchiyama, A; Kuroki, S; Tanaka, M; Torisu, M

1996-03-01

Angiogenesis is a prerequisite for tumor growth and metastasis. Tumor angiogenesis may be mediated by several angiogenic factors such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), transforming growth factor-alpha, and basic fibroblast growth factor. Differential mRNA expressions of VEGF, PDGF (A chain), transforming growth factor-alpha and basic fibroblast growth factor in 32 primary invasive breast tumors were examined by reverse transcriptase-polymerase chain reaction. We analyzed relationships between mRNA expressions of these angiogenic factors and the degree of angiogenesis, tumor size, and metastasis. Quantification of angiogenesis was achieved by the immunohistochemical staining of endothelial cells with antibody to CD31. VEGF and PDGF-A mRNAs were expressed more frequently in breast tumors than in nontumor breast tissues, whereas no difference was found in expression frequency of either transforming growth factor-alpha or basic fibroblast growth factor mRNA. Vascular counts in tumors correlated with each expression frequency of VEGF and PDGF-A mRNA. PDGF-A mRNA was expressed more frequently in tumors with lymph node metastasis than in those without metastasis. Expression of VEGF and PDGF mRNAs detected by reverse transcriptase-polymerase chain reaction in breast tumors correlates with tumor-related characteristics of angiogenesis and metastatic potential. Analysis of these mRNAs by reverse transcriptase-polymerase chain reaction may be useful for assessing the biologic behavior of a breast tumor before surgical treatment.

Medicinal Flowers. XXXII. Structures of oleanane-type triterpene saponins, perennisosides VIII, IX, X, XI, and XII, from the flowers of Bellis perennis.

PubMed

Morikawa, Toshio; Li, Xuezheng; Nishida, Eriko; Nakamura, Seikou; Ninomiya, Kiyofumi; Matsuda, Hisashi; Hamao, Makoto; Muraoka, Osamu; Hayakawa, Takao; Yoshikawa, Masayuki

2011-01-01

Five new triterpene saponins perennisosides VIII (1), IX (2), X (3), XI (4), and XII (5) were isolated from the MeOH-eluated fraction of the methanolic extract from the flowers of Bellis perennis. The MeOH-eluted fraction of the methanolic extract from the flowers of B. perennis was found to inhibit gastric emptying in olive oil-loaded mice at a dose of 200 mg/kg, per os (p.o.). The stereostructures of 1-5 were elucidated on the basis of chemical and spectroscopic evidence.

Analysis of transactivation potential of rice (Oryza sativa L.) heat shock factors.

PubMed

Lavania, Dhruv; Dhingra, Anuradha; Grover, Anil

2018-06-01

Based on yeast one-hybrid assays, we show that the presence of C-terminal AHA motifs is not a prerequisite for transactivation potential in rice heat shock factors. Transcriptional activation or transactivation (TA) of heat stress responsive genes takes place by binding of heat shock factors (Hsfs) to heat shock elements. Analysis of TA potential of thirteen rice (Oryza sativa L.) Hsfs (OsHsfs) carried out in this study by yeast one-hybrid assay showed that OsHsfsA3 possesses strong TA potential while OsHsfs A1a, A2a, A2b, A4a, A4d, A5, A7b, B1, B2a, B2b, B2c and B4d lack TA potential. From a near complete picture of TA potential of the OsHsf family (comprising of 25 members) emerging from this study and an earlier report from our group (Mittal et al. in FEBS J 278(17):3076-3085, 2011), it is concluded that (1) overall, six OsHsfs, namely A3, A6a, A6b, A8, C1a and C1b possess TA potential; (2) four class A OsHsfs, namely A3, A6a, A6b and A8 have TA potential out of which A6a and A6b contain AHA motifs while A3 and A8 lack AHA motifs; (3) nine class A OsHsfs, namely A1a, A2a, A2b, A2e, A4a, A4d, A5, A7a and A7b containing AHA motif(s) lack TA function in the yeast assay system; (4) all class B OsHsfs lack AHA motifs and TA potential (B4a not analyzed) and (5) though all class C OsHsf members lack AHA motifs, two members C1a and C1b possess TA function, while one member C2a lacks TA potential (C2b not analyzed). Thus, the presence or absence of AHA motif is possibly not the only factor determining TA potential of OsHsfs. Our findings will help to identify the transcriptional activators of rice heat shock response.

Phonon dynamics in type-VIII silicon clathrates: Beyond the rattler concept

NASA Astrophysics Data System (ADS)

Norouzzadeh, Payam; Myles, Charles W.; Vashaee, Daryoosh

2017-05-01

Clathrates can form a type of guest-host solid structures that, unlike most crystalline solids, have very low thermal conductivity. It is generally thought that the guest atoms caged inside the host framework act as "rattlers" and induce lattice dynamics disorders responsible for the small thermal conductivity. We performed a systematic study of the lattice dynamical properties of type-VIII clathrates with alkali and alkaline-earth guests, i.e., X8S i46 (X =Na , K, Rb, Cs, Ca, Sr, and Ba). The energy dependent participation ratio (PR) and the atomic participation ratio of phonon modes extracted from density functional theory calculations revealed that the rattler concept is not adequate to describe the effect of fillers as they manifest strong hybridization with the framework. For the case of heavy fillers, such as Rb, Sr, Cs, and Ba, a phonon band gap was formed between the acoustic and optical branches. The calculated PR indicated that the fillers suppress the acoustic phonon modes and change the energy transport mechanism from propagative to diffusive or localized resulting in "phonon-glass" characteristics. This effect is stronger for the heavy fillers. Furthermore, in all cases, the guest insertion depressed the phonon bandwidth, reduced the Debye temperature, and reduced the phonon group velocity, all of which should lead to reduction of the thermal conductivity.

Medication Errors in Vietnamese Hospitals: Prevalence, Potential Outcome and Associated Factors

PubMed Central

Nguyen, Huong-Thao; Nguyen, Tuan-Dung; van den Heuvel, Edwin R.; Haaijer-Ruskamp, Flora M.; Taxis, Katja

2015-01-01

Background Evidence from developed countries showed that medication errors are common and harmful. Little is known about medication errors in resource-restricted settings, including Vietnam. Objectives To determine the prevalence and potential clinical outcome of medication preparation and administration errors, and to identify factors associated with errors. Methods This was a prospective study conducted on six wards in two urban public hospitals in Vietnam. Data of preparation and administration errors of oral and intravenous medications was collected by direct observation, 12 hours per day on 7 consecutive days, on each ward. Multivariable logistic regression was applied to identify factors contributing to errors. Results In total, 2060 out of 5271 doses had at least one error. The error rate was 39.1% (95% confidence interval 37.8%- 40.4%). Experts judged potential clinical outcomes as minor, moderate, and severe in 72 (1.4%), 1806 (34.2%) and 182 (3.5%) doses. Factors associated with errors were drug characteristics (administration route, complexity of preparation, drug class; all p values < 0.001), and administration time (drug round, p = 0.023; day of the week, p = 0.024). Several interactions between these factors were also significant. Nurse experience was not significant. Higher error rates were observed for intravenous medications involving complex preparation procedures and for anti-infective drugs. Slightly lower medication error rates were observed during afternoon rounds compared to other rounds. Conclusions Potentially clinically relevant errors occurred in more than a third of all medications in this large study conducted in a resource-restricted setting. Educational interventions, focusing on intravenous medications with complex preparation procedure, particularly antibiotics, are likely to improve patient safety. PMID:26383873

[Potential risk factors for children in the family diet].

PubMed

Pavlović, M; Bijelović, S; Berenji, K; Balać, D

2001-01-01

It has been proven that high-energy diet with predominance of saturated fatty acids, cholesterol, animal proteins and sugar increases disease incidence. The aim of this study was to determine the potential risk factors of family diet of schoolchildren in Subotica. Evaluation of energy and nutrient intake in family diet (n = 357 families with schoolchildren) was examined by a Food Consumption Questionnaire during 7 days in February-March 1998. Data were elaboreted using a software "NUTQ". The potential nutritive risk factors were determined according to Recommended Dietary Allowances (RDA) index of dietary adequacy, as well as Population Nutrition Goals. Mean energy intake was 2197 kcal, where proteins made 14.64%, fats 41.39% and carbohydrates 43.97%. Mean intake of dietary saturated fatty acids (S) was 11.17%, of polyunsaturated fatty acids (P) 14.39%, of monounsaturated fatty acids 15.82%, dietary cholesterol 82.68 g/1000 kcal, dietary fiber 10.67 g daily, while the P/S ratio was 1.28. Analytical questionnaire of schoolchildren family diet shows that daily about 7.5% of children take in more than 30% of fats, 7% of them over 300 mg of dietary cholesterol, 65% of them over 10% of refined sugars, 50% of them over 10% of saturated fatty acids and all of them more than 6 g of NaCl and less than 20 g of dietary fiber a day. According to WHO recommendations, the average daily energy intake values are appropriate for boys, but exceeding for girls aged ten. Domination of meat, meat products, fats, oils, sugars, as well as mean intake of total fats, saturated fatty acids, potassium and sodium, represent potential nutritive risk factors for developing cardiovascular diseases, which are at the first place of morbidity and the second cause of mortality. In regard to our data from 1998, which have shown that among schoolchildren (n = 478) 10.04% boys and 11.47% girls were obese, 8.55% boys and 6.42% girls were overweight, 9.15% had hypercholesterolemia, 14.83% had

Calculating inspector probability of detection using performance demonstration program pass rates

NASA Astrophysics Data System (ADS)

Cumblidge, Stephen; D'Agostino, Amy

2016-02-01

The United States Nuclear Regulatory Commission (NRC) staff has been working since the 1970's to ensure that nondestructive testing performed on nuclear power plants in the United States will provide reasonable assurance of structural integrity of the nuclear power plant components. One tool used by the NRC has been the development and implementation of the American Society of Mechanical Engineers (ASME) Boiler and Pressure Vessel Code Section XI Appendix VIII[1] (Appendix VIII) blind testing requirements for ultrasonic procedures, equipment, and personnel. Some concerns have been raised, over the years, by the relatively low pass rates for the Appendix VIII qualification testing. The NRC staff has applied statistical tools and simulations to determine the expected probability of detection (POD) for ultrasonic examinations under ideal conditions based on the pass rates for the Appendix VIII qualification tests for the ultrasonic testing personnel. This work was primarily performed to answer three questions. First, given a test design and pass rate, what is the expected overall POD for inspectors? Second, can we calculate the probability of detection for flaws of different sizes using this information? Finally, if a previously qualified inspector fails a requalification test, does this call their earlier inspections into question? The calculations have shown that one can expect good performance from inspectors who have passed appendix VIII testing in a laboratory-like environment, and the requalification pass rates show that the inspectors have maintained their skills between tests. While these calculations showed that the PODs for the ultrasonic inspections are very good under laboratory conditions, the field inspections are conducted in a very different environment. The NRC staff has initiated a project to systematically analyze the human factors differences between qualification testing and field examinations. This work will be used to evaluate and prioritize

Damage to urban buildings in zones of intensities VIII and VII during the Wenchuan earthquake and discussion on some typical damages

NASA Astrophysics Data System (ADS)

Sun, Jingjiang; Tang, Yuhong; Zheng, Chao; Shi, Hongbin; Lin, Lin; Sun, Zhongxian

2009-04-01

The outline and typical characteristics of damages to building in Jiangyou city and Anxian county (intensity VIII), Mianyang city and Deyang city (intensity VII) are introduced in the paper. The damage ratios, based on the sample statistics of multi-story brick buildings together with multi-story brick buildings with RC frame at first story (BBF), are presented. Then some typical damages, such as horizontal cricks of brick masonry buildings, X-shaped cricks on the walls under windows, the damages to columns, beams and infill walls of frame buildings and the damage to half circle-shaped masonry walls, are discussed.

Biliary stent migration: a brief review of potential complications and possible etiological factors.

PubMed

Cheruvu, Srinivas; Kennedy, Robert; Moshenyat, Yitzak; Momen, Mojdeh; Krishnaiah, Mahesh; Anand, Sury

2014-01-01

Biliary endoprostheses continue to demonstrate their utility and simplicity in daily therapeutic endoscopy. However, the transient nature of these foreign bodies also underscores their potential detrimental effects even after successful deployment. Stent related factors, such as type, length and caliber offer potential avenues to minimize the risk of migration. However, a patient related factor such as the presence of prior abdominal surgeries makes it paramount for endoscopists to ascertain the location of a migrated stent. There is a ripe niche for continued research and development in biodegradable stents.

Adolescent mothers and child abuse potential: an evaluation of risk factors.

PubMed

Dukewich, T L; Borkowski, J G; Whitman, T L

1996-11-01

This research examines maternal and child factors that place adolescent mothers at risk for abusing their children. Using a longitudinal design, relationships among four risk factors (social supports, maternal psychological adjustment, maternal preparation for parenting, and child temperament), maternal psychological predisposition for aggressive coping (perceptions of stress and endorsements of punitive parenting), and maternal abuse potential were examined in a sample of 75 primiparous adolescent mothers and their children. Preparation for parenting, a construct which included knowledge and attitudes about children's development, was the strongest direct predictor of abuse potential; however, its effects were also partially mediated by the mother's psychological predisposition for aggressive coping. Similarly, the effects of child temperament on abuse were mediated by the mother's psychological predisposition for aggressive coping. Implications for designing intervention programs, and identifying at-risk adolescents, were also discussed.

The effect of prothrombotic blood abnormalities on risk of deep vein thrombosis in users of hormone replacement therapy: a prospective case-control study.

PubMed

Douketis, Jim D; Julian, Jim A; Crowther, Mark A; Kearon, Clive; Bates, Shannon M; Barone, Marisa; Piovella, Franco; Middeldorp, Saskia; Prandoni, Paolo; Johnston, Marilyn; Costantini, Lorrie; Ginsberg, Jeffrey S

2011-01-01

Few studies have assessed the effect of prothrombotic blood abnormalities on the risk of deep vein thrombosis (DVT) with hormone replacement therapy (HRT). We studied postmenopausal women with suspected DVT in whom HRT use and prothrombotic blood abnormalities were sought. Cases had unprovoked DVT and controls had no DVT and without DVT risk factors. The risk of DVT was determined in women with and without prothrombotic abnormalities. A total of 510 postmenopausal women with suspected DVT were assessed; 57 cases and 283 controls were identified. Compared to HRT, nonusers without the factor V Leiden mutation, the risk of DVT was increased in estrogen-progestin HRT users (odds ratio [OR], 3.2; 95% confidence interval [CI]: 1.2-8.6) and in nonusers with the factor V Leiden mutation (OR, 5.3; 1.9-15.4) and appears multiplied in users of estrogen-progestin HRT with the factor V Leiden mutation (OR, 17.1; 3.7-78). Compared to HRT, nonusers with normal factor VIII, the risk of DVT was increased in estrogen-progestin HRT users with normal factor VIII (OR, 2.8; 1.0-7.9) and in HRT nonusers with the highest factor VIII quartile (OR, 6.0; 2.1-17), and appears to be multiplied in women who are users of estrogen-progestin HRT with the highest factor VIII quartile (OR, 17.0; 3.6-80). In postmenopausal women who are estrogen-progestin HRT users, the presence of the factor V Leiden mutation or an elevated factor VIII level appears to have a multiplicative effect on their overall risk of DVT, increasing it 17-fold compared to women without these blood abnormalities who are HRT nonusers.

Mapping Soil Erosion Factors and Potential Erosion Risk for the National Park "Central Balkan"

NASA Astrophysics Data System (ADS)

Ilieva, Diliana; Malinov, Ilia

2014-05-01

Soil erosion is widely recognised environmental problem. The report aims at presenting the main results from assessment and mapping of the factors of sheet water erosion and the potential erosion risk on the territory of National Park "Central Balkan". For this purpose, the Universal Soil Loss Equation (USLE) was used for predicting soil loss from erosion. The influence of topography (LS-factor) and soil erodibility (K-factor) was assessed using small-scale topographic and soil maps. Rainfall erosivity (R-factor) was calculated from data of rainfalls with amounts exceeding 9.5 mm from 14 hydro-meteorological stations. The values of the erosion factors (R, K and LS) were presented for the areas of forest, sub-alpine and alpine zones. Using the methods of GIS, maps were plotted presenting the area distribution among the classes of the soil erosion factors and the potential risk in the respective zones. The results can be used for making accurate decisions for soil conservation and sustainable land management in the park.

Haemophilia A: carrier detection and prenatal diagnosis by linkage analysis using DNA polymorphism.

PubMed Central

Tuddenham, E G; Goldman, E; McGraw, A; Kernoff, P B

1987-01-01

Restriction fragment length polymorphisms (RFLPs) within or close to the factor VIII locus are very useful for genetic linkage analysis. Such RFLPs allow a mutant allele to be tracked in a family, segregating haemophilia A even when, as is usually the case, the precise mutation causing failure to synthesise factor VIII is unknown. To date two markers tightly linked to the factor VIII locus have been described, one of which is highly polymorphic and therefore informative in most kindreds. A significant crossover rate, however, does not make diagnosis absolute. Three intragenic RFLPs have been defined, which, taken together, are informative in about 70% of women, providing virtually deterministic genetic diagnosis. PMID:2889753

Sperm-derived factors enhance the in vitro developmental potential of haploid parthenotes.

PubMed

Nair, Ramya; Aboobacker, Shahin; Mutalik, Srinivas; Kalthur, Guruprasad; Adiga, Satish Kumar

2017-12-01

Parthenotes are characterized by poor in vitro developmental potential either due to the ploidy status or the absence of paternal factors. In the present study, we demonstrate the beneficial role of sperm-derived factors (SDF) on the in vitro development of mouse parthenotes. Mature (MII) oocytes collected from superovulated Swiss albino mice were activated using strontium chloride (SrCl2) in the presence or absence of various concentrations of SDF in M16 medium. The presence of SDF in activation medium did not have any significant influence on the activation rate. However, a significant increase in the developmental potential of the embryos and increased blastocyst rate (P < 0.01) was observed at 50 µg/ml concentration. Furthermore, the activated oocytes from this group exhibited early cleavage and cortical distribution of cortical granules that was similar to that of normally fertilized zygotes. Culturing 2-cell stage parthenotes in the presence of SDF significantly improved the developmental potential (P < 0.05) indicating that they also play a significant role in embryo development. In conclusion, artificial activation of oocytes with SDF can improve the developmental potential of parthenotes in vitro.

Incidence and risk factors of bleeding-related adverse events in patients with chronic lymphocytic leukemia treated with ibrutinib

PubMed Central

Lipsky, Andrew H.; Farooqui, Mohammed Z.H.; Tian, Xin; Martyr, Sabrina; Cullinane, Ann M.; Nghiem, Khanh; Sun, Clare; Valdez, Janet; Niemann, Carsten U.; Herman, Sarah E. M.; Saba, Nakhle; Soto, Susan; Marti, Gerald; Uzel, Gulbu; Holland, Steve M.; Lozier, Jay N.; Wiestner, Adrian

2015-01-01

Ibrutinib is associated with bleeding-related adverse events of grade ≤2 in severity, and infrequently with grade ≥3 events. To investigate the mechanisms of bleeding and identify patients at risk, we prospectively assessed platelet function and coagulation factors in our investigator-initiated trial of single-agent ibrutinib for chronic lymphocytic leukemia. At a median follow-up of 24 months we recorded grade ≤2 bleeding-related adverse events in 55% of 85 patients. No grade ≥3 events occurred. Median time to event was 49 days. The cumulative incidence of an event plateaued by 6 months, suggesting that the risk of bleeding decreases with continued therapy. At baseline, von Willebrand factor and factor VIII levels were often high and normalized on treatment. Platelet function measured via the platelet function analyzer (PFA-100™) was impaired in 22 patients at baseline and in an additional 19 patients on ibrutinib (often transiently). Collagen and adenosine diphosphate induced platelet aggregation was tested using whole blood aggregometry. Compared to normal controls, response to both agonists was decreased in all patients with chronic lymphocytic leukemia, whether on ibrutinib or not. Compared to untreated chronic lymphocytic leukemia patients, response to collagen showed a mild further decrement on ibrutinib, while response to adenosine diphosphate improved. All parameters associated with a significantly increased risk of bleeding-related events were present at baseline, including prolonged epinephrine closure time (HR 2.74, P=0.012), lower levels of von Willebrand factor activity (HR 2.73, P=0.009) and factor VIII (HR 3.73, P=0.0004). In conclusion, both disease and treatment-related factors influence the risk of bleeding. Patients at greater risk for bleeding of grade ≤2 can be identified by clinical laboratory tests and counseled to avoid aspirin, non-steroidal anti-inflammatory drugs and fish oils. ClinicalTrials.gov identifier NCT01500733 PMID

Factors Potentially Influencing Student Acceptance of Biological Evolution

NASA Astrophysics Data System (ADS)

Wiles, Jason R.

This investigation explored scientific, religious, and otherwise nonscientific factors that may influence student acceptance of biological evolution and related concepts, how students perceived these factors to have influenced their levels of acceptance of evolution and changes therein, and what patterns arose among students' articulations of how their levels of acceptance of evolution may have changed. This exploration also measured the extent to which students' levels of acceptance changed following a treatment designed to address factors identified as potentially affecting student acceptance of evolution. Acceptance of evolution was measured using the MATE instrument (Rutledge and Warden, 1999; Rutledge and Sadler, 2007) among participants enrolled in a secondary-level academic program during the summer prior to their final year of high school and as they transitioned to the post-secondary level. Student acceptance of evolution was measured to be significantly higher than pre-treatment levels both immediately following and slightly over one year after treatment. Qualitative data from informal questionnaires, from formal course evaluations, and from semi-structured interviews of students engaged in secondary level education and former students at various stages of post-secondary education confirmed that the suspected factors were perceived by participants to have influenced their levels of acceptance of evolution. Furthermore, participant reports provided insight regarding the relative effects they perceived these factors to have had on their evolution acceptance levels. Additionally, many participants reported that their science teachers in public schools had avoided, omitted, or denigrated evolution during instruction, and several of these students expressed frustration regarding what they perceived to have been a lack of education of an important scientific principle. Finally, no students expressed feelings of being offended by having been taught about

Benchmarking Potential Factors Leading to Education Quality: A Study of Cambodian Higher Education

ERIC Educational Resources Information Center

Chen, Ching-Yaw; Sok, Phyra; Sok, Keomony

2007-01-01

Purpose: To study the quality in higher education in Cambodia and explore the potential factors leading to quality in Cambodian higher education. Design/methodology/approach: Five main factors that were deemed relevant in providing quality in Cambodian higher education were proposed: academic curriculum and extra-curricular activities, teachers'…

Lupus anticoagulant, anticardiolipin antibodies, and human immunodeficiency virus in haemophilia.

PubMed Central

Cohen, H; Mackie, I J; Anagnostopoulos, N; Savage, G F; Machin, S J

1989-01-01

The prevalence of lupus anticoagulant, using the dilute Russell's viper venom time (DRVT), was determined in 22 patients with mild to severe haemophilia A to see if there was any association with the presence of viral disease. Twelve haemophiliacs (58%) were lupus anticoagulant positive, with a mean patient:control ratio of 1.24 (range 1.15-1.52, normal range 0.84-1.06 which partially corrected with lysed, washed platelets). Nine of these patients were IgG or IgM, or both, anticardiolipin antibody positive and nine were human immunodeficiency virus (HIV) antibody positive, but associations between lupus anticoagulant, anticardiolipin antibodies, and HIV antibody positivity were not significant. Mixing studies of normal plasma and immune depleted factor VIII deficient plasma showed that the DRVT ratio increased when the factor VIII concentration fell below 0.15 IU/ml. There was no significant association between plasma factor VIII concentration and positive DRVT results in haemophiliacs. The addition of porcine factor VIII concentrate produced no correction in eight of the 12 with DRVTs indicative of lupus anticoagulant, suggesting that these were prolonged by antiphospholipid activity. It is concluded that the presence of lupus anticoagulant and anticardiolipin antibodies in haemophiliacs may represent an antiphospholipid response to viraemic challenge, not only to HIV but also to other viral antigens, and that a very low factor VIII concentration may produce a false positive DRVT result. PMID:2500459

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.

Prevalence of nucleic acid sequences specific for human parvoviruses, hepatitis A and hepatitis E viruses in coagulation factor concentrates.

PubMed

Modrow, S; Wenzel, J J; Schimanski, S; Schwarzbeck, J; Rothe, U; Oldenburg, J; Jilg, W; Eis-Hübinger, A M

2011-05-01

Due to their high resistance to inactivation procedures, nonenveloped viruses such as parvovirus B19, human bocavirus (HBoV), human parvovirus 4 (PARV4), hepatitis A (HAV) and hepatitis E virus (HEV) pose a particular threat to blood products. Virus transmission to patients treated with blood products presents an additional burden to disease. We determined the frequency and the amount of nucleic acid specific for nonenveloped viruses in recently manufactured preparations of commercial coagulation factor concentrates. At least three different batches of each of 13 different plasma-derived and recombinant coagulation factor products were tested for the presence and the amount of nucleic acid for parvovirus B19, HBoV, human parvovirus 4, hepatitis A virus and HEV by using quantitative polymerase chain reaction. Whereas none of the recombinant products tested positive for any of these viruses, parvovirus B19 DNA with amounts ranging between 2×10(1) and 1.3×10(3) genome equivalents/ml was detected in five plasma-derived products. In addition to parvovirus B19 genotype 1, genotypes 2 and 3 were observed in two batches of a factor VIII/von-Willebrand factor product. In two products (one factor VIII concentrate and one activated prothrombin complex concentrate), a combination of both genotypes 1 and 2 of parvovirus B19 was detected. The data show that nucleic acids from several relevant nonenveloped viruses are not found at detectable levels in coagulation factor concentrates. In some cases, parvovirus B19 DNA was detectable at low levels. Testing of the plasma pools for the full range of parvovirus genotypes is advocated for ensuring product safety. © 2010 The Author(s). Vox Sanguinis © 2010 International Society of Blood Transfusion.

Endogenous Antiangiogenic Factors in Chronic Kidney Disease: Potential Biomarkers of Progression.

PubMed

Tanabe, Katsuyuki; Sato, Yasufumi; Wada, Jun

2018-06-24

Chronic kidney disease (CKD) is a major global health problem. Unless intensive intervention is initiated, some patients can rapidly progress to end-stage kidney disease. However, it is often difficult to predict renal outcomes using conventional laboratory tests in individuals with CKD. Therefore, many researchers have been searching for novel biomarkers to predict the progression of CKD. Angiogenesis is involved in physiological and pathological processes in the kidney and is regulated by the balance between a proangiogenic factor, vascular endothelial growth factor (VEGF)-A, and various endogenous antiangiogenic factors. In recent reports using genetically engineered mice, the roles of these antiangiogenic factors in the pathogenesis of kidney disease have become increasingly clear. In addition, recent clinical studies have demonstrated associations between circulating levels of antiangiogenic factors and renal dysfunction in CKD patients. In this review, we summarize recent advances in the study of representative endogenous antiangiogenic factors, including soluble fms-related tyrosine kinase 1, soluble endoglin, pigment epithelium-derived factor, VEGF-A 165 b, endostatin, and vasohibin-1, in associations with kidney diseases and discuss their predictive potentials as biomarkers of progression of CKD.

Ergonomic factors that cause the presence of pain muscle in students of dentistry.

PubMed

Diaz-Caballero, Antonio-José; Gómez-Palencia, Isabel-Patricia; Díaz-Cárdenas, Shyrley

2010-11-01

To identify the ergonomic factors and the presence of muscular pain in dental students of VIII, IX, X semesters presently practicing at the clinics of the College of Dentistry of university of Cartagena, Colombia, South America. This is a descriptive study carried out in dental students of the VIII, IX, and X semesters which were undergoing clinical practice at the College of Dentistry of University of Cartagena. A convenience sample of 83 students who met the inclusion criteria was taken and those who agreed to participate signed an informed consent. Data collection was obtained by means of a structured questionnaire for ergonomic factors and the presence of pain was identified palpating the muscles object of the study by a physical therapist. The variables evaluated were: presence of pain, affected muscles, affected zones, gender, postures and work environment. The adoption of inadequate postures such as exaggerated flexions or cervical torsions could generate a higher frequency of muscular pain in dental students. The approximating muscle of the thumb showed 11% frequency of pain. The presence of muscular pain was higher for the female group participating in this study. Dentists are prone, since the beginning of their clinical practice as students, to lesions of the skeletal muscle system due to the clinical exercise of the profession, being the most common, muscle pain in the back, neck, shoulders and hands. This would imply initiating an occupational health program promoting healthy lifestyles in their academic environment and their future professional life, at the beginning of their clinical practice in dental school.

Orthodontic extrusion of Ellis Class VIII fracture of maxillary lateral incisor - The sling shot method.

PubMed

Felicita, A Sumathi

2018-07-01

The aim of this paper is to evaluate the efficacy of forced extrusion using the sling shot elastic. A 21 year adult patient reported with an Ellis Class VIII fracture of the maxillary right lateral incisor. Root canal treatment followed by a fiber reinforced composite post was placed and core build up was done. A metal button was bonded to the tooth. Begg brackets were placed from the second premolar on one side to the second premolar on the opposite side. 0.016″ × 0.025″ stainless steel was placed in ribbon mode. The ligature wire was placed as a sling shot from the button on the fractured tooth to the two adjacent teeth. 4 mm of extrusion was achieved and there was no evidence of root resorption. Forced extrusion was achieved in four months. The sling shot method is a very effective method of ligation. Light forces are delivered over a long duration with definitive results as compared to the inconsistent force delivery with conventional extrusion mechanics.

Surface and subsurface geologic risk factors to ground water affecting brownfield redevelopment potential.

PubMed

Kaufman, Martin M; Murray, Kent S; Rogers, Daniel T

2003-01-01

A model is created for assessing the redevelopment potential of brownfields. The model is derived from a space and time conceptual framework that identifies and measures the surface and subsurface risk factors present at brownfield sites. The model then combines these factors with a contamination extent multiplier at each site to create an index of redevelopment potential. Results from the application of the model within an urbanized watershed demonstrate clear differences between the redevelopment potential present within five different near-surface geologic units, with those units containing clay being less vulnerable to subsurface contamination. With and without the extent multiplier, the total risk present at the brownfield sites within all the geologic units is also strongly correlated to the actual costs of remediation. Thus, computing the total surface and subsurface risk within a watershed can help guide the remediation efforts at broad geographic scales, and prioritize the locations for redevelopment.

Autotransfusion from experimental hemothorax: levels of coagulation factors.

PubMed

Napoli, V M; Symbas, P J; Vroon, D H; Symbas, P N

1987-03-01

The coagulation system was investigated in five dogs undergoing autotransfusion from experimental hemothorax. One fourth of the blood volume was bled into the pleural space, drained, and autotransfused. The hemothorax blood showed: very prolonged PT and PTT; very low platelets and fibrinogen; midly elevated FDP; very low coagulation factors VIII, and V; reduced XII, prothrombin, X, XI, and VII. Partial clotting, mild fibrinolysis, and fibrin deposition over the pulmonary pleura seemed to cause incoagulability of hemothorax blood. Post autotransfusion arterial blood showed: normal PT and PTT; 25% decrease in platelets, and 31% decrease in fibrinogen from baseline values. There was also an overall 20% reduction of fibrinogen from baseline values. There was also an overall 20% reduction of all clotting factors, but their levels remained above 50% activity. It was concluded that autotransfusion from a hemothorax of 25% the blood volume in dogs causes a mild loss of hemostatic components, but does not significantly compromise the clotting mechanism.

Potential for use of environmental factors in urban planning

NASA Astrophysics Data System (ADS)

Teixeira da Silva, Ricardo; van der Ploeg, Martine; van Delden, Hedwig; Fleskens, Luuk

2016-04-01

Projections for population growth estimate, on top of the current 7.4 billion world population, an increase of 2 billion people for the next 40 years. It is also projected that 66 per cent of the world population in 2050 will live in urban areas. To accommodate the urban population growth cities are changing continuously land cover to urban areas. Such changes are a threat for natural resources and food production systems stability and capability to provide food and other functions. However, little has been done concerning a rational soil management for food production in urban and peri-urban areas. This study focuses on the assessment of soil lost due to urban expansion and discusses the potential loss regarding the quality of the soil for food production and environmental functions. It is relevant to increase the knowledge on the role of soils in peri-urban areas and in the interaction of physical, environmental and social factors. The methodology consists of assessing the soil quality in and around urban and peri-urban areas. It focuses particularly on the physical properties and the environmental factors, for two periods of time and account the potential losses due to urban expansion. This project is on-going, therefore current advances will be presented and will look for a discussion on the contribution of soil quality for decision-making and land management in urban and peri-urban areas.

Potential risk factors for haematological cancers in semiconductor workers.

PubMed

Lee, K; Kim, S-G; Kim, D

2015-10-01

There has recently been increased interest in cancer incidence in electronics workers. To determine the cancer incidence ratio in electronics workers and the potential factors affecting the risk for development of cancer. Epidemiological study performed in electronics workers who were employed between 1999 and 2008 in South Korea. Cancer incidence ratio was analysed with respect to departments, divisions, job titles, gender, age, hepatitis B and C virus infection and work duration. We compared the incidence of haematological cancer in this cohort with that expected in the general population. The study population was 56283. Overall, the standardized incidence ratio (SIR) for haematological cancer was 0.85. In particular, the SIR for leukaemia was 0.86 and for non-Hodgkin lymphoma (NHL) was 0.93, which were not statistically significant. The SIR for NHL was significantly increased [SIR 5.23, 95% confidence interval (CI) 1.31-20.95] in female office workers. We also found that the SIR for NHL was significantly increased in female workers who tested positive for hepatitis virus infection (SIR 7.69, 95% CI 1.08-54.60). The raised SIR for NHL among female workers was due to potential risk factors such as hepatitis virus infection although additional research and an ongoing, long-term, prospective epidemiological cohort study is needed. © The Author 2015. Published by Oxford University Press on behalf of the Society of Occupational Medicine. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Simulation of LV pacemaker lead in marginal vein: potential risk factors for acute dislodgement.

PubMed

Zhao, Xuefeng; Burger, Mike; Liu, Yi; Das, Mithilesh K; Combs, William; Wenk, Jonathan F; Guccione, Julius M; Kassab, Ghassan S

2011-03-01

Although left ventricular (LV) coronary sinus lead dislodgement remains a problem, the risk factors for dislodgement have not been clearly defined. In order to identify potential risk factors for acute lead dislodgement, we conducted dynamic finite element simulations of pacemaker lead dislodgement in marginal LV vein. We considered factors such as mismatch in lead and vein diameters, velocity of myocardial motion, branch angle between the insertion vein and the coronary sinus, degree of slack, and depth of insertion. The results show that large lead-to-vein diameter mismatch, rapid myocardial motion, and superficial insertion are potential risk factors for lead dislodgement. In addition, the degree of slack presents either a positive or negative effect on dislodgement risk depending on the branch angle. The prevention of acute lead dislodgment can be enforced by inducing as much static friction force as possible at the lead-vein interface, while reducing the external force. If the latter exceeds the former, dislodgement will occur. The present findings underscore the major risk factors for lead dislodgment, which may improve implantation criterion and future lead design.

Methods for detection of haemophilia carriers: a Memorandum*

PubMed Central

1977-01-01

This Memorandum discusses the problems and techniques involved in the detection of carriers of haemophilia A (blood coagulation factor VIII deficiency) and haemophilia B (factor IX deficiency), particularly with a view to its application to genetic counselling. Apart from the personal suffering caused by haemophilia, the proper treatment of haemophiliacs places a great strain on the blood transfusion services, and it is therefore important that potential carriers should have precise information about the consequences of their having children. The Memorandum classifies the types of carrier and describes the laboratory methods used for the assessment of coagulant activity and antigen concentration in blood. Particular emphasis is laid on the establishment of international, national, and laboratory (working) standards for factors VIII and IX and their calibration in international units (IU). This is followed by a detailed account of the statistical analysis of pedigree and laboratory data, which leads to an assessment of the likelihood that a particular person will transmit the haemophilia gene to her children. Finally, the problems and responsibilities involved in genetic counselling are considered. PMID:304395

Ionization-potential depression and dynamical structure factor in dense plasmas

NASA Astrophysics Data System (ADS)

Lin, Chengliang; Röpke, Gerd; Kraeft, Wolf-Dietrich; Reinholz, Heidi

2017-07-01

The properties of a bound electron system immersed in a plasma environment are strongly modified by the surrounding plasma. The modification of an essential quantity, the ionization energy, is described by the electronic and ionic self-energies, including dynamical screening within the framework of the quantum statistical theory. Introducing the ionic dynamical structure factor as the indicator for the ionic microfield, we demonstrate that ionic correlations and fluctuations play a critical role in determining the ionization potential depression. This is, in particular, true for mixtures of different ions with large mass and charge asymmetry. The ionization potential depression is calculated for dense aluminum plasmas as well as for a CH plasma and compared to the experimental data and more phenomenological approaches used so far.

Treatment of haemophilia and related disorders in Britain and Northern Ireland during 1976-80: report on behalf of the directors of haemophilia centres in the United Kingdom.

PubMed Central

Rizza, C R; Spooner, R J

1983-01-01

A five year survey of the treatment of patients in the United Kingdom suffering from haemophilia and related disorders was carried out on behalf of the directors of haemophilia centres. The survey showed an increase in the number of patients receiving treatment from the centres, a substantial increase in the total amount of therapeutic materials used, and an increase in the average amount of factor VIII or factor IX used yearly per patient. Home treatment became established for severely affected patients and accounted for roughly half of the total amount of material used. Study of the acquisition of factor VIII or factor IX antibodies (inhibitors) in patients with haemophilia A or haemophilia B showed no increase in antibodies during the survey period, despite the increased use of factor VIII and factor IX concentrates. The occurrence of acute hepatitis in treated patients was also studied and no increased incidence was observed. A near normal median expectation of life in patients with severe haemophilia A was found. PMID:6403138

Identifying factors for optimal development of health-related websites: a delphi study among experts and potential future users.

PubMed

Schneider, Francine; van Osch, Liesbeth; de Vries, Hein

2012-02-14

The Internet has become a popular medium for offering tailored and targeted health promotion programs to the general public. However, suboptimal levels of program use in the target population limit the public health impact of these programs. Optimizing program development is considered as one of the main processes to increase usage rates. To distinguish factors potentially related to optimal development of health-related websites by involving both experts and potential users. By considering and incorporating the opinions of experts and potential users in the development process, involvement in the program is expected to increase, consequently resulting in increased appreciation, lower levels of attrition, and higher levels of sustained use. We conducted a systematic three-round Delphi study through the Internet. Both national and international experts (from the fields of health promotion, health psychology, e-communication, and technical Web design) and potential users were invited via email to participate. During this study an extensive list of factors potentially related to optimal development of health-related websites was identified, by focusing on factors related to layout, general and risk information provision, questionnaire use, additional services, and ease of use. Furthermore, we assessed the extent to which experts and potential users agreed on the importance of these factors. Differences as well as similarities among experts and potentials users were deduced. In total, 20 of 62 contacted experts participated in the first round (32% response rate); 60 of 200 contacted experts (30% response rate) and 210 potential users (95% response rate) completed the second-round questionnaire, and 32 of 60 contacted experts completed the third round (53% response rate). Results revealed important factors consented upon by experts and potential users (eg, ease of use, clear structure, and detailed health information provision), as well as differences regarding

Earmuff restricts progenitor cell potential by attenuating the competence to respond to self-renewal factors.

PubMed

Janssens, Derek H; Komori, Hideyuki; Grbac, Daniel; Chen, Keng; Koe, Chwee Tat; Wang, Hongyan; Lee, Cheng-Yu

2014-03-01

Despite expressing stem cell self-renewal factors, intermediate progenitor cells possess restricted developmental potential, which allows them to give rise exclusively to differentiated progeny rather than stem cell progeny. Failure to restrict the developmental potential can allow intermediate progenitor cells to revert into aberrant stem cells that might contribute to tumorigenesis. Insight into stable restriction of the developmental potential in intermediate progenitor cells could improve our understanding of the development and growth of tumors, but the mechanisms involved remain largely unknown. Intermediate neural progenitors (INPs), generated by type II neural stem cells (neuroblasts) in fly larval brains, provide an in vivo model for investigating the mechanisms that stably restrict the developmental potential of intermediate progenitor cells. Here, we report that the transcriptional repressor protein Earmuff (Erm) functions temporally after Brain tumor (Brat) and Numb to restrict the developmental potential of uncommitted (immature) INPs. Consistently, endogenous Erm is detected in immature INPs but undetectable in INPs. Erm-dependent restriction of the developmental potential in immature INPs leads to attenuated competence to respond to all known neuroblast self-renewal factors in INPs. We also identified that the BAP chromatin-remodeling complex probably functions cooperatively with Erm to restrict the developmental potential of immature INPs. Together, these data led us to conclude that the Erm-BAP-dependent mechanism stably restricts the developmental potential of immature INPs by attenuating their genomic responses to stem cell self-renewal factors. We propose that restriction of developmental potential by the Erm-BAP-dependent mechanism functionally distinguishes intermediate progenitor cells from stem cells, ensuring the generation of differentiated cells and preventing the formation of progenitor cell-derived tumor-initiating stem cells.

Relaxation and approximate factorization methods for the unsteady full potential equation

NASA Technical Reports Server (NTRS)

Shankar, V.; Ide, H.; Gorski, J.

1984-01-01

The unsteady form of the full potential equation is solved in conservation form, using implicit methods based on approximate factorization and relaxation schemes. A local time linearization for density is introduced to enable solution to the equation in terms of phi, the velocity potential. A novel flux-biasing technique is applied to generate proper forms of the artificial viscosity, to treat hyperbolic regions with shocks and sonic lines present. The wake is properly modeled by accounting not only for jumps in phi, but also for jumps in higher derivatives of phi obtained from requirements of density continuity. The far field is modeled using the Riemann invariants to simulate nonreflecting boundary conditions. Results are presented for flows over airfoils, cylinders, and spheres. Comparisons are made with available Euler and full potential results.

Antisymmetrization effects and the form factor of the real part of the. cap alpha. -nucleus potential

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

Majka, Z.; Budzanowski, A.; Grotowski, K.

1978-07-01

Antisymmetrization effects in the ..cap alpha..-nucleus interaction are investigated on the basis of a microscopic model in an one nucleon exchange approximation. It influences the form factor, increasing the halfway radius and decreasing the diffuseness as compared with the direct term of the potential only. Antisymmetrization preserves the shape of the potential which can be parametrized by a Woods-Saxon squared form. The phenomenological potential with the energy independent form factor of the above shape fits experimental data in a wide energy region.

The potential contribution of dietary factors to breast cancer prevention.

PubMed

Shapira, Niva

2017-09-01

Breast cancer (BC), the leading cancer in women, is increasing in prevalence worldwide, concurrent with western metabolic epidemics, that is, obesity, metabolic syndrome, and diabetes, and shares major risk factors with these diseases. The corresponding potential for nutritional contributions toward BC prevention is reviewed and related to critical stages in the life cycle and their implications for carcinogenic and pathometabolic trajectories. BC initiation potentially involves diet-related pro-oxidative, inflammatory, and procarcinogenic processes, that interact through combined lipid/fatty acid peroxidation, estrogen metabolism, and related DNA-adduct/depurination/mutation formation. The pathometabolic trajectory is affected by high estrogen, insulin, and growth factor cascades and resultant accelerated proliferation/progression. Anthropometric risk factors - high birth weight, adult tallness, adiposity/BMI, and weight gain - are often reflective of these trends. A sex-based nutritional approach targets women's specific risk in western obesogenic environments, associated with increasing fatness, estrogen metabolism, n-6 : n-3 polyunsaturated fatty acid ratio, and n-6 polyunsaturated fatty acid conversion to proinflammatory/carcinogenic eicosanoids, and effects of timing of life events, for example, ages at menarche, full-term pregnancy, and menopause. Recent large-scale studies have confirmed the effectiveness of the evidence-based recommendations against BC risk, emphasizing low-energy density diets, highly nutritious plant-based regimes, physical activity, and body/abdominal adiposity management. Better understanding of dietary inter-relationships with BC, as applied to food intake, selection, combination, and processing/preparation, and recommended patterns, for example, Mediterranean, DASH, plant-based, low energy density, and low glycemic load, with high nutrient/phytonutrient density, would increase public motivation and authoritative support for early

Von Willebrand factor, a versatile player in gastrointestinal bleeding in left ventricular assist device recipients?

PubMed

Fischer, Quentin; Huisse, Marie-Geneviève; Voiriot, Guillaume; Caron, Claudine; Lepage, Laurent; Dilly, Marie-Pierre; Nataf, Patrick; Ajzenberg, Nadine; Kirsch, Matthias

2015-01-01

Bleeding originating in the gastrointestinal (GI) tract is one of the most common adverse events after left ventricular assist device (LVAD) implantation. In these patients, GI bleeding appears to be the consequence of altered hemostasis on the one hand and alterations of the GI microvasculature on the other. We report the case of a patient who suffered repeated, severe GI bleeding early after implantation of a HeartMate II continuous-flow LVAD. After failure of conventional treatment strategies, GI bleeding was controlled using repeated transfusions of a purified von Willebrand factor (VWF) concentrate, almost devoid of Factor VIII (Wilfactin, LFB). No episodes of pump thrombosis were noted. Subsequent to VWF transfusions, we observed a progressive normalization of circulating vascular endothelial growth factor levels. Our data raise the possibility that, in addition to its hemostatic properties, transfusions of VWF might have acted as an antiangiogenic factor. © 2014 AABB.

Identification of pathogenic factors potentially involved in Staphylococcus aureus keratitis using proteomics.

PubMed

Khan, Shamila; Cole, Nerida; Hume, Emma B H; Garthwaite, Linda L; Nguyen-Khuong, Terry; Walsh, Bradley J; Willcox, Mark D P

2016-10-01

Staphylococcus is a leading cause of microbial keratitis, characterized by destruction of the cornea by bacterial exoproteins and host-associated factors. The aim of this study was to compare extracellular and cell-associated proteins produced by two different isolates of S. aureus, a virulent clinical isolate (Staph 38) and a laboratory strain (Staphylococcus aureus 8325-4) of weaker virulence in the mouse keratitis model. Proteins were analyzed using 2D polyacrylamide gel electrophoresis and identified by subsequent mass spectrometry. Activity of staphylococcal adhesins was assessed by allowing strains to bind to various proteins adsorbed onto polymethylmethacrylate squares. Thirteen proteins in the extracellular fraction and eight proteins in the cell-associated fractions after bacterial growth were produced in increased amounts in the clinical isolate Staph 38. Four of these proteins were S. aureus virulence factor adhesins, fibronectin binding protein A, staphopain, glyceraldehyde-3-phosphate dehydrogenase 2 and extracellular adherence protein. The clinical isolate Staph 38 adhered to a greater extent to all mammalian proteins tested, indicating the potential of the adhesins to be active on its surface. Other proteins with increased expression in Staph 38 included potential moonlighting proteins and proteins involved in transcription or translation. This is the first demonstration of the proteome of S. aureus isolates from keratitis. These results indicate that the virulent clinical isolate produces more potentially important virulence factors compared to the less virulent laboratory strain and these may be associated with the ability of a S. aureus strain to cause more severe keratitis. Copyright © 2016 Elsevier Ltd. All rights reserved.

Myopathy induced by statin-ezetimibe combination: Evaluation of potential risk factors.

PubMed

Brahmachari, Ballari; Chatterjee, Suparna

2015-01-01

Although both atorvastatin and ezetimibe may cause myopathy, statin-induced myopathy is less likely at low doses, and ezetimibe is only rarely reported to induce myopathy. Also, ezetimibe is not usually known to potentiate statin-induced myopathy. We report a case of myalgia with elevated serum creatinine phosphokinase in a patient after 2 months of therapy with fixed dose combination of atorvastatin and ezetimibe (10 mg each). At the time of the event, patient was undertaking moderate physical exertion in the form of brisk walking for 30-40 min a day and was detected to have low serum Vitamin D levels. The adverse event resolved after stopping atorvastatin-ezetimibe combination therapy. Potential risk factors, such as physical exertion and Vitamin D deficiency, co-existent in dyslipidemic patients, may exacerbate myopathy potential of these drugs, and precipitate muscular symptoms even at a low-dose.

A questionnaire study of associations between potential risk factors and salmonella status in Swedish dairy herds.

PubMed

Ågren, Estelle C C; Frössling, Jenny; Wahlström, Helene; Emanuelson, Ulf; Sternberg Lewerin, Susanna

2017-08-01

In this study associations between potential risk factors and salmonella status in Swedish dairy herds were investigated. A case-control study design was used, including existing as well as new cases. Herds were assigned a salmonella status on the basis of antibody analysis of bulk milk samples. Information on potential risk factors was collected from registry data and from farmers via a questionnaire. Univariable and multivariable logistic regression analyses were used to investigate associations between salmonella status and potential risk factors. In addition, multivariate analysis with Additive Bayesian Network (ABN) modelling was performed to improve understanding of the complex relationship between all the variables. Because of the difficulty in identifying associations between potential risk factors and infections with low prevalence and a large regional variation, exposure of potential risk factors in the high-prevalence region (Öland) were compared to exposure in other regions in Sweden. In total 483 of 996 (48%) farmers responded to the questionnaire, 69 herds had test-positive bulk milk samples. The strongest association with salmonella status was 'presence of salmonella test-positive herds <5 km' (OR 4.3, 95% CI 2.0-9.4). Associations with salmonella status were also seen between 'feeding calves residue milk only' (OR 2.4, 95% CI 1.2-4.6), 'certified organic herds' (OR 2.5, 95% CI 1.2-4.9) and 'frequently seeing signs of rodents' (OR 0.4, 95% CI 0.13-0.97). The ABN model showed associations between Öland and four of the variables: salmonella status, presence of test-positive herds <5km, shared pastures and providing protective clothing for visitors. The latter is probably a reflection of increased disease awareness in Öland. The ABN model showed associations between herd size and housing as well as several management procedures. This provides an explanation why herd size frequently has been identified as a risk factor for salmonella by other studies

Clotting Factor Changes during the First Cycle of Oral Contraceptive Use

PubMed Central

Westhoff, Carolyn L.; Eisenberger, Andrew; Tang, Rosalind; Cremers, Serge; Grossman, Lisa V.; Pike, Malcolm C.

2016-01-01

Objectives The risk of venous thromboembolism (VTE) is highest during the initial months of oral contraceptive (OC) use. We sought to evaluate the extent of hemostatic variable changes during the initial OC cycle and if such changes are related to systemic ethinyl estradiol (EE2) exposure. Study Design Participants provided multiple blood samples during a 21-day OC cycle (30 mcg EE2; 150 mcg levonorgestrel) and after a single dose following a wash-out period. Analytes included D-dimer, factor VIII activity, protein C total antigen and the hepatic proteins corticosteroid- and sex-hormone-binding globulins (CBG and SHBG). EE2 pharmacokinetic analyses related to the 24 hours after the first OC tablet (OC1) and at steady state (OC21). Results Seventeen women completed the study. D-dimer more than doubled by OC6 (p = 0.013) and remained elevated at OC21 (p=0.012). D-dimer levels within women varied widely from day-to-day. Factor VIII increased 27% by OC2 (p < 0.001), but declined to a 9% increase by OC21. Protein C increased only 6%. EE2 steady-state area-under-the-curve ranged from 488 to 1103 pg·h/mL; higher levels were not correlated with greater increases in clotting variables. CBG and SHBG increased significantly, but were not significantly correlated with levels of EE2 or with the hemostatic variables. Conclusions D-dimer increases during the first OC cycle were at least as great as increases seen with longer OC use. These results provide support for the increased VTE risk during initial OC use. The extreme variability in D-dimer levels may be an important component of this risk. PMID:26452328

Canine splenic haemangiosarcoma: influence of metastases, chemotherapy and growth pattern on post-splenectomy survival and expression of angiogenic factors.

PubMed

Göritz, M; Müller, K; Krastel, D; Staudacher, G; Schmidt, P; Kühn, M; Nickel, R; Schoon, H-A

2013-07-01

Splenic haemangiosarcomas (HSAs) from 122 dogs were characterized and classified according to their patterns of growth, survival time post splenectomy, metastases and chemotherapy. The most common pattern of growth was a mixture of cavernous, capillary and solid tumour tissue. Survival time post splenectomy was independent of the growth pattern; however, it was influenced by chemotherapy and metastases. Immunohistochemical assessment of the expression of angiogenic factors (fetal liver kinase-1, angiopoietin-2, angiopoietin receptor-2 and vascular endothelial growth factor A) and conventional endothelial markers (CD31, factor VIII-related antigen) revealed variable expression, particularly in undifferentiated HSAs. Therefore, a combination of endothelial markers should be used to confirm the endothelial origin of splenic tumours. Copyright © 2012 Elsevier Ltd. All rights reserved.

Ramsay Hunt syndrome with unilateral polyneuropathy involving cranial nerves V, VII, VIII, and XII in a diabetic patient.

PubMed

Sun, Wei-Lian; Yan, Jian-Liang; Chen, Li-Li

2011-01-01

Ramsay Hunt syndrome is a rare complication of the varicella zoster virus, defined as a peripheral facial palsy that typically results from involvement of the facial and auditory nerves. Ramsay Hunt syndrome can be associated with cranial nerves V, VI, IX, and X but rarely with XII. We describe an atypical case of Ramsay Hunt syndrome with multiple cranial nerve involvement of nerves V, VII, VIII, and XII. Antiviral drugs, antibiotics, insulin, and traditional Chinese drugs were administered immediately after admission. After 3 months of combination therapy, the patient had recovered satisfactorily. Herpes zoster can cause severe infections in diabetic patients and should be treated as soon after detection as possible. Ramsay Hunt syndrome should be recognized as a polycranial neuritis characterized by damage to sensory and motor nerves. In addition to facial and vestibular nerve paralysis, Ramsay Hunt syndrome may also involve cranial nerves V and XII.

Contributory factors and potentially avoidable neonatal encephalopathy associated with perinatal asphyxia.

PubMed

Sadler, Lynn C; Farquhar, Cynthia M; Masson, Vicki L; Battin, Malcolm R

2016-06-01

The recently published monograph, Neonatal encephalopathy and neurologic outcome, from the American College of Obstetricians and Gynecologists calls for a root cause analysis to identify components of care that contributed to cases of neonatal encephalopathy to design better practices, surveillance mechanisms, and systems. All cases of infants born in New Zealand with moderate and severe neonatal encephalopathy were reported to the New Zealand Perinatal and Maternal Mortality Review Committee from 2010. A national clinical review of these individual cases has not previously been undertaken. The objective of the study was to undertake a multidisciplinary structured review of all cases of neonatal encephalopathy that arose following the onset of labor in the absence of acute peripartum events in 2010-2011 to determine the frequency of contributory factors, the proportion of potentially avoidable morbidity and mortality and to identify themes for quality improvement. National identification of, and collection of clinical records on, cases of moderate or severe neonatal encephalopathy occurring after the onset of labor in the absence of an acute peripartum event, excluding those with normal gases and Apgar scores at 1 minute, among all cases of moderate and severe neonatal encephalopathy at term in New Zealand in 2010-2011 was undertaken. Cases were included if they had abnormal gases as defined by any of pH of ≤ 7.2, base excess of ≤ -10, or lactate of ≥ 6 or if there were no cord gases, an Apgar score at 1 minute of ≤ 7. A clinical case review was undertaken by a multidisciplinary team using a structured tool to record contributory factors (organization and/or management, personnel, and barriers to access and/or engagement with care), potentially avoidable morbidity and mortality and to identify themes to guide quality improvement. Eighty-three babies fulfilled the inclusion criteria for the review, 56 moderate (67%) and 27 severe (33%), 21 (25%) of whom were

Prevalence and Potential Risk Factors for Bartonella Infection in Tunisian Stray Dogs.

PubMed

Belkhiria, Jaber; Chomel, Bruno B; Ben Hamida, Taoufik; Kasten, Rickie W; Stuckey, Matthew J; Fleischman, Drew A; Christopher, Mary M; Boulouis, Henri-Jean; Farver, Thomas B

2017-06-01

Bartonellae are blood-borne and vector-transmitted pathogens, some are zoonotic, which have been reported in several Mediterranean countries. Transmission from dogs to humans is suspected, but has not been clearly demonstrated. Our objectives were to determine the seroprevalence of Bartonella henselae, Bartonella vinsonii subsp. berkhoffii, Bartonella clarridgeiae, and Bartonella bovis (as a proxy for Candidatus Bartonella merieuxii) in stray dogs from Tunisia, identify the Bartonella species infecting the dogs and evaluate potential risk factors for canine infection. Blood samples were collected between January and November 2013 from 149 dogs in 10 Tunisian governorates covering several climatic zones. Dog-specific and geographic variables were analyzed as potential risk factors for Bartonella spp. seropositivity and PCR-positivity. DNA was extracted from the blood of all dogs and tested by PCR for Bartonella, targeting the ftsZ and rpoB genes. Partial sequencing was performed on PCR-positive dogs. Twenty-nine dogs (19.5%, 95% confidence interval: 14-27.4) were seropositive for one or more Bartonella species, including 17 (11.4%) for B. vinsonii subsp. berkhoffii, 14 (9.4%) for B. henselae, 13 (8.4%) for B. clarridgeiae, and 7 (4.7%) for B. bovis. Statistical analysis revealed a few potential risk factors, mainly dog's age and breed, latitude and average winter temperature. Twenty-two (14.8%) dogs, including 8 of the 29 seropositive dogs, were PCR-positive for Bartonella based on the ftsZ gene, with 18 (81.8%) of these 22 dogs also positive for the rpoB gene. Partial sequencing showed that all PCR-positive dogs were infected with Candidatus B. merieuxii. Dogs from arid regions and regions with cold average winter temperatures were less likely to be PCR-positive than dogs from other climatic zones. The widespread presence of Bartonella spp. infection in Tunisian dogs suggests a role for stray dogs as potential reservoirs of Bartonella species in Tunisia.

Anorexia of Aging: Risk Factors, Consequences, and Potential Treatments.

PubMed

Landi, Francesco; Calvani, Riccardo; Tosato, Matteo; Martone, Anna Maria; Ortolani, Elena; Savera, Giulia; Sisto, Alex; Marzetti, Emanuele

2016-01-27

Older people frequently fail to ingest adequate amount of food to meet their essential energy and nutrient requirements. Anorexia of aging, defined by decrease in appetite and/or food intake in old age, is a major contributing factor to under-nutrition and adverse health outcomes in the geriatric population. This disorder is indeed highly prevalent and is recognized as an independent predictor of morbidity and mortality in different clinical settings. Even though anorexia is not an unavoidable consequence of aging, advancing age often promotes its development through various mechanisms. Age-related changes in life-style, disease conditions, as well as social and environmental factors have the potential to directly affect dietary behaviors and nutritional status. In spite of their importance, problems related to food intake and, more generally, nutritional status are seldom attended to in clinical practice. While this may be the result of an "ageist" approach, it should be acknowledged that simple interventions, such as oral nutritional supplementation or modified diets, could meaningfully improve the health status and quality of life of older persons.

Anorexia of Aging: Risk Factors, Consequences, and Potential Treatments

PubMed Central

Landi, Francesco; Calvani, Riccardo; Tosato, Matteo; Martone, Anna Maria; Ortolani, Elena; Savera, Giulia; Sisto, Alex; Marzetti, Emanuele

2016-01-01

Older people frequently fail to ingest adequate amount of food to meet their essential energy and nutrient requirements. Anorexia of aging, defined by decrease in appetite and/or food intake in old age, is a major contributing factor to under-nutrition and adverse health outcomes in the geriatric population. This disorder is indeed highly prevalent and is recognized as an independent predictor of morbidity and mortality in different clinical settings. Even though anorexia is not an unavoidable consequence of aging, advancing age often promotes its development through various mechanisms. Age-related changes in life-style, disease conditions, as well as social and environmental factors have the potential to directly affect dietary behaviors and nutritional status. In spite of their importance, problems related to food intake and, more generally, nutritional status are seldom attended to in clinical practice. While this may be the result of an “ageist” approach, it should be acknowledged that simple interventions, such as oral nutritional supplementation or modified diets, could meaningfully improve the health status and quality of life of older persons. PMID:26828516

Incidence and risk factors of bleeding-related adverse events in patients with chronic lymphocytic leukemia treated with ibrutinib.

PubMed

Lipsky, Andrew H; Farooqui, Mohammed Z H; Tian, Xin; Martyr, Sabrina; Cullinane, Ann M; Nghiem, Khanh; Sun, Clare; Valdez, Janet; Niemann, Carsten U; Herman, Sarah E M; Saba, Nakhle; Soto, Susan; Marti, Gerald; Uzel, Gulbu; Holland, Steve M; Lozier, Jay N; Wiestner, Adrian

2015-12-01

Ibrutinib is associated with bleeding-related adverse events of grade ≤ 2 in severity, and infrequently with grade ≥ 3 events. To investigate the mechanisms of bleeding and identify patients at risk, we prospectively assessed platelet function and coagulation factors in our investigator-initiated trial of single-agent ibrutinib for chronic lymphocytic leukemia. At a median follow-up of 24 months we recorded grade ≤ 2 bleeding-related adverse events in 55% of 85 patients. No grade ≥ 3 events occurred. Median time to event was 49 days. The cumulative incidence of an event plateaued by 6 months, suggesting that the risk of bleeding decreases with continued therapy. At baseline, von Willebrand factor and factor VIII levels were often high and normalized on treatment. Platelet function measured via the platelet function analyzer (PFA-100™) was impaired in 22 patients at baseline and in an additional 19 patients on ibrutinib (often transiently). Collagen and adenosine diphosphate induced platelet aggregation was tested using whole blood aggregometry. Compared to normal controls, response to both agonists was decreased in all patients with chronic lymphocytic leukemia, whether on ibrutinib or not. Compared to untreated chronic lymphocytic leukemia patients, response to collagen showed a mild further decrement on ibrutinib, while response to adenosine diphosphate improved. All parameters associated with a significantly increased risk of bleeding-related events were present at baseline, including prolonged epinephrine closure time (HR 2.74, P=0.012), lower levels of von Willebrand factor activity (HR 2.73, P=0.009) and factor VIII (HR 3.73, P=0.0004). In conclusion, both disease and treatment-related factors influence the risk of bleeding. Patients at greater risk for bleeding of grade ≤ 2 can be identified by clinical laboratory tests and counseled to avoid aspirin, non-steroidal anti-inflammatory drugs and fish oils. ClinicalTrials.gov identifier NCT01500733

The Potential Role of Recombinant Activated Factor VIIa (rFVIIa) in Military Pre-Hospital Setting

DTIC Science & Technology

2004-09-01

coagulation factors and platelets by crystalloids, colloids, or blood products The severity of dilutional coagulopathy is determined by both volume and...RTO-MP-HFM-109 3 - 1 The Potential Role of Recombinant Activated Factor VIIa (rFVIIa) in Military Pre-Hospital Setting LTC (ret.) Uri...decrease mortality from exsanguinations. Recombinant factor VIIa (rFVIIa) has been shown to overcome a variety of coagulation and platelet disorders

Clinical application of neurotrophic factors: the potential for primary auditory neuron protection

PubMed Central

Gillespie, Lisa N.; Shepherd, Robert K.

2007-01-01

Sensorineural hearing loss, as a result of damage to or destruction of the sensory epithelia within the cochlea, is a common cause of deafness. The subsequent degeneration of the neural elements within the inner ear may impinge upon the efficacy of the cochlear implant. Experimental studies have demonstrated that neurotrophic factors can prevent this degeneration in animal models of deafness, and can even provide functional benefits. Neurotrophic factor therapy may, therefore, provide similar protective effects in humans, resulting in improved speech perception outcomes among cochlear implant patients. There are, however, numerous issues pertaining to delivery techniques and treatment regimes which need to be addressed prior to any clinical application. This review considers these issues in view of the potential therapeutic application of neurotrophic factors within the auditory system. PMID:16262651

The rational design of a 'type 88' genetically stable peptide display vector in the filamentous bacteriophage fd.

PubMed

Enshell-Seijffers, D; Smelyanski, L; Gershoni, J M

2001-05-15

Filamentous bacteriophages are particularly efficient for the expression and display of combinatorial random peptides. Two phage proteins are often employed for peptide display: the infectivity protein, PIII, and the major coat protein, PVIII. The use of PVIII typically requires the expression of two pVIII genes: the wild-type and the recombinant pVIII gene, to generate mosaic phages. 'Type 88' vectors contain two pVIII genes in one phage genome. In this study a novel 'type 88' expression vector has been rationally designed and constructed. Two factors were taken into account: the insertion site and the genetic stability of the second pVIII gene. It was found that selective deletion of recombinant genes was encountered when inserts were cloned into either of the two non-coding regions of the phage genome. The deletions were independent of recA yet required a functional F-episome. Transcription was also found to be a positive factor for deletion. Taking the above into account led to the generation of a novel vector, designated fth1, which can be used to express recombinant peptides as pVIII chimeric proteins in mosaic bacteriophages. The fth1 vector is not only genetically stable but also of high copy number and produces high titers of recombinant phages.

Studies of thermostability in Camelus bactrianus (Bactrian camel) single-domain antibody specific for the mutant epidermal-growth-factor receptor expressed by Pichia.

PubMed

Omidfar, Kobra; Rasaee, Mohhamad Javad; Kashanian, Soheila; Paknejad, Malieheh; Bathaie, Zahra

2007-01-01

Camelids have a unique immune system capable of producing heavy-chain antibodies lacking the light chains and CH1 (constant heavy-chain domain 1). It has been shown that, in contrast with conventional antibody fragments, the variable domains of these heavy-chain antibodies are functional at or after exposure to high temperatures. In the present study, the VHH (variable domain of heavy-chain antibody) camel antibody was subcloned into vector Ppiczc and expressed in Pichia pastoris. ORB1-83 VHH antibody recognizes the external domain of the mutant EGFR [EGF (epidermal growth factor) receptor], EGFR VIII. This tumour-specific antigen is ligand-independent, contains a constitutively active tyrosine kinase domain and has been shown to be present in a number of human malignancies. We report here that, although expression from P. pastoris resulted in a significantly increased level of expression of the anti-EGFR VIII VHH antibodies compared with Escherichia coli [Omidfar, Rasaee, Modjtahedi, Forouzandeh, Taghikhani, Bakhtiari, Paknejad and Kashanian (2004) Tumor Biol. 25, 179-187; Omidfar, Rasaee, Modjtahedi, Forouzandeh, Taghikhani and Golmakany (2004) Tumor Biol. 25, 296-305], this antibody selectively bound to the EGFR VIII peptide and reacted specifically with the immunoaffinity-purified antigen from non-small-cell lung cancer. Furthermore, thermal denaturation stability and CD spectra analysis of the Camelus bactrianus (Bactrian camel) VHH and heavy-chain antibodies at different temperature proved reversibility and binding activity after heat denaturation. Our results indicate that the P. pastoris expression system may be useful for the expression of camel single domain antibody and the ability of the expressed protein to reversibly melt without aggregation, allowing it to regain binding activity after heat denaturation.

Enhancement of the efficacy of therapeutic proteins by formulation with PEGylated liposomes; a case of FVIII, FVIIa and G-CSF.

PubMed

Yatuv, Rivka; Robinson, Micah; Dayan, Inbal; Baru, Moshe

2010-02-01

Improving the pharmacodynamics of protein drugs has the potential to improve the care and the quality of life of patients suffering from a variety of diseases. Four approaches to improve protein drugs are described: PEGylation, amino acid substitution, fusion to carrier proteins and encapsulation. A new platform technology based on the binding of proteins/peptides to the outer surface of PEGylated liposomes (PEGLip) is then presented. Binding of proteins to PEGLip is non-covalent, highly specific and dependent on an amino acid consensus sequence within the proteins. Association of proteins with PEGLip results in substantial enhancement of the pharmacodynamic properties of proteins following administration. This has been demonstrated in preclinical studies and clinical trials with coagulation factors VIII and VIIa. It has also been demonstrated in preclinical studies with granulocyte colony-stimulating factor. A mechanism is presented that explains the improvements in hemostatic efficacy of PEGLip-formulated coagulation factors VIII and VIIa. The reader will gain an understanding of the advantages and disadvantages of each of the approaches discussed. PEGLip formulation is an important new approach to improve the pharmacodynamics of protein drugs. This approach may be applied to further therapeutic proteins in the future.

Recombinant factor concentrates may increase inhibitor development: a single centre cohort study.

PubMed

Strauss, T; Lubetsky, A; Ravid, B; Bashari, D; Luboshitz, J; Lalezari, S; Misgav, M; Martinowitz, U; Kenet, G

2011-07-01

Recent reports have raised concerns regarding potential risk factors for inhibitor development. In Israel, all haemophilia patients (n = 479) are followed by the National Hemophilia Center. Most children are neonatally exposed to factor concentrate (due to circumcision performed at the age of 8 days). The impact of early exposure and recombinant FVIII products (rFVIII) administration (approved in Israel since 1996) upon inhibitor occurrence in our cohort of haemophilia A (HA) patients was analysed. Two hundred ninety-two consecutive paediatric cases with a first symptomatic onset of HA were enrolled and followed over a median time of 7 years [min-max: 9 months to 17 years]. Study endpoint was inhibitor development against factor VIII. In addition, the treatment regimens applied, i.e. bolus administration or 'continuous infusion' and the family history of inhibitor development were investigated. During the follow-up period 31/292 children (10.6%) developed high titre inhibitors. Inhibitors occurred in 14/43 (32.5%) HA patients neonatally exposed to rFVIII, as compared to 22/249 previously treated with Plasma Derived (PD) products (8.8%). The odds ratio for inhibitor formation in rFVIII treated HA patients was 3.43 (95% CI: 1.36-8.65). Transient inhibitor evolved among 2/43 paediatric HA patients, only among those treated with rFVIII. The risk of inhibitor detection significantly increased among HA children treated by continuous infusion (P = 0.025). Our experience shows that the risk of inhibitor formation may be increased by early exposure to recombinant concentrates. The multiple variables affecting inhibitor incidence deserve further attention by larger prospective studies. © 2011 Blackwell Publishing Ltd.

Genetic engineering for haemophilia A.

PubMed

Gan, Shu Uin; Kon, Oi Lian; Calne, Roy Y

2006-10-01

At first sight, haemophilia A would appear to be an ideal candidate for treatment by gene therapy. There is a single gene defect; cells in different parts of the body, but especially the liver, produce Factor VIII, and only 5% of normal levels of Factor VIII are necessary to prevent the serious symptoms of bleeding. This review attempts to outline the status of gene therapy at present and efforts that have been made to overcome the difficulties and remaining problems that require solving. Undoubtedly, success will be achieved, but it is likely that considerably more work will be necessary before experimental models can be introduced into the clinic with any likelihood of success. The most successful results in animals that may have clinical application were from introducing the Factor VIII gene to newborn animals before antibodies are produced, presumably inducing a state of tolerance.

Impact on hepatic estrogen-sensitive proteins by a 1-year contraceptive vaginal ring delivering Nestorone® and ethinyl estradiol.

PubMed

Archer, D F; Thomas, M A; Conard, J; Merkatz, R B; Creasy, G W; Roberts, K; Plagianos, M; Blithe, D; Sitruk-Ware, R

2016-01-01

Estrogen-sensitive hepatic proteins were assessed in women using a contraceptive vaginal ring (CVR) delivering 150mcg Nestorone® (NES) and 15mcg ethinyl estradiol (EE). A substudy of the Contraceptive Clinical Trials Network of the National Institute of Child Health and Human Development enrolled 129 participants, with assessments of factor VIII, fibrinogen, protein S (PS) and sex hormone binding globulin (SHBG). Thirty-six participants had used combined hormonal contraceptives (CHCs) in the cycle preceding first CVR use (recent users) and 70 had no history of recent use (nonusers). Mean values at baseline were within the normal range for all four proteins but were higher for factor VIII, fibrinogen and SHBG and significantly lower for PS in recent compared to nonusers. During NES/EE CVR use, factor VIII, fibrinogen and PS were within the normal range; however, SHBG levels were increased by nearly 100% at Cycle 13. The change from baseline to final evaluation was statistically significant for all proteins in nonusers. The change in recent users was significant for factor VIII at Cycle 6 and for SHBG at Cycles 6 and 13, but not for PS or fibrinogen. NES/EE CVR for up to 13cycles was associated with changes from baseline in plasma levels of factor VIII, fibrinogen and PS that were within the normal range, with SHBG levels above the normal range by Cycle 6. Nonusers of CHC before CVR showed wider changes in values versus recent users whose baseline values were increased by previous EE exposure. Recent use of CHCs demonstrated significant changes in all four measured hepatic proteins at baseline compared to nonusers. Use of the NES/EE CVR further changed these hepatic protein markers, but values remained within the normal range. Prebaseline exposure to estrogen can obscure interpretation of hepatic proteins changes associated with a second CHC. Copyright © 2016 Elsevier Inc. All rights reserved.

UKPDS 59: hyperglycemia and other potentially modifiable risk factors for peripheral vascular disease in type 2 diabetes.

PubMed

Adler, Amanda I; Stevens, Richard J; Neil, Andrew; Stratton, Irene M; Boulton, Andrew J M; Holman, Rury R

2002-05-01

To determine the role of hyperglycemia in prospective analyses of peripheral vascular disease (PVD) in type 2 diabetes, taking into account other potential risk factors. Potential risk factors for the development of PVD were examined in 3,834 of 5,102 individuals enrolled in the U.K. Prospective Diabetes Study (UKPDS) without PVD at diagnosis of diabetes, followed for 6 years, and for whom relevant data were available. PVD was defined as two of the following: ankle-arm blood pressure index < 0.8, absence of both dorsalis pedis and posterior tibial pulses to palpation in one or both legs, and intermittent claudication. Logistic regression was used to estimate the association between potential risk factors measured 3-4 months after diagnosis of diabetes and incident PVD. The prevalence of PVD at 3-year intervals to 18 years was determined. Hyperglycemia, assessed as HbA(1c), was associated with an increased risk for incident PVD, independent of other risk factors including age, increased systolic blood pressure, reduced HDL cholesterol, smoking, prior cardiovascular disease, peripheral sensory neuropathy, and retinopathy. Each 1% increase in HbA(1c) was associated with a 28% increased risk of PVD (95% CI 12-46), and each 10-mmHg increase in systolic blood pressure with a 25% increase in risk (95% CI 10-43). Hyperglycemia, as well as smoking, dyslipidemia, and blood pressure are potentially modifiable risk factors for the development of PVD.

On the potential impact of the newly proposed quality factors on space radiation protection

NASA Technical Reports Server (NTRS)

Wilson, John W.; Townsend, Lawrence W.; Cucinotta, Francis A.

1987-01-01

The recently proposed changes in the defined quality factor hold great potential for easing some of the protection requirements from electrons and protons in the near-Earth environment. At the same time, the high Linear Energy Transfer (LET) components play an even more important role which must be further evaluated. Several recommendations are made which need to be addressed before these new quality factors can be implemented into space radiation potection practice.

Photothermal conversion of CO₂ into CH₄ with H₂ over Group VIII nanocatalysts: an alternative approach for solar fuel production.

PubMed

Meng, Xianguang; Wang, Tao; Liu, Lequan; Ouyang, Shuxin; Li, Peng; Hu, Huilin; Kako, Tetsuya; Iwai, Hideo; Tanaka, Akihiro; Ye, Jinhua

2014-10-20

The photothermal conversion of CO2 provides a straightforward and effective method for the highly efficient production of solar fuels with high solar-light utilization efficiency. This is due to several crucial features of the Group VIII nanocatalysts, including effective energy utilization over the whole range of the solar spectrum, excellent photothermal performance, and unique activation abilities. Photothermal CO2 reaction rates (mol h(-1) g(-1)) that are several orders of magnitude larger than those obtained with photocatalytic methods (μmol h(-1) g(-1)) were thus achieved. It is proposed that the overall water-based CO2 conversion process can be achieved by combining light-driven H2 production from water and photothermal CO2 conversion with H2. More generally, this work suggests that traditional catalysts that are characterized by intense photoabsorption will find new applications in photo-induced green-chemistry processes. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Evaluation of risk factors for thrombophilia in patients with cerebral venous thrombosis.

PubMed

Yokuş, Osman; Şahin Balçık, Özlem; Albayrak, Murat; Ceran, Funda; Dağdaş, Simten; Yılmaz, Mesude; Özet, Gülsüm

2010-09-05

The increased risk for thrombosis is known as hypercoagulability or thrombophilia. In our study, we aimed to compare the frequency of the identified defects for thrombophilia in patients with central venous thrombosis and under the age of 50 years, with the findings in the current literature. Forty-three patients (16-50 years old) were retrospectively evaluated. Thrombophilia investigation included determinations of protein C, protein S, antithrombin, and activated protein C resistance, factor V Leiden (FVL), prothrombin 20210A (PT 20210) and methylene tetrahydrofolate reductase (MTHFR) C677T mutations, antiphospholipid antibodies (APA), factor VIII levels, and homocysteine levels. We detected a single thrombophilic defect in 67.4%, two defects in 27.9% and three defects in 4.7% of our patients. The most common thrombophilic defect was mutation in the MTHFR gene (41.8%), and this was followed by the FVL mutation (34.9%). Since the prevalence of individual thrombophilic defects varies in each population, ethnic group and geographical location, screening for thrombophilic defects in patients presenting with cerebral venous thrombosis should primarily investigate the most frequent thrombophilia risk factors.

Dysphagia in the high-risk infant: potential factors and mechanisms123

PubMed Central

Jadcherla, Sudarshan

2016-01-01

Neonatal dysphagia, or abnormalities of swallowing, represent a major global problem, and consequences of dysfunctional feeding patterns carry over into infancy and toddler age groups. Growth, development, and independent feeding skills are all delayed among high-risk infants. Such a group comprises premature birth, low-birth-weight, congenital anomalies, perinatal asphyxia, postsurgical, and sepsis categories. The conflict between pathophysiologic and pragmatic feeding strategies remains a major conundrum and is largely due to a lack of validated diagnostic approaches amid heterogeneity of the patient phenotype. Thus, well-tested feeding management strategies that can be generalizable are lacking. Furthermore, the aerodigestive symptoms and signs, potential risk factors, and contributory etiologies remain nonspecific. This article presents mechanistic evidence related to the pathophysiologic basis of neonatal dysphagia as well as potential opportunities to improve feeding abilities and long-term development. PMID:26791178

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

Parvinen, M.; Soeder, O.M.; Mali, P.

Levels of rat testicular interleukin-1-like factor (tIL-1) have been shown to correlate with DNA synthetic activity during the cycle of the rat seminiferous epithelium, suggesting its role as a spermatogonial or meiotic growth factor. To explore this further, a new in vitro model system was developed. Rat seminiferous tubule segments from stages I, V, VIIa, and VIII-IX of the cycle were isolated by transillumination-assisted microdissection, cultured in chemically defined serum-free medium supplemented with human recombinant IL-1 {alpha}, and labeled with (3H)thymidine. During incubation, spontaneous progression of spermatogenesis was noted. Inactive stage VIIa tubule segments differentiated to stage VIII and initiatedmore » DNA synthesis, and concomitantly started to secrete IL-1-like factor. DNA synthesis of stages VIII-IX ceased through differentiation of spermatocytes to leptotene-zygotene (stages XII-XIII of the cycle). IL-1 {alpha} stimulated DNA synthesis significantly in spermatogonia of stage I. Meiotic DNA synthesis at stage VIIa was stimulated (48 h/34 C) and maintained at stages VIII-IX (48 h/34 C). IL-1 {alpha} seems to act as a regulator of spermatogenic DNA synthesis in both mitotic and meiotic phases. It has mainly stimulating and maintaining effects, but it may also be inhibitory under certain conditions.« less

Analysis of factors controlling sediment phosphorus flux potential of wetlands in Hulun Buir grassland by principal component and path analysis method.

PubMed

He, Jing; Su, Derong; Lv, Shihai; Diao, Zhaoyan; Ye, Shengxing; Zheng, Zhirong

2017-11-08

Phosphorus (P) flux potential can predict the trend of phosphorus release from wetland sediments to water and provide scientific parameters for further monitoring and management for phosphorus flux from wetland sediments to overlying water. Many studies have focused on factors affecting sediment P flux potential in sediment-water interface, but rarely on the relationship among these factors. In the present study, experiment on sediment P flux potential in sediment-water interface was conducted in six wetlands in Hulun Buir grassland, China and the relationships among sediment P flux potential in sediment-water interface, sediment physical properties, and sediment chemical characteristics were examined. Principal component analysis and path analysis were used to discuss these data in correlation coefficient, direct, and indirect effects on sediment P flux potential in sediment-water interface. Results indicated that the major factors affecting sediment P flux potential in sediment-water interface were amount of organophosphate-degradation bacterium in sediment, Ca-P content, and total phosphorus concentrations. The factors of direct influence sediment P flux potential were sediment Ca-P content, Olsen-P content, SOC content, and sediment Al-P content. The indirect influence sediment P flux potential in sediment-water interface was sediment Olsen-P content, sediment SOC content, sediment Ca-P content, and sediment Al-P content. And the standard multiple regression describing the relationship between sediment P flux potential in sediment-water interface and its major effect factors was Y = 5.849 - 1.025X 1  - 1.995X 2  + 0.188X 3  - 0.282X 4 (r = 0.9298, p < 0.01, n = 96), where Y is sediment P flux potential in sediment-water interface, X 1 is sediment Ca-P content, X 2 is sediment Olsen-P content, X 3 is sediment SOC content, and X 4 is sediment Al-P content. Therefore, future research will focus on these sediment properties to analyze the

Bone morphogenetic protein-4 strongly potentiates growth factor-induced proliferation of mammary epithelial cells

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

Montesano, Roberto; Sarkoezi, Rita; Schramek, Herbert

2008-09-12

Bone morphogenetic proteins (BMPs) are multifunctional cytokines that elicit pleiotropic effects on biological processes such as cell proliferation, cell differentiation and tissue morphogenesis. With respect to cell proliferation, BMPs can exert either mitogenic or anti-mitogenic activities, depending on the target cells and their context. Here, we report that in low-density cultures of immortalized mammary epithelial cells, BMP-4 did not stimulate cell proliferation by itself. However, when added in combination with suboptimal concentrations of fibroblast growth factor (FGF)-2, FGF-7, FGF-10, epidermal growth factor (EGF) or hepatocyte growth factor (HGF), BMP-4 potently enhanced growth factor-induced cell proliferation. These results reveal a hithertomore » unsuspected interplay between BMP-4 and growth factors in the regulation of mammary epithelial cell proliferation. We suggest that the ability of BMP-4 to potentiate the mitogenic activity of multiple growth factors may contribute to mammary gland ductal morphogenesis as well as to breast cancer progression.« less

Potentially harmful microalgal distribution in an area of the NW Adriatic coastline: Sampling procedure and correlations with environmental factors

NASA Astrophysics Data System (ADS)

Penna, Antonella; Ingarao, Cristina; Ercolessi, Manuela; Rocchi, Marco; Penna, Nunzio

2006-10-01

In this study, the trend of potentially Harmful Algal (HA) taxa (genera and species), was analysed along a coastal area of the NW Adriatic Sea on a monthly scale. The study included the use of a phytoplankton net for sample collection. The investigation was carried out in four sampling stations characterised by different ecological features. The composition of potentially HA phytoplankton taxa and their succession were related to the environmental factors. The potentially HA group abundance accounted for 8% of all the phytoplankton taxa considered. Multivariate analyses of environmental factors suggested that potentially HA taxa are sensitive to phosphate content: potential DSP-YTX (Diarrhetic Shellfish Poisoning-Yessotoxin) producers were positively correlated with P content ( p = 0.023), while potential ASP (Amnesic Shellfish Poisoning) producers were negatively correlated with P content ( p = 0.006). Phosphorus could be considered to be the limiting factor for phytoplankton taxa density in the NW Adriatic Sea. There was a highly positive correlation between the occurrences of potentially HA taxa and low values of salinity ( p = 0.001 for potential producers of ASP, p = 0.029 for potential DSP-YTX producers). The counting of potential HA dinoflagellates in net samples represented a more accurate estimation of potential HA abundances in the water column making it possible to concentrate a greater number of potential HA dinoflagellate cells by net sampling along the entire water column rather than by sampling only at the surface as in routine monitoring procedures.

Early intraoperative blood collection does not affect complete blood counts, von Willebrand factor or factor VIII levels in normal children.

PubMed

Darwish, Hanni; Mundell, Gillianne; Engen, Dale; Lillicrap, David; Silva, Mariana; James, Paula

2011-01-01

Obtaining blood from children for research studies can be difficult, particularly for controls. One solution is to obtain samples during elective surgery; however, consideration must be given to the potential effects of the timing of phlebotomy. Ten children were recruited and phlebotomy was carried out during a preoperative clinic visit and intraoperatively immediately after the induction of anesthesia but before the start of surgery. CBCs, VWF, and FVIII levels were measured at both time points and no significant differences were seen. This negative result may be beneficial to pediatric research by suggesting that early intraoperative blood collection for controls does not affect the results.

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.

Adolescent clavicle nonunions: potential risk factors and surgical management.

PubMed

Pennock, Andrew T; Edmonds, Eric W; Bae, Donald S; Kocher, Mininder S; Li, Ying; Farley, Frances A; Ellis, Henry B; Wilson, Philip L; Nepple, Jeffrey; Gordon, J Eric; Willimon, Samuel C; Busch, Michael T; Spence, David D; Kelly, Derek M; Pandya, Nirav K; Sabatini, Coleen S; Shea, Kevin G; Heyworth, Benton E

2018-01-01

Clavicle nonunions in adolescent patients are exceedingly rare. The purpose of this study was to evaluate a series of clavicle nonunions from a pediatric multicenter study group to assess potential risk factors and treatment outcomes. A retrospective review of all clavicle nonunions in patients younger than 19 years was performed at 9 pediatric hospitals between 2006 and 2016. Demographic and surgical data were documented. Radiographs were evaluated for initial fracture classification, displacement, shortening, angulation, and nonunion type. Clinical outcomes were evaluated, including rate of healing, time to union, return to sports, and complications. Risk factors for nonunion were assessed by comparing the study cohort with a separate cohort of age-matched patients with a diaphyseal clavicle fracture. There were 25 nonunions (mean age, 14.5 years; range, 10.0-18.9 years) identified, all of which underwent surgical fixation. Most fractures were completely displaced (68%) initially, but 21% were partially displaced and 11% were nondisplaced. Bone grafting was performed in 24 of 25 cases, typically using the hypertrophic callus. Radiographic healing was achieved in 96% of cases. One patient (4%) required 2 additional procedures to achieve union. The primary risk factor for development of a nonunion was a previous history of an ipsilateral clavicle fracture. Clavicle nonunions can occur in the adolescent population but are an uncommon clinical entity. The majority occur in male patients with displaced fractures, many of whom have sustained previous fractures of the same clavicle. High rates of union were achieved with plate fixation and the use of bone graft. Copyright © 2017 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.

Effects of exposure to factor concentrates containing donations from identified AIDS patients

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

Jason, J.; Holman, R.C.; Dixon, G.

1986-10-03

The authors recipients of eight lots of factors VII and IX voluntarily withdrawn from distribution because one donor was known to have subsequently developed the acquired immunodeficiency syndrome with a nonexposed cohort matched by age, sex, and factor use. The factor VIII recipient cohorts did not differ in prevalence of antibody to human immunodeficiency virus (HIV), T-cell subset numbers, T-helper to T-suppressor ratios, or immunogloubulin levels. Exposed individuals had higher levels of immune complexes by C1q binding and staphylococcal binding assays and lower responses to phytohemagglutinin and concanavalin A. However, only the staphylococcal binding assay values were outside the normalmore » range for our laboratory. Factor IX recipient cohorts did not differ in HIV antibody prevalence or any immune tests. Although exposed and nonexposed individuals did not differ from each other in a clinically meaningful fashion at initial testing, both the exposed and nonexposed cohorts had high rats of HIV seroprevalence. Market withdrawals were clearly insufficient means of limiting the spread of HIV in hemophilic patients; however, the currently available methods of donor screening and viral inactivation of blood products will prevent continued exposed within this population.« less

Structural basis for signal recognition and transduction by platelet-activating-factor receptor.

PubMed

Cao, Can; Tan, Qiuxiang; Xu, Chanjuan; He, Lingli; Yang, Linlin; Zhou, Ye; Zhou, Yiwei; Qiao, Anna; Lu, Minmin; Yi, Cuiying; Han, Gye Won; Wang, Xianping; Li, Xuemei; Yang, Huaiyu; Rao, Zihe; Jiang, Hualiang; Zhao, Yongfang; Liu, Jianfeng; Stevens, Raymond C; Zhao, Qiang; Zhang, Xuejun C; Wu, Beili

2018-06-01

Platelet-activating-factor receptor (PAFR) responds to platelet-activating factor (PAF), a phospholipid mediator of cell-to-cell communication that exhibits diverse physiological effects. PAFR is considered an important drug target for treating asthma, inflammation and cardiovascular diseases. Here we report crystal structures of human PAFR in complex with the antagonist SR 27417 and the inverse agonist ABT-491 at 2.8-Å and 2.9-Å resolution, respectively. The structures, supported by molecular docking of PAF, provide insights into the signal-recognition mechanisms of PAFR. The PAFR-SR 27417 structure reveals an unusual conformation showing that the intracellular tips of helices II and IV shift outward by 13 Å and 4 Å, respectively, and helix VIII adopts an inward conformation. The PAFR structures, combined with single-molecule FRET and cell-based functional assays, suggest that the conformational change in the helical bundle is ligand dependent and plays a critical role in PAFR activation, thus greatly extending knowledge about signaling by G-protein-coupled receptors.

Urogenital tract infections in pregnancy at King Edward VIII Hospital, Durban, South Africa.

PubMed

Dietrich, M; Hoosen, A A; Moodley, J; Moodley, S

1992-02-01

To evaluate the role of detecting asymptomatic bacteriuria and endocervical infections in the black prenatal patients attending King Edward VIII Hospital (KEH), Durban, with the view of justifying a screening programme. Screening for syphilis and human immunodeficiency virus (HIV) infection were also evaluated. 181 asymptomatic black prenatal patients attending the antenatal clinic for their first antenatal visit volunteered for the study and gave their written consent. Examination of each prenatal patient included obtaining of endocervical swabs to detect endocervical infections (C trachomatis, N gonorrhoeae), serum for syphilitic and HIV testing, and a midstream specimen of urine for microscopy and culture. Asymptomatic bacteriuria was found in 5.6% of patients in this study. Cervical infections were diagnosed microbiologically in 8.2% of women. These were N gonorrhoeae in 4.1% and C trachomatis in 4.7%. Serological tests for sexually transmitted diseases showed the presence of syphilis in 7.6% and antibody to the HIV in 1.9%. Overall, one or more sexually transmitted diseases were found in 16.5% of the women studied. This study suggests that all women presenting for routine antenatal care in a setting such as Durban should be screened for lower genital tract infections. Ideally this should include a midstream urine specimen for culture, serum for syphilitic and HIV antibody testing and endocervical swabs for sexually transmitted pathogens. In developing communities, however, more reliable and cheaper methods of endocervical screening need to be available before antenatal screening for cervico-vaginal infections can be justified.

L-ascorbic acid 2-phosphate and fibroblast growth factor-2 treatment maintains differentiation potential in bone marrow-derived mesenchymal stem cells through expression of hepatocyte growth factor.

PubMed

Bae, Sung Hae; Ryu, Hoon; Rhee, Ki-Jong; Oh, Ji-Eun; Baik, Soon Koo; Shim, Kwang Yong; Kong, Jee Hyun; Hyun, Shin Young; Pack, Hyun Sung; Im, Changjo; Shin, Ha Cheol; Kim, Yong Man; Kim, Hyun Soo; Eom, Young Woo; Lee, Jong In

2015-04-01

l-ascorbic acid 2-phosphate (Asc-2P) acts as an antioxidant and a stimulator of hepatocyte growth factor (HGF) production. Previously, we reported that depletion of growth factors such as fibroblast growth factor (FGF)-2, epidermal growth factor (EGF), FGF-4 and HGF during serial passage could induce autophagy, senescence and down-regulation of stemness (proliferation via FGF-2/-4 and differentiation via HGF). In this study, we investigated the proliferation and differentiation potential of BMSCs by FGF-2 and Asc-2P. Co-treatment with FGF-2 and Asc-2P induced optimal proliferation of BMSCs and increased the accumulation rate of BMSC numbers during a 2-month culture period. Moreover, differentiation potential was maintained by co-treatment with FGF-2 and Asc-2P via HGF expression. Adipogenic differentiation potential by FGF-2 and Asc-2P was dramatically suppressed by c-Met inhibitors (SU11274). These data suggest that co-treatment with FGF-2 and Asc-2P would be beneficial in obtaining BMSCs that possess "stemness" during long-term culture.

Influence of potentially confounding factors on sea urchin porewater toxicity tests

USGS Publications Warehouse

Carr, R.S.; Biedenbach, J.M.; Nipper, M.

2006-01-01

The influence of potentially confounding factors has been identified as a concern for interpreting sea urchin porewater toxicity test data. The results from >40 sediment-quality assessment surveys using early-life stages of the sea urchin Arbacia punctulata were compiled and examined to determine acceptable ranges of natural variables such as pH, ammonia, and dissolved organic carbon on the fertilization and embryological development endpoints. In addition, laboratory experiments were also conducted with A. punctulata and compared with information from the literature. Pore water with pH as low as 6.9 is an unlikely contributor to toxicity for the fertilization and embryological development tests with A. punctulata. Other species of sea urchin have narrower pH tolerance ranges. Ammonia is rarely a contributing factor in pore water toxicity tests using the fertilization endpoint, but the embryological development endpoint may be influenced by ammonia concentrations commonly found in porewater samples. Therefore, ammonia needs to be considered when interpreting results for the embryological development test. Humic acid does not affect sea urchin fertilization at saturation concentrations, but it could have an effect on the embryological development endpoint at near-saturation concentrations. There was no correlation between sediment total organic carbon concentrations and porewater dissolved organic carbon concentrations. Because of the potential for many varying substances to activate parthenogenesis in sea urchin eggs, it is recommended that a no-sperm control be included with every fertilization test treatment. ?? 2006 Springer Science+Business Media, Inc.

The sea surface currents as a potential factor in the estimation and monitoring of wave energy potential

NASA Astrophysics Data System (ADS)

Zodiatis, George; Galanis, George; Nikolaidis, Andreas; Stylianoy, Stavros; Liakatas, Aristotelis

2015-04-01

The use of wave energy as an alternative renewable is receiving attention the last years under the shadow of the economic crisis in Europe and in the light of the promising corresponding potential especially for countries with extended coastline. Monitoring and studying the corresponding resources is further supported by a number of critical advantages of wave energy compared to other renewable forms, like the reduced variability and the easier adaptation to the general grid, especially when is jointly approached with wind power. Within the framework, a number of countries worldwide have launched research and development projects and a significant number of corresponding studies have been presented the last decades. However, in most of them the impact of wave-sea surface currents interaction on the wave energy potential has not been taken into account neglecting in this way a factor of potential importance. The present work aims at filling this gap for a sea area with increased scientific and economic interest, the Eastern Mediterranean Sea. Based on a combination of high resolution numerical modeling approach with advanced statistical tools, a detailed analysis is proposed for the quantification of the impact of sea surface currents, which produced from downscaling the MyOcean-FO regional data, to wave energy potential. The results although spatially sensitive, as expected, prove beyond any doubt that the wave- sea surface currents interaction should be taken into account for similar resource analysis and site selection approaches since the percentage of impact to the available wave power may reach or even exceed 20% at selected areas.

Hemangiosarcoma in a geriatric Labrador retriever

PubMed Central

Sharma, Diya

2012-01-01

A geriatric Labrador retriever dog was presented for acute collapse. The dog was conscious but lethargic, tachypneic, tachycardic with weak femoral pulses, occasional pulse deficits, and pale mucous membranes. Radiography, ultrasonography, quick assessment tests, and a complete blood (cell) count (CBC)/biochemistry panel indicated internal hemorrhage and potential problems with hemostasis. The dog was euthanized. A necropsy, histopathology, and immunohistochemistry for CD31 and Factor VIII-related antigen cell markers supported a diagnosis of splenic hemangiosarcoma. PMID:23372199

Microzonation of Seismic Hazard Potential in Taipei, Taiwan

NASA Astrophysics Data System (ADS)

Liu, K. S.; Lin, Y. P.

2017-12-01

The island of Taiwan lies at the boundary between the Philippine Sea plate and the Eurasia plate. Accordingly, the majority of seismic energy release near Taiwan originates from the two subduction zones. It is therefore not surprising that Taiwan has repeatedly been struck by large earthquakes such as 1986 Hualien earthquake, 1999 Chi Chi and 2002 Hualien earthquake. Microzonation of seismic hazard potential becomes necessary in Taipei City for the Central Geological Survey announced the Sanchiao active fault as Category II. In this study, a catalog of more than 2000 shallow earthquakes occurred from 1900 to 2015 with Mw magnitudes ranging from 5.0 to 8.2, and 11 disastrous earthquakes occurred from 1683-1899, as well as Sanchiao active fault in the vicinity are used to estimate the seismic hazard potential in Taipei City for seismic microzonation. Furthermore, the probabilities of seismic intensity exceeding CWB intensity 5, 6, 7 and MMI VI, VII, VIII in 10, 30, and 50-year periods in the above areas are also analyzed for the seismic microzonation. Finally, by comparing with the seismic zoning map of Taiwan in current building code that was revised after 921 earthquakes, Results of this study will show which areas with higher earthquake hazard potential in Taipei City. They provide a valuable database for the seismic design of critical facilities. It will help mitigate Taipei City earthquake disaster loss in the future, as well as provide critical information for emergency response plans.

What is the Main Potential Factor Influencing Ocular Protrusion?

PubMed

Li, Yinwei; Su, Yun; Song, Xuefei; Zhou, Huifang; Fan, Xianqun

2017-01-05

BACKGROUND The aim of the present study was to establish the normal-range orbital parameters and to explore the relationships between ocular protrusion and various orbital morphological factors. MATERIAL AND METHODS A retrospective, non-comparative case series was conducted from January 2014 to December 2015. We recruited 56 subjects (112 orbits), including 27 males (21 to 87 years of age) and 29 females (22 to 88 years of age) in this study. Nine length measurements, 2 angle measurements, and 2 volume measurements of various aspects of the orbit were obtained using Mimics v18.0 software. The data were collected manually using a 3D measurement technique. Statistical analyses using t tests and Pearson's correlation analyses were performed to evaluate the differences and relationships between the parameters, respectively. RESULTS Ocular protrusion in both sexes was closely related to the following values: orbital soft tissue volume (OSTV) (males: r=0.61, p<0.001; females: r=0.39, p=0.003), orbital soft tissue volume/bony orbital volume (OSTV/BOV) (males: r=0.90, p<0.001; females: r=0.87, p<0.001), orbital width (males: r=0.40, p=0.003; females: r=0.53, p<0.001), orbital height (males: r=0.29, p=0.038; females: r=0.45, p<0.001), and globe diameter (males: r=0.52, p<0.001; females: r=0.48, p<0.001). No differences were found between the right and left orbits. CONCLUSIONS The study provides insight into the potential factors that influence ocular protrusion, which include the OSTV/BOV ratio, the shape of the orbital aperture, and the ocular axial length. The results of orbital surgery can be made more predictable by accounting for these 3 factors. The database and regression formula might provide support for surgical planning in the future.

Relationships of inflammatory and haemostatic markers with social class: results from a population-based study of older men.

PubMed

Ramsay, Sheena; Lowe, Gordon D O; Whincup, Peter H; Rumley, Ann; Morris, Richard W; Wannamethee, S Goya

2008-04-01

Haemostatic and inflammatory markers have been hypothesised to mediate the relationship of social class and cardiovascular disease (CVD). We investigated whether a range of inflammatory/haemostatic markers are associated with social class independent of chronic diseases and behavioural risk factors in a population-based sample of 2682 British men aged 60-79 without a physician diagnosis of CVD, diabetes or musculoskeletal disease requiring anti-inflammatory medications. Men in lower social classes had higher mean levels of C-reactive protein, fibrinogen, interleukin-6, white blood cell count, von Willebrand factor (vWF), factor VIII, activated protein C (APC) resistance, plasma viscosity, fibrin D-dimer and platelet count, compared to higher social class groups; but not of tissue plasminogen activator antigen, haematocrit or activated partial prothrombin time. After adjustment for behavioural risk factors (smoking, alcohol, physical activity and body mass), the associations of social class with vWF, factor VIII, APC resistance, plasma viscosity, and platelet count though weakened, remained statistically significant, while those of other markers were considerably attenuated. In this study of older men without CVD, the social gradient in inflammatory and haemostatic markers was substantially explained by behavioural risk factors. The effect of socio-economic gradient on the factor VIII-vWF complex, APC resistance, plasma viscosity and platelet count merits further study.

Aviation human factors research in US universities: Potential contributions to national needs

NASA Technical Reports Server (NTRS)

Dismukes, R. Key

1994-01-01

Universities can and should make vital contributions to national needs in aviation human factors. However, to guide and utilize university research effectively we must understand what types of expertise and facilities universities can bring to bear on aviation problems. We should be aware of where relevant research is already underway and where untapped potential exists. How does the character of research in universities differ from and complement research in government and industry laboratories? What conditions would encourage universities to focus on national priorities and would promote high quality, relevant research? This paper attempts to address these issues. It is based on a survey conducted by the author, which included site visits to several universities, telephone interviews with faculty members at other universities, and a search of the aviation human factors research literature.

Identification and assessment of potential water quality impact factors for drinking-water reservoirs.

PubMed

Gu, Qing; Deng, Jinsong; Wang, Ke; Lin, Yi; Li, Jun; Gan, Muye; Ma, Ligang; Hong, Yang

2014-06-10

Various reservoirs have been serving as the most important drinking water sources in Zhejiang Province, China, due to the uneven distribution of precipitation and severe river pollution. Unfortunately, rapid urbanization and industrialization have been continuously challenging the water quality of the drinking-water reservoirs. The identification and assessment of potential impacts is indispensable in water resource management and protection. This study investigates the drinking water reservoirs in Zhejiang Province to better understand the potential impact on water quality. Altogether seventy-three typical drinking reservoirs in Zhejiang Province encompassing various water storage levels were selected and evaluated. Using fifty-two reservoirs as training samples, the classification and regression tree (CART) method and sixteen comprehensive variables, including six sub-sets (land use, population, socio-economy, geographical features, inherent characteristics, and climate), were adopted to establish a decision-making model for identifying and assessing their potential impacts on drinking-water quality. The water quality class of the remaining twenty-one reservoirs was then predicted and tested based on the decision-making model, resulting in a water quality class attribution accuracy of 81.0%. Based on the decision rules and quantitative importance of the independent variables, industrial emissions was identified as the most important factor influencing the water quality of reservoirs; land use and human habitation also had a substantial impact on water quality. The results of this study provide insights into the factors impacting the water quality of reservoirs as well as basic information for protecting reservoir water resources.

Correlation between Novel Potential Indoor Risk Factors and Frequency of Doctor's Visit for Respiratory Problem in Taiwan's Tropical Environment.

PubMed

Wang, Yu-Hao; Su, Hsing-Hao; Hsu, Lan; Wang, Chung-Yang; Wu, Pi-Hsiung

2018-01-01

With a global rising trend in prevalence of allergic diseases, more attention has been paid to investigation of environmental risk factors. Many risk factors have so far been identified. However, novel risk factors specific to Taiwanese environment and lifestyle were still relatively unknown. To investigate the potential effects of a number of little-known indoor risk factors on the frequency of doctor's visit for respiratory problems in context of Taiwanese environment and lifestyle. A cross-sectional, population-based study was performed on a 861 participants around Kaohsiung area, Taiwan. Survey investigation was employed to assess the household environment and the frequency of doctor's visit for respiratory problems. Participants who performed "daily cleaning" was shown to have a significantly (p=0.007) higher mean number of doctor's visits in comparison to those who did not. Similar observation was made for participants who periodically took out beddings (p=0.042). Age had a significant positive correlation (linear regression β 0.089) with frequency of respiratory problems. The habit of daily cleaning was implicated as a potential indoor risk factor due to the unique nature of Taiwanese cleaning habit and close contact with cleaning supplies, which could serve as chemical irritants. Bedding takeout was predicted to be an indicator of chronic allergies rather than an actual risk factor. However, both were controversial in their role as potential indoor risk factor, and required further examination.

Risk factors for inhibitor development in severe hemophilia a.

PubMed

Garagiola, Isabella; Palla, Roberta; Peyvandi, Flora

2018-05-25

Although significant advances in hemophilia treatment have improved patient outcomes and quality of life, one of the greatest complications in severe hemophilia A is the development of anti-Factor VIII (FVIII) antibodies that inhibit FVIII activity in almost 30% of previously untreated patients (PUPs). Inhibitors make very difficult the management of patients and increase their morbidity and mortality reducing drastically their quality of life. Numerous studies have investigated the mechanisms leading to the development of FVIII inhibitors. However, the etiology of their onset is complex and not yet fully understood. Inhibitors develop from a multicausal immune response involving both genetic (unmodifiable) and environmental (modifiable) factors. F8 gene mutations are the most important genetic risk factor, with null mutations being associated with the highest risk of inhibitor development. Immune response genes (e.g. the human leukocyte antigen complex) and proteins (e.g. cytokines) were studied without any strong confirmation of their role in modulating of inhibitor development. Type of FVIII product is the most important modifiable risk factor. The plasma-derived products containing von Willebrand factor were recently suggested to determine a lower incidence of inhibitor development than recombinant products in PUPs, in the first 50 exposure days (EDs). Other environmental factors including, age at first treatment, treatment intensity and the danger signal effect (surgery, severe bleeds, vaccinations and infections) has also been postulated as an explanation for environment-related inhibitor risk. This review reports the current knowledge on genetic and environmental risk factors on inhibitor development in patients with severe hemophilia A. Copyright © 2018 Elsevier Ltd. All rights reserved.

Clinical concerns of immunogenicity produced at cellular levels by biopharmaceuticals following their parenteral administration into human body.

PubMed

Tamilvanan, Shunmugaperumal; Raja, Natarajan Livingston; Sa, Biswanath; Basu, Sanat Kumar

2010-08-01

Similar to the low molecular weight traditional drugs, biopharmaceuticals are capable of producing not only therapeutic effects but also side effects provided if the dose of these compounds exceeds certain concentration and/or if the exposure duration of these compounds at subtoxic doses is being lengthened. In addition, a major drawback of biopharmaceuticals is the risk of antibody formation. Following the administration of biopharmaceuticals into human body, the formation of antidrug-antibody (ADA) or neutralizing antibody and other general immune system effects (including allergy, anaphylaxis, or serum sickness) are of clinical concern regarding therapeutic efficacy and patient safety. For example, drug-induced neutralizing antibodies to erythropoietin (EPO) result in pure red cell aplasia, whereas drug-induced acquired anti-factor VIII antibodies worsen the pathology associated with hemophilia. Since most of the already developed or under development biopharmaceuticals are to some extent immunogenic, the regulatory agencies insist to conduct potential ADA formation during the drug development process itself. This review encompasses a short overview on the clinical concerns of immunogenicity produced at cellular levels by growth hormone, interferon-alpha, EPO, factor VIII, and factor IX following their parenteral administration into human body. Clinical concerns related to immunogenicity produced by the biosimilar versions of these drugs are also presented wherever possible.

Effective bichromatic potential for ultra-high Q-factor photonic crystal slab cavities

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

Alpeggiani, Filippo, E-mail: filippo.alpeggiani01@ateneopv.it; Andreani, Lucio Claudio; Gerace, Dario

2015-12-28

We introduce a confinement mechanism in photonic crystal slab cavities, which relies on the superposition of two incommensurate one-dimensional lattices in a line-defect waveguide. It is shown that the resulting photonic profile realizes an effective quasi-periodic bichromatic potential for the electromagnetic field confinement yielding extremely high quality (Q) factor nanocavities, while simultaneously keeping the mode volume close to the diffraction limit. We apply these concepts to pillar- and hole-based photonic crystal slab cavities, respectively, and a Q-factor improvement by over an order of magnitude is shown over existing designs, especially in pillar-based structures. Thanks to the generality and easy adaptationmore » of such confinement mechanism to a broad class of cavity designs and photonic lattices, this work opens interesting routes for applications where enhanced light–matter interaction in photonic crystal structures is required.« less

Ozone dosing alters the biological potential and therapeutic outcomes of plasma rich in growth factors.

PubMed

Anitua, E; Zalduendo, M M; Troya, M; Orive, G

2015-04-01

Until now, ozone has been used in a rather empirical way. This in-vitro study investigates, for the first time, whether different ozone treatments of plasma rich in growth factors (PRGF) alter the biological properties and outcomes of this autologous platelet-rich plasma. Human plasma rich in growth factors was treated with ozone using one of the following protocols: a continuous-flow method; or a syringe method in which constant volumes of ozone and PRGF were mixed. In both cases, ozone was added before, during and after the addition of calcium chloride. Three ozone concentrations, of the therapeutic range 20, 40 and 80 μg/mL, were tested. Fibrin clot properties, growth factor content and the proliferative effect on primary osteoblasts and gingival fibroblasts were evaluated. Ozone treatment of PRGF using the continuous flow protocol impaired formation of the fibrin scaffold, drastically reduced the levels of growth factors and significantly decreased the proliferative potential of PRGF on primary osteoblasts and gingival fibroblasts. In contrast, treatment of PRGF with ozone using the syringe method, before, during and after the coagulation process, did not alter the biological outcomes of the autologous therapy. These findings suggest that ozone dose and the way that ozone combines with PRGF may alter the biological potential and therapeutic outcomes of PRGF. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

ABO blood grouping: A potential risk factor for early childhood caries - A cross-sectional study.

PubMed

Govindaraju, Lavanya; Jeevanandan, Ganesh; Subramanian, E M G

2018-01-01

The paradigm of etiology of early childhood caries (ECC) is shifting toward genetics. Of various inherited factors, blood group of an individual is genetically determined. The aim of the study is to determine if blood group of an individual will serve as a potential risk factor in the development of ECC. A cross-sectional study was conducted in Chennai. Blood samples were collected from a total of 500 children <71 months of age for determination of the blood group. Of which 96 children (24 per blood group) were randomly selected and were included in the study. Oral screening of the selected children was done by a pediatric dentist who was blinded to the blood group of the children. Decayed, extracted, and filling index was noted. Details on other associated factors for the development of ECC such as the socioeconomic status, oral hygiene measures, diet, and feeding practices were collected by directly interviewing the parents through a questionnaire. Statistical analysis was done using Chi-square and Kruskal-Wallis test and post hoc Tukey test with significance level set at 0.05. Intergroup analysis of the associated factors showed no significant differences between the children of different blood groups. A statistically significant relation was noted between the blood groups and development of ECC (P = 0.025). Blood group is a potential risk indicator for the development of ECC.

Shotgun Proteomic Analysis of Plasma from Dairy Cattle Suffering from Footrot: Characterization of Potential Disease-Associated Factors

PubMed Central

Sun, Dongbo; Zhang, Hong; Guo, Donghua; Sun, Anguo; Wang, Hongbin

2013-01-01

The plasma proteome of healthy dairy cattle and those with footrot was investigated using a shotgun LC-MS/MS approach. In total, 648 proteins were identified in healthy plasma samples, of which 234 were non-redundant proteins and 123 were high-confidence proteins; 712 proteins were identified from footrot plasma samples, of which 272 were non-redundant proteins and 138 were high-confidence proteins. The high-confidence proteins showed significant differences between healthy and footrot plasma samples in molecular weight, isoelectric points and the Gene Ontology categories. 22 proteins were found that may differentiate between the two sets of plasma proteins, of which 16 potential differential expression (PDE) proteins from footrot plasma involved in immunoglobulins, innate immune recognition molecules, acute phase proteins, regulatory proteins, and cell adhesion and cytoskeletal proteins; 6 PDE proteins from healthy plasma involved in regulatory proteins, cytoskeletal proteins and coagulation factors. Of these PDE proteins, haptoglobin, SERPINA10 protein, afamin precursor, haptoglobin precursor, apolipoprotein D, predicted peptidoglycan recognition protein L (PGRP-L) and keratan sulfate proteoglycan (KS-PG) were suggested to be potential footrot-associated factors. The PDE proteins PGRP-L and KS-PG were highlighted as potential biomarkers of footrot in cattle. The resulting protein lists and potential differentially expressed proteins may provide valuable information to increase understanding of plasma protein profiles in cattle and to assist studies of footrot-associated factors. PMID:23418487

Factors associated with potentially harmful antibiotic prescription during pregnancy: a population-based study.

PubMed

Lee, Yichen; Chen, Chuchieh; Chu, Dachen; Ko, Mingchung

2016-04-01

Inappropriate antibiotic prescriptions during pregnancy may adversely affect the fetus. There were few studies on factors associated with antibiotic prescriptions potentially harmful to the fetus. This was a population-based cross-sectional study using data from National Health Insurance Research Database. We calculated the frequency of antibiotic prescription according to the status of pregnancy, type of infections, characteristics of patients, doctors and medical institutions. According to the British National Formulary, sulfonamides, trimethoprim, tetracycline and quinolones were classified as antibiotics potentially harmful to the fetus. A multivariate logistic regression analysis was performed to evaluate the independent effect of various characteristic on antibiotic prescriptions, during pregnancy, potentially harmful to the fetus. Among the 19 464 pregnant subjects, 6554 (33.67%) received antibiotic prescriptions during pregnancy. Antibiotic prescriptions potentially harmful to the fetus accounted for 6.31% of all antibiotic prescriptions during pregnancy. Pregnant women aged <20 years, in their first trimester, and who were presenting with urogenital infections had the highest risks of receiving antibiotic prescriptions potentially harmful to the fetus. Non-gynaecologists, doctors aged 39-49 or ≥50 years, and doctors at clinics had higher risks of prescribing antibiotics potentially harmful to the fetus. Measures to improve the quality of practices should include efforts to increase awareness of antibiotic prescription guidelines for the treatment of infections in the pregnant population. © 2015 John Wiley & Sons, Ltd.

The role of angiogenic factors in fibroid pathogenesis: potential implications for future therapy

PubMed Central

Tal, Reshef; Segars, James H.

2014-01-01

Background It is well established that tumors are dependent on angiogenesis for their growth and survival. Although uterine fibroids are known to be benign tumors with reduced vascularization, recent work demonstrates that the vasculature of fibroids is grossly and microscopically abnormal. Accumulating evidence suggests that angiogenic growth factor dysregulation may be implicated in these vascular and other features of fibroid pathophysiology. Methods Literature searches were performed in PubMed and Google Scholar for articles with content related to angiogenic growth factors and myometrium/leiomyoma. The findings are hereby reviewed and discussed. Results Multiple growth factors involved in angiogenesis are differentially expressed in leiomyoma compared with myometrium. These include epidermal growth factor (EGF), heparin-binding-EGF, vascular endothelial growth factor, basic fibroblast growth factor, platelet-derived growth factor, transforming growth factor-β and adrenomedullin. An important paradox is that although leiomyoma tissues are hypoxic, leiomyoma feature down-regulation of key molecular regulators of the hypoxia response. Furthermore, the hypoxic milieu of leiomyoma may contribute to fibroid development and growth. Notably, common treatments for fibroids such as GnRH agonists and uterine artery embolization (UAE) are shown to work at least partly via anti-angiogenic mechanisms. Conclusions Angiogenic growth factors play an important role in mechanisms of fibroid pathophysiology, including abnormal vasculature and fibroid growth and survival. Moreover, the fibroid's abnormal vasculature together with its aberrant hypoxic and angiogenic response may make it especially vulnerable to disruption of its vascular supply, a feature which could be exploited for treatment. Further experimental studies are required in order to gain a better understanding of the growth factors that are involved in normal and pathological myometrial angiogenesis, and to assess

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.

Potential drugs which activate nuclear factor E2-related factor 2 signaling to prevent diabetic cardiovascular complications: A focus on fumaric acid esters.

PubMed

Zhou, Shanshan; Jin, Jingpeng; Bai, Tao; Sachleben, Leroy R; Cai, Lu; Zheng, Yang

2015-08-01

Diabetes and its cardiovascular complications have been a major public health issue. These complications are mainly attributable to a severe imbalance between free radical and reactive oxygen species production and the antioxidant defense systems. Nuclear factor E2-related factor 2 (Nrf2) is a transcription factor that controls the basal and inducible expression of a battery of antioxidant enzyme genes and other cyto-protective phase II detoxifying enzymes. As a result, Nrf2 has gained great attention as a promising drug target for preventing diabetic cardiovascular complications. And while animal studies have shown that several Nrf2 activators manifest a potential to efficiently prevent the diabetic complications, their use in humans has not been approved due to the lack of substantial evidence regarding safety and efficacy of the Nrf2 activation. We provide here a brief review of a few clinically-used drugs that can up-regulate Nrf2 with the potential of extending their usage to diabetic patients for the prevention of cardiovascular complications and conclude with a closer inspection of dimethyl fumarate and its mimic members. Copyright © 2015 Elsevier Inc. All rights reserved.

Identification and Assessment of Potential Water Quality Impact Factors for Drinking-Water Reservoirs

PubMed Central

Gu, Qing; Deng, Jinsong; Wang, Ke; Lin, Yi; Li, Jun; Gan, Muye; Ma, Ligang; Hong, Yang

2014-01-01

Various reservoirs have been serving as the most important drinking water sources in Zhejiang Province, China, due to the uneven distribution of precipitation and severe river pollution. Unfortunately, rapid urbanization and industrialization have been continuously challenging the water quality of the drinking-water reservoirs. The identification and assessment of potential impacts is indispensable in water resource management and protection. This study investigates the drinking water reservoirs in Zhejiang Province to better understand the potential impact on water quality. Altogether seventy-three typical drinking reservoirs in Zhejiang Province encompassing various water storage levels were selected and evaluated. Using fifty-two reservoirs as training samples, the classification and regression tree (CART) method and sixteen comprehensive variables, including six sub-sets (land use, population, socio-economy, geographical features, inherent characteristics, and climate), were adopted to establish a decision-making model for identifying and assessing their potential impacts on drinking-water quality. The water quality class of the remaining twenty-one reservoirs was then predicted and tested based on the decision-making model, resulting in a water quality class attribution accuracy of 81.0%. Based on the decision rules and quantitative importance of the independent variables, industrial emissions was identified as the most important factor influencing the water quality of reservoirs; land use and human habitation also had a substantial impact on water quality. The results of this study provide insights into the factors impacting the water quality of reservoirs as well as basic information for protecting reservoir water resources. PMID:24919129

Appeals court reverses verdict favoring drug companies.

PubMed

1995-06-02

An appeals court reversed a verdict favoring drug companies after the widow of a hemophiliac, whose death was linked to HIV-tainted blood products, sued four pharmaceutical companies to pay damages. The four companies, Alpha Therapeutic Corp., Miles Laboratories Inc., Armour Pharmaceutical Co., and Baxter Travenol Laboratories Inc., provided Factor VIII, a clotting concentrate, to [name removed] [name removed], the plaintiff's husband, from 1972 until his death in 1987. [Name removed]'s wife sued the companies, alleging that the defendants negligently solicited blood plasma from paid donors who had a high risk of having HIV, failed to determine whether any lots of Factor VIII contained plasma from an at-risk donor, failed to warn consumers of possible risks, and failed to heat-treat HIV and other viruses in Factor VIII, despite industry-wide knowledge of the risk of infection. The three-judge panel said the trial judge's decision to avoid ruling on the antigenic stimulation theory, based on insufficient evidence, was improper. In addition, the appeals court said a retrial is necessary because of improper remarks made by Alpha's attorney.

Potential factors associated with knee pain in cyclists: a systematic review.

PubMed

Bini, Rodrigo Rico; Flores Bini, Alice

2018-01-01

The potential factors associated with overuse injuries and pain in cyclists that are supported by evidence remain unclear. Our study aimed at assessing, using a systematic search of the most updated evidence, the main factors related to overuse knee-related pain and/or injuries in cyclists. The search assessed any potential mechanism related to knee pain or injury that could be used in the clinical practice. Databases were searched (i.e., PubMed, Scopus, Web of Science, and EBSCO). Studies were included if they presented results from original studies. They had to include, preferably but not limited to, recreational and/or competitive cyclists with or without knee pain. Quality of articles was assessed. Eleven articles were deemed eligible for full text appraisal. Studies involved generally the assessment of biomechanical outcomes associated with knee pain in cyclists. Overall, studies showed that cyclists with knee pain present larger knee adduction and larger ankle dorsiflexion and differences in activation for hamstrings and quadriceps muscles. Unclear results were observed for knee moments and no differences were observed for knee flexion angle, tibiofemoral and patellofemoral forces. It is important to state that varied types of knee pain were mixed in most studies, with 2 focused on anterior-related pain. Cyclists with overuse-related pain or injuries on their knees presented an increased medial projection of their knees and an altered activation of the Vastus Medialis and Vastus Lateralis muscles. However, this limited evidence is based on retrospective studies comparing cyclists with and without pain, which limits the conclusion on how cyclists develop knee pain and what are the main options for treatment of knee pain.

Association of Vascular Endothelial Growth Factor Expression with Tumor Angiogenesis and with Early Relapse in Primary Breast Cancer

PubMed Central

Hoshina, Seigo; Takayanagi, Toshiaki; Tominaga, Takeshi

1994-01-01

Angiogenesis is an independent prognostic indicator in breast cancer. In this report, the relationship between expression of vascular endothclial growth factor (VEGF; a selective mitogen for endothelial cells) and the microvessel density was examined in 103 primary breast cancers. The expression of VEGF was evaluated by immunocytochemical staining using anti‐VEGF antibody. The microvessel density, which was determined by immunostaining for factor VIII antigen, in VEGF‐rich tumors was clearly higher than that in VEGF‐poor tumors (P<0.01). There was a good correlation between VEGF expression and the increment of microvessel density. Furthermore, postoperative survey demonstrated that the relapse‐free survival rate of VEGF‐rich tumors was significantly worse than that of VEGF‐poor tumors. It was suggested that the expression of VEGF is closely associated with the promotion of angiogenesis and with early relapse in primary breast cancer. PMID:7525523

Internal quality control of blood products: An experience from a tertiary care hospital blood bank from Southern Pakistan.

PubMed

Sultan, Sadia; Zaheer, Hasan Abbas; Waheed, Usman; Baig, Mohammad Amjad; Rehan, Asma; Irfan, Syed Mohammed

2018-01-01

Internal quality control (IQC) is the backbone of quality assurance program. In blood banking, the quality control of blood products ensures the timely availability of a blood component of high quality with maximum efficacy and minimal risk to potential recipients. The main objective of this study is to analyze the IQC of blood products as an indicator of our blood bank performance. An observational cross-sectional study was conducted at the blood bank of Liaquat National Hospital and Medical College, from January 2014 to December 2015. A total of 100 units of each blood components were arbitrarily chosen during the study. Packed red cell units were evaluated for hematocrit (HCT); random platelet concentrates were evaluated for pH, yield, and culture; fresh frozen plasma (FFP) and cryoprecipitate (CP) were evaluated for unit volume, factor VIII, and fibrinogen concentrations. A total of 400 units were tested for IQC. The mean HCT of packed red cells was 69.5 ± 7.24, and in 98% units, it met the standard (<80% of HCT). The mean platelet yield was 8.8 ± 3.40 × 10 9 /L and pH was ≥6.2 in 98% bags; cultures were negative in 97% of units tested. Mean factor VIII and fibrinogen levels were found to be 84.24 ± 15.01 and 247.17 ± 49.69 for FFP, respectively. For CP, mean factor VIII and fibrinogen level were found to be 178.75 ± 86.30 and 420.7 ± 75.32, respectively. The IQC of blood products at our blood bank is in overall compliance and met recommended international standards. Implementation of standard operating procedures, accomplishment of standard guidelines, proper documentation with regular audit, and staff competencies can improve the quality performance of the transfusion services.

Potentially Modifiable Factors Associated With Physical Activity in Individuals With Multiple Sclerosis.

PubMed

Reider, Nadia; Salter, Amber R; Cutter, Gary R; Tyry, Tuula; Marrie, Ruth Ann

2017-04-01

Physical activity levels among persons with multiple sclerosis (MS) are worryingly low. We aimed to identify the factors associated with physical activity for people with MS, with an emphasis on factors that have not been studied previously (bladder and hand dysfunction) and are potentially modifiable. This study was a secondary analysis of data collected in the spring of 2012 during the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry. NARCOMS participants were surveyed regarding smoking using questions from the Behavioral Risk Factor Surveillance Survey; disability using the Patient Determined Disease Steps; fatigue, cognition, spasticity, sensory, bladder, vision and hand function using self-reported Performance Scales; health literacy using the Medical Term Recognition Test; and physical activity using questions from the Health Information National Trends Survey. We used a forward binary logistic regression to develop a predictive model in which physical activity was the outcome variable. Of 8,755 respondents, 1,707 (19.5%) were classified as active and 7,068 (80.5%) as inactive. In logistic regression, being a current smoker, moderate or severe level of disability, depression, fatigue, hand, or bladder dysfunction and minimal to mild spasticity were associated with lower odds of meeting physical activity guidelines. MS type was not linked to activity level. Several modifiable clinical and lifestyle factors influenced physical activity in MS. Prospective studies are needed to evaluate whether modification of these factors can increase physical activity participation in persons with MS. © 2016 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Development and evaluation of the McKnight Risk Factor Survey for assessing potential risk and protective factors for disordered eating in preadolescent and adolescent girls.

PubMed

Shisslak, C M; Renger, R; Sharpe, T; Crago, M; McKnight, K M; Gray, N; Bryson, S; Estes, L S; Parnaby, O G; Killen, J; Taylor, C B

1999-03-01

To describe the development, test-retest reliability, internal consistency, and convergent validity of the McKnight Risk Factor Survey-III (MRFS-III). The MRFS-III was designed to assess a number of potential risk and protective factors for the development of disordered eating in preadolescent and adolescent girls. Several versions of the MRFS were pilot tested before the MRFS-III was administered to a sample of 651 4th through 12th- grade girls to establish its psychometric properties. Most of the test-retest reliability coefficients of individual items on the MRFS-III were r > .40. Alpha coefficients for each risk and protective factor domain on the MRFS-III were also computed. The majority of these coefficients were r > .60. High convergent validity coefficients were obtained for specific items on the MRFS-III and measures of self-esteem (Rosenberg Self-Esteem Scale) and weight concerns (Weight Concerns Scale). The test-retest reliability, internal consistency, and convergent validity of the MRFS-III suggest that it is a useful new instrument to assess potential risk and protective factors for the development of disordered eating in preadolescent and adolescent girls.

[Rehabilitation potential of disabled persons with consequences of cerebral stroke and effects of factors of the organization of rehabilitation assistance].

PubMed

Voskresenskaia, O N; Klemesheva, Iu N; Akimova, T N

2012-01-01

The authors demonstrated the possibility for the practical use of the index "Rehabilitation Potential" in the evaluation of the degree of restoration of neurological deficit developed due to cerebral stroke. The most significant factors characterizing the organization and implementation of rehabilitation measures in different periods of stroke and the effect of these factors on the level of rehabilitation potential of disabled persons with consequences of stroke are specified. It has been shown that the perfect organization of restorative treatment has a positive effect on the level of rehabilitation potential of disabled persons.